everyperson'sguidetoantioxidants

JOHNR.SMYTHIESM.D.F.R.C.P.

RUTGERSUNIVERSITYPRESSNEWBRUNSWICK,NEWJERSEY,ANDLONDON

title: EveryPerson'sGuidetoAntioxidantsauthor: Smythies,JohnR.

publisher: RutgersUniversityPress

isbn10|asin: 0813525756printisbn13: 9780813525754ebookisbn13: 9780585023083

language: English

subjectOxidation,Physiological,Antioxidants--Healthaspects,Freeradicals(Chemistry)--Pathophysiology.

publicationdate: 1998lcc: RB170.S691998ebddc: 616.07

subject:Oxidation,Physiological,Antioxidants--Healthaspects,Freeradicals(Chemistry)--Pathophysiology.

LibraryofCongressCataloging-in-PublicationData

Smythies,JohnR.(JohnRaymond),1922-Everyperson'sguidetoantioxidants/JohnR.Smythies.p.cm.Includesbibliographicalreferencesandindex.ISBN0-8135-2574-8(alk.paper).-ISBN0-8135-2575-6(pbk.:alk.paper)I.Oxidation,Physiological.2.Antioxidants-Healthaspects.3.Freeradicals(Chemistry)-Pathophysiology.1.Title.RB170.S691998616.07-dc2198-6810CIP

BritishCataloging-in-PublicationinformationavailableCopyright©1998byJohnR.SmythiesAllrightsreserved

Nopartofthisbookmaybereproducedorutilizedinanyformorbyanymeans,electronicormechanical,orbyanyinformationstorageandretrievalsystem,withoutwrittenpermissionfromthepublisher.PleasecontactRutgersUniversityPress,LivingstonCampus,100JoyceKilmerAvenue,Piscataway,NewJersey08854-8099.Theonlyexceptiontothisprohibitionis"fairuse"asdefinedbyU.S.copyrightlaw.

ManufacturedintheUnitedStatesofAmerica

forVanna

contentsIntroduction 1

part1

thebasics:oxygen,reactiveoxygenspecies,andoxidativestress

5

part2

theroleofoxidativestressandantioxidantsinhealthanddisease

17

part3

thesafetyofantioxidantsandrecomendations 89

APPENDIX 109

ABREVIATIONS 111

REFERENCES 113

INDEX 127

acknowledgementsIammostgratefultoLesleySmythiesforherexcellentandpainstakingeditorialworkonthisbookandheradviceaboutimmunology;toChristopherSmythiesforhelpfulcommentsfromthepointofviewofneurosurgeryandforsupplyingtheepitaphfromTombstone;andtoVannaSmythiesforhelpinadjustingthematerialforthelayreader.IshouldalsoliketothankmydedicatedagentJuliePopkin;CharlesThomasofPantoxLaboratories,SanDiego;JessicaHornikEvans,copyeditor;andDoreenValentineofRutgersUniversityPressforherskilledandtirelesseditorialguidance.IshouldalsoliketorecordthedebtthatweallowetotheIrelandfamilyofBirmingham,Alabama,pioneersintheactivesupportofpromotingtheimportanceofantioxidantvitaminsinhealthanddisease.

everyperson'sguidetoantioxidants

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introductionWeliveinanageinwhichmillionsofpeopleintheUnitedStatesandelsewheretakevitaminstosupplementtheirdietunderthebeliefthatthesewillhelptomaintaingoodhealthandwardoffillness.Anenormousindustryformanufacturing,packaging,anddistributingvitaminshasgrownuptomeetthisneed.IntheUnitedStatestherearemorethaneleventhousandhealth-foodstoresandnutritioncentersthatsellonlyvitaminsandrelatedproducts.Furthermore,nearlyeverydrugstoreandsupermarkethasanextensiveareadevotedtovitaminpreparations,ofwhichtherearehundredsofvarietiesandbrandnames.Thesevitaminsaresoldeitherasmixturesofmultivitaminsandessentialmineralsorindividually.Amongthe"special"typesofvitaminsthatfilltheseshelvesarethoselabeled"antioxidants."TheseincludesuchfamiliarvitaminsasA,C,E,andbeta-carotene.Lesswell-knownantioxidantsincludemelatonin,lycopene,zeaxanthin,andvariousflavonoids.

Newspapers,magazines,andtalkshowsarebrimmingwithdiscussionsofantioxidants.Theseaccountsclaimthatantioxidantsareeffectiveinhelpingtopreventcancer,heartdisease,andotherchronicillnesses.Butthemassmediaalsocarryreportsonsomeallegedalarmingsideeffectsofantioxidants.

Forexample,theNovember25,1996,issueofTimemagazinecarriedalongarticlecalled"CanWeStayYoung?,"whichstatedthat,althoughsomenutritionistshaverecommendedadiethigh

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infruitsandvegetablesthatcontainantioxidantstocombatdisease,thisapproachhasan"unevenrecord."Accordingtothearticle,insomestudiestheuseofantioxidantsappearstobeassociatedwitha"dramatic"reductionincancerandotherdiseases,butinotherstudiesbeta-carotene(theonlyantioxidantmentionedbynameinthearticle)actuallyseemstobeassociatedwithanincreaseincancer.Thearticleconcluded:"Ineithereventfewcontemporaryagingresearchersthinkself-medicatingatasaladbaristhebestwaytoextendthehumanlifespan."Thisreportisseriouslymisleading,asthisbookshows,andindicatesthelevelofconfusionthatthepublicfaceswithregardtothescienceofantioxidants.TheMarch1997issueofConsumerReportscarriedasectiononantioxidantsthatalsoprovidedconsumerswithconflictinginformation.ThearticlecorrectlystatedthatvitaminEhadbeenshowntobeprotectiveagainstheartattacksbutcastdoubtontheeffectivenessofbeta-caroteneandvitaminCasprotectiveagents.However,thearticleneglectedtomentionamostimportantfact:antioxidantsshouldalwaysbegivenasawell-balancedmixture(eitherinthedietorassupplements)andnotsingly.InitsAugust1997issue,ConsumerReportshadasectiononmethodsthatwomenshouldusetoreducetheirriskofaheartattack.Itfailedtomentionanydietaryfactorsotherthanalowfatandalcoholintake.

TheNationalAcademyofScienceshasformanyyearspublishedalistofrecommendeddailyallowances(RDAs)forthecommonvitamins.Forexample,thecurrentRDAforvitaminCis60mgperdayandforvitaminE,20mgperday.Butfrequentlythedosagesofvitaminspertabletonthemarketcontainmanytimestheamountoftherecommendeddailyallowance.Whyso?Sometwenty-fiveyearsagoNobelLaureateLinusPaulingclaimedthatpeoplewouldbenefitiftheytook"megadoses"ofvitamins.Hisargumentwasthattherecommendeddailyallowancesreflectedonlywhatwasneededtoavoidspecificvitamindeficiencydiseasessuchasscurvy,pellagra,

andberi-beri.Whatisreallyneeded,heclaimed,is"optimum"doses:if10mgofavitaminisbeneficial,then100mgisboundtobetentimesbetter.Althoughtherewaslittleevidencetosupportthisclaimatthetime,itsoonbecameapopularbeliefandthebasisformarketingmegavitamins.Paulingwascorrectinhisobservationthattherecommendeddailyallowancesofvitaminstodayarecalculatedonthebasisoftheamountneededtoavoiddeficiencydiseases,

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buthenevergaveanyconvincingreasonforhisideaofoptimumlevelsofintake.Pauling'sideaswerenotreceivedwithenthusiasmbythemedicalestablishment;infact,thegeneralopinionwasthattheyamountedtoquackery.Wehavenowcometorealize,onthebasisoffactsthatwerenotknowntwenty-fiveyearsago,thattheamountofeachantioxidantvitaminneededtoavoiddeficiencydiseasesisindeednotthesameastheamountthatahealthybodyneeds,asDr.LelandTolbertandIpointedoutinapaperpublishedin1981[193].Thisisbecauseantioxidantvitaminsplayaveryimportantroleinthebodythatisquitedistinctfromtheirparticularroleinpreventingscurvyandotherdeficiencydiseases:theyprovidethebodywithitsownantioxidantdefenses.ItwouldbefittingtoreevaluatetheroleofLinusPaulinginmedicine.AfamousepitaphonagravestoneinaTombstone,Arizona,cemetery,sumsupthissituationwell:"HereliesthebodyofGeorgeThompson/Hungformurder1882/Hewasrightandwewaswrong/Butwestrunghimup/andnowhe'sgone."

Althoughwe'veallheardtheterm"antioxidants,"manypeoplearenotveryclearaboutwhatantioxidantsare,whattheyaresupposedtodo,andif-andwhenandwhy-itisadvisabletotakethem.Thisbookdescribeswhatantioxidantsareandhowtheywork.Tohelpthereaderunderstandtheroleplayedbyantioxidants,Idiscussoxidativestress,whichisduetotheoverproductionofpotentiallyharmfuloxidantsinthebody.Itisthejobofantioxidantstocounteractthedeleteriouseffectsofharmfullevelsofoxidants.Oxidantsplaymanynormalrolesinthebody;itisonlytheiroverproduction(orthefailureofantioxidantdefenses)thatresultsinharmfuloxidativestress(i.e.,disease).Antioxidantsmaybetakeneitherbyhealthypeopleinanattempttowardoffthedevelopmentofchronicdiseaseslikecancerandheartattacks,orbysickpeoplewhoarefacingadiseaseforwhichthereisevidencethatantioxidanttherapywillhelp.Iexploreindepththerelationshipbetweenoxidantsandoxidativestressanddiseaseand

lookathowantioxidantsmayfunctiontopreventorcombatdisease.

Manyscientificexperimentsandclinicaltrialshavebeencarriedouttotesttheideathatantioxidantsareimportanttomaintaingoodhealth.InthisbookIreviewthecurrentmedicalandscientificliteratureonoxidativestressandantioxidantsandpresentthemostimportantoriginal

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datafromthesescientificexperimentsandclinicaltrials,withtheirgoodandbadpoints.Itismyhopeisthat,armedwithanunderstandingoftheresearchandafairevaluationoftheresultsaspresentedhere,thereaderwillbeabletodecideforhim-orherselfastotheneedtotakeantioxidants.Suchadecisionwillbebasedoninformedknowledgeofthefactsratherthanonthepropagandaputoutbyuncriticalenthusiastseitherfororagainsttakingantioxidantsupplements.Thisinformationwillalsoenablethereadertodiscussantioxidantswithadoctor.Itisstillunfortunatelytruethatmanyphysicianshavenotkeptupwiththerecentadvancesinthisfield,whichisstillregardedbysomeastaintedwiththe"alternativemedicine"stigma.Forthoseinthehealthprofessions,thisbookwillhelpestablishthatantioxidantsareimportantforthecareofpatients.

Mycredentialsforwritingthisbookderivefrommanyyearsofscientificresearchonoxidativestressandantioxidants.Inparticular,Ihavestudiedtherolethatoxidativestressplaysinschizophrenia;Iwasthecodeveloperin1952ofthefirstspecificbiochemicaltheoryofschizophrenia-thetransmethylationhypothesis.In1954Dr.AbramHoffer,Dr.HumphryOsmond,andIdiscoveredthatanoxidizedderivativeofepinephrine,oneofthehormonesthatissecretedbytheadrenalglandandisalsofoundinthebrain,producespsychoticsymptomsinnonpsychoticvolunteers[89].Althoughmyworkhasfocusedontherelationshipbetweenoxidativestressandpsychiatricillness,Ihavealsostudiedtheroleofoxidativestressandantioxidantsinalldiseases.

Thisbookisdirectedatallpeopleinterestedinthequestionofwhethertheyneedtochangetheirdietinordertoimprovetheirlong-termhealthandwhethertheyalsoneedtotakeantioxidantsupplementstodoso.Itisalsodirectedathealthprofessionalsinvolvedinpreventativemedicineandintreatingthediseasescoveredinthebook.Thisbookwillalsobeofinteresttothosewhoworkfor

governmenthealthprograms,includingMedicare,andnongovernmentorganizationsconcernedwithhealthcaredelivery;thehealthinsuranceindustry;andanyotherswhoareresponsibleforpublichealthpolicyandfunding.Themeasuresthisbooksupportshavethepotentialnotonlytoreducetheamountofchronicdiseasessufferedbypeoplebutalsosubstantiallytoreducethecurrentcripplingcostsofmedicalcare.

Knowledgeofchemistryisnotnecessarytoreadthisbook.

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part1thebasics:oxygen,reactiveoxygenspecies,and

oxidativestressbeforewecantalkclearlyaboutwhatantioxidantsareandhowtheypreventdisease,weneedtoconsidersomebasicconceptsaboutthebody'scellsandorgans.Everycellinthebody-whetheraheartcell,alivercell,orabraincell-functionslikeaminiaturechemicalfactory.Alargenumberofdifferenttypesofchemicalreactionsoccurwithinthecell,leadingtothebreakdownoflargecomplexmoleculesintosmallerproductsortothesynthesisofnewmoleculesfromsmallerbuildingblocks.Otherchemicalreactionsoccurthatmayleadtothetransferofsmallelectricalchargesfromonechemicalsubstancetoanother.Amongthesetransferreactionsareoxidation-inwhichanegativelychargedparticlecalledanelectronislost-andreduction,inwhichtheelectronisgained.Burningisoneformofoxidation,aswhencoal(carbon)burnstoformcarbondioxide.Butamoregeneralformofoxidationinvolvesthistransferofelectronsfromonemoleculetoanother.

Curiouslyenough,oxidativestressarisesinevitablyfromthechemistryofthelife-givingmoleculeofoxygen.Exceptfor

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someveryprimitivebacteria,oxygenisessentialforlifeandprovidestheenergyonwhichallcellsinthebodyoperate.Thatisthegoodnews.Thebadnewsisthattheordinaryoxygenmoleculeeasilyturnsintooxidizingagents,calledreactiveoxygenspecies,thatpossessgreatpotentialdanger.Insimpletermsoxidizingagents(alsocalledpro-oxidants)areshortofelectrons(eachatomhasanucleus,composedofprotonsandneutrons,surroundedbynegativelychargedelectrons)andwillstealthemfromanyneighboringmoleculeinthebodythatdoesnotkeepatightholdonitsownelectrons.Thisdamagestheneighboringmoleculeseverely.Commonhouseholdbleachisanexampleofapowerfuloxidizingagentinwhichtheactiveingredientisthepoisonousgaschlorine.Reactiveoxygenspeciesplaynormalrolesinthebody,butinexcesstheydevelophighlypoisonousproperties.

Themostimportantreactiveoxygenspeciesinthebodyarethesuperoxideion(O-),thehydroxylradical(OH),andhydrogenperoxide(H202).Thestablemoleculeofwaterismadeupoftwoatomsofhydrogenandoneofoxygen(H20).Notethatthehighlytoxichydroxylradicaliscomposedofoneatomofoxygenandonlyoneofhydrogen.Hydrogenperoxide,usedwidelyinhouseholdsasanantiseptic,ismadeupoftwoatomsofhydrogenandtwoatomsofoxygen.Thesereactiveoxygenspeciesareallshortofelectronsandarethuspowerfuloxidizingagents.Hydrogenperoxideisactuallysomewhatdifferent,asitisnotitselfshortofelectronsbuteasilyconvertsinthebodytocompounds,suchasthehydroxylradical,thatareshortofelectronsandthatdothedamage.Technically,compoundsthatareshortofelectronsarecalledfreeradicals.Thesuperoxideionandthehydroxylradicalarefreeradicals.Thus,reactiveoxygenspeciesincludebothoxygen-derivedfreeradicalsandcompoundslikehydrogenperoxidethatarenotthemselvesfreeradicalsbutthateasilygeneratethem.Leftfreetoreactinthebody'stissues,reactiveoxygen

specieswillattackanddamagekeymoleculesinthebody,suchasfats,proteins,andDNAthemoleculethatcarriesgeneticinformation.

Tounderstandwhyreactiveoxygenspeciesarepotentiallysoharmfulforcells,wehavetolookabitmorecloselyatthecellitself.Eachcellinthebodyiscomposedofamembraneboundary,afluidinterior,andacentralnucleus,alongwithasetofothersmallstructurescalledorganelles.Themembraneofthecellismadelargelyoffat.Whenthefatsinthemem-

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braneareoxidizedbyareactiveoxygenspecies,themembranebecomesbrittleandleaky;eventually,itfallsapartandthecelldies.Thisisalotlikebutterturningrancid,whichhappenswhenthefatsinbuttergetoxidized.Hencedairiesputantioxidantsinthebuttertopreventthisfromhappening.Proteinsarelocatedeitherembeddedinthefattymembraneorthroughouttheinteriorofthecell.Manyproteinsaresmallmachinesthatperformimportantfunctionsinthecell.Otherproteinshaveapurelystructuralrole.Someproteinsareenzymesthatmanufacturesubstancesneededbythecell,andsomearehormonesthatactassignalstoothercells.Otherscontroltheentryandexitofsubstancesacrossthecellmembrane.Whenareactiveoxygenspeciesattacksaproteinanddamagesit,somekeyfunctionofthecellwillbejeopardized.DNA,themoleculethatcarriesthegeneticinformationofthecell,isfoundinthecell'snucleus.Oxidativedamagetoitcancausemutationsthatpredisposethecelltocancerformation.Intheseways,throughdamagetofats,proteins,andDNA,variouspartsofthebodycanbeweakenedbyoxidativeattackandwillsuccumbtoawidevarietyofdiseases.Iexplainthisfullyinpart2.

Ifoxidizingagentsaresoharmfultocells,wehavetoaskwhynaturewouldhaveproducedacellularsystemthatmanufacturesthem.Indeed,severalessentialbiochemicaloperationsinthebodygeneratereactiveoxygenspeciesasapartoftheessentialmechanismbywhichtheywork.Takeseveralexamples:

1.Thebasicmechanismofenergyproductionofthecellproducesreactiveoxygenspeciesasaninescapableby-productofthenecessarychemistryinvolved.Ithasbeenestimatedthat10percentoftheoxygenwebreatheisturnedintoreactiveoxygenspeciesduringthisprocess.

2.Thejobofsomewhitebloodcellsofthebody'simmunesystemis

toattackandkillinvadingpathogenicbacteriaandviruses.Oneweapontheyusetodothisishighlypoisonousreactiveoxygenspecies.

3.Duringtheprocessofinflammationasetofchemicalscalledprostaglandinsissecreted.Prostaglandinscausetheredness,pain,andswellingassociatedwithinflammation.Theyareinvolved,forexample,ininfections,burns,andarthritis.Akeyenzyme(calledprostaglandinHsynthase,orPGHsynthaseforshort)thatmakesthem

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generateslargeamountsofreactiveoxygenspeciesasaby-product.Aspirinworksbyswitchingoffthisenzyme.Thisresultsinlessprostaglandin-inducedpainandswelling.

4.Asthebraindevelops,manymorenervecellsandmanymoreconnectionsbetweenthemaremadethanareactuallyneeded.Asthebraingrowsduringchildhood,theexcessnumbersoftheseareprunedaway.Duringthisprocessreactiveoxygenspeciesmoleculesareprobablyusedasapruningagenttokilltheunwantedcells.Duringthelearningprocessinadultsaswellasinchildren,manynewconnectionsbetweennerves(calledsynapses)aremadeandold,failed,onesremoved.Reactiveoxygenspeciesareprobablyinvolvedintheselectiveremovalofunwantedsynapses(asisdiscussedlaterinmoredetail).ReactiveoxygenspeciesalsohavenormalfunctionsinrelationtothecontrolofDNAaction.TheydothisbyactivatingamoleculecalledNF-KB.Thismoleculeswitchesonanumberofgenes,includingthoseresponsibleformakingkeymoleculesconcernedininflammation.Thepresentfocusofattentionofresearchersisontheroleofreactiveoxygenspeciesinthemechanismsbywhichcellssignaltoeachotherduringtheinflammationprocess[222].Theindirectfunctionofreactiveoxygenspeciesoperatesinadditiontothedirectattackbyreactiveoxygenspeciesonproteins,fats,andDNA.Thisnewresearchisimportant,asabnormalitiesinNF-KBactivationareinvolvedinatherosclerosis,Alzheimer'sdisease,HIVinfection,rheumatoidarthritis,asthma,andotherdisorders.

Theseprocessesillustratethefactthatreactiveoxygenspeciesarenotalwaysvillainsbuthavesomenormalfunctionsinthebody.Itisonlywhenthereissomedisturbanceinthissystemthatdiseaseresults.SimonianandCoyle[185]giveagraphicaccountofoxidativestressas''anexpanding,self-perpetuating,andreinforcingseriesofmetabolicevents,whichpromotethegenerationof[more]reactive

oxygenspeciesandimpairpotentialprotectivemechanisms.Likeaspreadingwildfire,thesiteoftheinitiatingsparkmaybeobscuredinitsterminalstages."

Oxidativestresscanresultfromfourmaincauses:(1)Reactiveoxygenspeciescanbeingestedinexcessfromsomeenvironmentalsource(suchastobaccosmokeordieseloilfumes);(2)thedietmaycontaininsuffi-

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cientantioxidants;(3)theremaybesomedisturbanceintheelaboratebiochemicalsystemsthatcontroltheirproductionanddistribution(asinthecaseofmanydiseases);(4)theremaybeafailureinprotectiveantioxidantmechanisms(asinthecaseofmanyotherdiseases).Thetopicofoxidativestressisdealtwithindetailinpart2.

antioxidantsThebiochemicalreactionsthatproducereactiveoxygenspeciesareessentialforlifeandcanbetracedveryearlyoninevolution.Theyarefoundincellsrangingfrombacteriatohumancells.But,aswediscoveredabove,theseessential,naturallyoccurringsubstancescanalsodamageandkillcells.Sohowisitthatcellssurvivedespitetheconstantonslaughtofreactiveoxygenspecies?Theansweristhatevolutionhadtoproduceefficientdefensesthatwouldpreventreactiveoxygenspeciesfromkillingthecells.Thesedefensesconsistofasetofspecializedmoleculesknownasantioxidants.Astheirnamesuggests,antioxidantsfunctiontopreventthedamagetocellsthatwouldotherwiseoccurasaresultofanattackbyreactiveoxygenspecies.

tounderstandhowantioxidantsperformtheirroleandwhydifferenttypesareneeded,wemustreturntothestructureofthecellitself.Theinteriorofthecellandthefluidbetweencellsarecomposedmainlyofwater.Thecellmembrane,aswehaveseen,ismadelargelyoffat.Asweknowfromexperience,oilandwaterdonotmix.Chemicallyspeaking,thegeneralruleisthatsubstancesthataresolubleinwaterarenotsolubleinfat,andviceversa.

Asoxidantscanstrikeeitheratthefattycellmembraneoratthewaterycellcontents,antioxidantsareneededthatwillworkeitherinthefattymembraneorinthewaterycompartments.Inotherwords,

thecellneedstohaveavailableantioxidantsthataresolubleinwaterandothersthataresolubleinfat.Besidessolubility,anotherwayinwhichantioxidantsdifferfromeachotherissize.Someantioxidantsaresmallmolecules,whereasothersarelargeproteins.Thesmallmoleculetypesworkinpartbymoppingupor"scavenging"thereactiveoxygenspeciesandcarryingthemaway,andinpartbyneutralizingthemchemically.Theproteinantioxidantsareeitherenzymesthatturnreactiveoxygenspeciesinto

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harmlesssubstances,ortheyareinessential"sacrificial"proteins(likealbumin).Asacrificialproteinwillabsorbreactiveoxygenspeciesandthuspreventthemfromattackingsomeessentialprotein.

Thebodygetsitsessentialantioxidantsfromtwomainsources:someantioxidantsareproducedinthebodyitself,whereasothershavetobeobtainedfromthediet.Someofthedietaryantioxidantsarecalledvitamins-meaning"vitalamine"-becausetheyareessentialforlife,andlowlevelsoftheminthedietcausedeficiencydiseasessuchasscurvyandpellagra.Thereareotherdietaryantioxidantsthatthebodycannotsynthesize,butthesearenotessentialforlife,andtheirabsenceinthedietdoesnotleadtodisease.Forthisreasontheseantioxidantsarenotcalledvitamins.Althoughtheyarenotessentialingredientsinthediet,theyareneverthelesshelpfulincombatingoxidativestress.

SMALL-MOLECULEANTIOXIDANTS

Ofthesmall-moleculetypesthechiefwater-solubleantioxidantsarevitaminCandglutathione.VitaminC,whosechemicalnameisascorbicacidorascorbate,isarelativeofthesimplesugarglucose.Glutathione,alessfamiliaralthoughjustasimportantantioxidant,isasmall,proteinlikemolecule.HumanscannotmaketheirownvitaminC,sowemustacquireitfromourdiet;butmostanimalscanproducetheirownvitaminC.Allanimals,includinghumans,canmakeglutathione.Whennaturallevelsofglutathionearelow,N-acetylcysteine(NAC)canbeadministeredclinicallyasanantioxidant.Aprecursormolecule,NACisturnedintoglutathioneinthebody.Inthebrain,vitaminCisthemainantioxidantinthefluidbetweennervecells,andglutathioneisthemainantioxidantinsidethem.

Themainfat-soluble,small-moleculeantioxidantsarevitaminE,variouscarotenes(relativesofvitaminA),lipoicacid,andvitamin

Q10.VitaminEisalpha-tocopherol.Ithasarelative-gamma-tocopherolthatisalsoasignificantantioxidant.VitaminEalsoboostsimmuneresponses,bothbyprotectingthemembranesoftherapidlydividingimmunecellsinthetissuesfromoxidativestressandbyprotectingthesympatheticnervesinthelymphoidtissue,wheretheimmunecellsareformed,againstoxidativestress.

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Thecarotenesaretheredandyellowpigmentsfoundinredandyellowvegetables;thebestknownisbeta-carotene.However,only25percentofthecarotenesinthedietconsistofbeta-carotene.Beta-caroteneisparticularlyimportantintheovary,whereitisfoundinveryhighconcentrationinthecorpusluteum,theovarianstructurethatsustainspregnancybymakingthekeypregnancyhormoneprogesterone.Thereareoverfivehundredothercarotenesfoundinfruitsandvegetablesinthediet,themostimportantofwhicharelycopene,reservatol,zeaxanthin,andlutein.LipoicacidregeneratestheactiveformsofvitaminsCandE.Itisfoundindarkgreenleafyvegetables.

Small-molecule,fat-solubleantioxidantshavetobeobtainedfromplantsbecauseanimals,includinghumans,cannotmakethem.Inthecaseofthisclassofantioxidants,therearesignificantchemicaldifferencesbetweenthenaturalformsfoundinplantsandtheformssynthesizedbychemists.Thenaturalformconsistsofonestereoisomer,thesyntheticvarietyofeight.Thevariousstereoisomershavethesamechemicalformulabutareputtogetherdifferentlyandmayhavedifferentbiologicalactivities.VitaminQ10isfoundinmeat,withhighlevelsinorganmeatssuchasliverandkidney.Otherimportantantioxidantsinthebody,particularlyintheblood,areuricacidandbilirubin;melatonin,apowerfulantioxidantproducedbythepinealgland,isinvolvedintheregulationofsleep.

LARGE-MOLECULEPROTEINANTIOXIDANTS

Someofthelarge-moleculeantioxidantsareenzymesthatturnreactiveoxygenspeciesintoinactiveproducts.Themainonesaresuperoxidedismutase(SOD),whichdetoxifiesthesuperoxideion(O-);catalase(CAT),whichdealswithhydrogenperoxide(H202);andglutathioneperoxidase(GSHpx),whichtakescareofseveraltypesofreactiveoxygenspecies.Theseareallessentialenzymesandare

synthesizedinthebody'scells.Otherlarge-moleculeantioxidantsarelargeinessentialproteins(likeserumalbumin)thatmopupreactiveoxygenspeciesandgetdamagedintheprocess.Their"sacrificial"functionprotectsessentialproteins,likeenzymesandDNA,bygettinginthewayofthebullet,asitwere.

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SYNTHETICMOLECULES

Thedrugindustryisbusymakingnewsyntheticantioxidantsthatmaybemoreeffectivethanthenaturalonesincombatingdisease.Theseincludesteroids(suchasthelazaroidgroup),fat-solublederivativesofvitaminC,mifepristone,andmanyothers,someofwhicharementionedlaterinthisbook.

SYNERGISMBETWEENANTIOXIDANTS

VitaminCactsbothonitsownandincooperationwithvitaminE.Itdoesthelatterbecause,whenvitaminEhasmoppedupareactiveoxygenspecies,thevitaminEisitselfoxidized.And,tobeeffective,thisoxidizedvitaminEmustbeturnedbacktotheactiveform;thisiswhatvitaminCdoes.OncethevitaminChasbeenoxidized,ittoomustbeturnedbacktoitsactiveform.ThisisdonebyanothercompoundthatincludesaformofvitaminB(nicotinamide)initsmolecule.Thus,thenicotinamideformofvitaminBalsohasindirectantioxidantproperties.Thischainlikehelpingorsynergisticprocesshasimportantconsequences.

CarotenoidsarealsoinvolvedinrecyclingvitaminEinanotherchain:vitaminE-carotenoid-vitaminC.However,vitaminChasimportantantioxidantfunctionsonitsowninadditiontoitsconnectionwithrecyclingvitaminE.

IMPORTANTANTIOXIDANTSFOUNDINPLANTS

Flavonoidsandphenols(whichtogetherarealsocalledphytochemicals)formalargeclassofnaturalantioxidantspresentinmanyplants,withmorethansixhundredantioxidantphytochemicalshavingbeendetected.Richsourcesoftheseagentsaretea,garlic,oliveoil,andmanyherbs,fruits,andvegetables.IthasbeenestimatedthattheaveragedailyintakeoftotalflavonoidsintheUnitedStatesis

about500mg.Theyactinseveralways-bymoppingupreactiveoxygenspeciesandtoxicheavymetals,bypreventingtheformationofreactiveoxygenspeciesandfatoxidation,andbyprotectingotherantioxidantssuchasvitaminC.TheyalsoinhibitLDL(badcholesterol)oxidation,therebysparingthepreciousvitaminE.However,onceallthevitamin

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Ehasbeenconsumedbyanoxidativeattack,flavonoidsfailtoinhibitfatoxidation.ThissuggeststhattheiractionisdependentonthepresenceofvitaminE-thatis,theybelongtothegroupofvitaminE"helpers."Buttheyactinmanyotherwaysbesidesbeingantioxidants.Manyflavonoidsinteractwithcytokines(keyproteinsinthecellthatactasmessengers,particularlyinconnectionwithinflammation),andtheyalsoblocktheproductionofinflammatoryprostaglandinsandpreventbloodplateletsfromstickingtogethertoformclots.

Antioxidantflavonoidsincludecatechin(greentea),gossypol(rice),apigenin(chamomiletea),quercetin(apples),hesperetin(oranges),andnaringenin(grapefruit).Antioxidantphenolsincludethymolandcarvacuol(thyme),ferulicacid(manyherbs),gallicacid(nutgall),hydroxytyrosol(oliveoil),fisetin,morin,andmanyothers.Antioxidantpolyphenolsarefoundinoranges(ascryptoxanthin)andmanyotherfruits,tea,coffee,chocolate,licorice,andwhitewine.Otherrelatedplantantioxidantsincluderhein(rhubarb)andaloe-emodin(aloe).Antioxidantpeptides(small,proteinlikemolecules)includecarnosine(whichisparticularlyassociatedwiththeglutamatereceptorinthebrain)andanserine.RosemarycontainscompoundsthatstimulatetheproductionoftheantioxidantglutathioneintheliverandactasantitumorcompoundsthatblockcancerproducingchemicalsfrombindingtoDNA.

SOYBEANS.

Soybeanscontainavarietyofanticancercompounds,suchasgenistin,whichareeffectiveatmoppingupreactiveoxygenspeciesbutarealsolikelytoactinadditionalwaystokillcancercells.Genistinandrelatedcompoundsarealsofoundinwholegraincereals,seeds,berries,andnuts.

REDANDWHITEWINE.

Redwinecontainsuptotwentytimesmoreflavonoidsandrelatedcompoundsthandoeswhitewineandtentimesmorethantea.Theseincludequercetin,rutin,andcatechin.Redwinealsocontainsapotentantioxidant-reservatol-foundalsoinpeanuts.Reservatolslowsthemakingoffatsbytheliverandinhibitsprostaglandinsynthesis(andthusinflammation);italsopreventsplateletsfromstickingtogether(amajorcauseoftheblockageofcoronaryarteriesleadingtoheartattacks).Aderivativeofreservatolisaningredientinafolkmedicinecalled

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kojo-kon.Itisalsofoundinanotherfolkmedicineobtainedfrompolygonumcuspidatum,whichhasbeenusedsinceancienttimesforthetreatmentofheartdisease,allergies,andinflammation.Ithasbeensuggestedthatsomeofthereportedbeneficialeffectsofredwinemayactuallybeattributabletoraisedbloodlevelsofthemajorbloodantioxidanturicacid.Portwineraisesblooduratelevels,butanequalamountofpurealcoholdoesnot.Portdrinkerstendtogetgout,whichstemsfromadisorderofuricacidmetabolism.

TEA.

ThecatechinsandrelatedflavinsinteahavebeenreportedtoinhibitfatoxidationinredcellmembranesandprotectDNAagainsthydrogenperoxide.Ateaantioxidant-epigallocatechingallate-inhibitsoxidativedamagetoDNA.Atest-tubeexperimentshowedthatflavonoidsfromgreenteaprotectedartificialfatbilayermembranesfromfatoxidation.Inthecaseofalcoholicextracts,greenteaismuchmorepotentthanblacktea[224].Therefore,someotherunknownantioxidantcompoundsmustbepresentingreenteathataresolubleinalcoholbutnotinwater.Waterysolutionsofgreenteaandblacktea(whichbothcontainquercetin,myrecetin,andkaempferol)areequallyeffectiveinpreventingfatoxidationintesttubeexperiments.Thesecompoundsalsohaveanticancereffectsinanumberoftests.

GARLIC.

InMediterraneancountriesgarlichasalwaysbeenregardedasahealth-givingfood.ThereisasayinginItalythattolivelongonemusteatplentyofaglio,olio,elimone(garlic,oliveoil,andlemons).Thehealth-givingeffectofgarlicisnotjustfolkwisdom;garliccontainsthepotentantioxidantsallinandallicin,whicharesulphur-containingaminoacids.

OLIVEOIL.

Oliveoilcontainsanumberofantioxidantcompounds(includingbeta-tyrosol,hydroxytyrosol,caffeicacid,andvanillicacid);theconcentrationofthesesubstancesishigherinextravirginoilthaninrefinedproducts.Thebitterprincipleofoliveoil(oleuropein)alsoprotectsLDLsagainstfatoxidation.Apotentphenolicantioxidantinoliveoilhastheeffectofpreventingbloodplateletsfromstickingtogetherandreducestheproductionofinflammation-producingthromboxanes(relativesofprostaglandins).Interestingly,ithasnowbeen

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discoveredthatthewastewatersfromoliveoilproductionareparticularlyrichinanumberofantioxidants.

OTHERPLANTANTIOXIDANTS.

Turmeric,aningredientofcurrypowder,containstheantioxidantcurcumin,apolyphenol.Inanimalexperimentslong-termfeedingofcurcuminsignificantlyreducedtheabilityofcarcinogenstoproducecoloncancer.Yeastandyeastextracts(suchasMarmite)areloadedwithantioxidants(includingglutathioneandvitaminQ10).

Manyherbalmedicineshaveahighcontentofantioxidantphytochemicals.Anayurvedic-theancientfolkmedicineofIndia-drugpreparedfromanumberofplantsismarketedtodayasaproductnamedGeniforte.Inanimalexperimentsthisinducesthesynthesisofantioxidantenzymesandreducestheleveloflipidoxidation.Boldine,aningredientinaChileanfolkmedicinemadefromtheboldotree,isusedforthetreatmentoflivercomplaintsandrheumatism.Verypotentatmoppinguphydroxylradicals,thisantioxidantisnontoxicandnonmutagenic.

Itislikelythatmanyherbalremediesworkbyvirtueoftheirantioxidantcontent,yetthereverseisalsotrue.Someflavonoidshavepropertiesthatdependonactionsunconnectedwiththeirantioxidantproperties.Forexample,ithasbeenshownthatsomeflavonoids,likequercetin,gossypol,chrysin,andapigenin,bindtoacertainreceptorinthebraintowhichbenzodiazepinetranquilizers,suchasValium,usuallybind.Theherbsfromwhichthesecompoundsareobtained(suchaspassifloracoeruleaandmatricariarecutitis)havebeenreportedinfolkmedicinetohavesedativeandpain-relievingproperties.AsyntheticderivativefromtheseflavonoidshasbeenproducedthatisonehundredtimesaspotentasValium[137].Moreover,itlackedsomeoftheannoyingsideeffectsofValium,suchassedationandmusclerelaxation.

ISOPRENOIDS

Thesearenotantioxidantsbutanticanceragentsthatretardtumorgrowthbyinhibitingcellproliferation.Examplesofisoprenoidsarealpha-limonene(foundincitrusoils),geraniol,carvone,andmenthol.Richsourcesinthedietareherbs,spices,barley,ricebran,olives,wine,eggs,dairyproducts,andcertainessentialoils

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usedinflavoring.Isoprenoidsinanimalexperimentsalsoleadtotheincreasedproductionofagroupofenzymesthatdetoxifymanyenvironmentalpoisons.Isoprenoidsalsoincreasetheliveroutputoftwoenzymesconcernedinantioxidantdefenses.Thus,isoprenoidshaveindirectantioxidantproperties.Notallbeneficialagentsinfruitandvegetablesareantioxidants.Ifyoudecidetorelyonantioxidantsupplementsratherthanincreasingthefruitsandvegetablesinyourdiet,youwillbedeprivingyourselfoftheaddedprotectionofferedbyisoprenoids(andprobablyotherasyetunknownchemicals)againstcancerandmanyenvironmentalpoisons.Itistobehopedthatsomeisoprenoidsmaybeaddedtoantioxidantsupplements.

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part2theroleofoxidativestressandantioxidantsinhealthand

diseaseInpart1wesawhowthenormalchemistryofoxygeninevitablyleadstotheproductioninthebodyofreactiveinevitablyleadstotheproductioninthebodyofreactiveoxygenspecies,whichplayanormalroleinimportantbodilyfunctions.However,theseagentsarepotentiallytoxic,andevolutionhasprovidedthebodywithaseriesofbiochemicaldefensesagainstthem.Inmanydiseasesthedelicatebalancebetweenreactiveoxygenspeciesandantioxidantsisdisturbed.Ifreactiveoxygenspeciesareproducedataratehigherthanwhattheantioxidantdefensescancopewith,oxidativestressresults,whichmayleadtotissuedamageanddisease.Medicalscienceisexploringthepossibilityofusingantioxidantsinthepreventionandcureofdisease.

Themegavitaminconceptwasonceregardedwithgreatsuspicionbypractitionersofmainstreammedicine.AccordingtoRuckerandStites,writingin1994,"adecadeago,itwasconsideredhighlyspeculativetoproposeapproachestodiseasepreventionthatinvolvedsupplementation.Nutritionparadigmsimportanttovitaminfunction,however,havenowshiftedtoincludemorefocusondiseasepreventionandconsideration

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ofsupplements.''[182].AsVoelkerputitinaneditorialintheJournaloftheAmericanMedicalAssociation,theflagshipofthemedicalestablishment,inthesameyear[222]:"Thestewofdatadescribingantioxidants'diseasepreventionpotentialiscomingtoaboil....[O]nethingiscertain,vitaminandmineralsupplementshaveenteredtheranksofbonafidescience."Beforewediscussindividualdiseasesinthecontextofthesenewdevelopments,wefirstlookatthemethodsusedbyscientiststostudytheroleofoxidativestressandantioxidanttherapyinthosediseases.

howdowestudytheeffectsofantioxidantsInhumandisease?Therearetwotypesofepidemiologicalstudies,calledtheretroactiveandtheprospective.Athirdtypeofstudy,andoftenthemostinstructive,isthedouble-blind,placebo-controlledmethod.

Intheretroactiveepidemiologicalmethod,researchersselectfromthegeneralpopulationarepresentativesampleof,say,tenthousandpeople.Theyapplycertaincriteriatoeliminatesubjectswhohaveconditionsthatmightcomplicatetheissue(illness,longevity,alcoholism,andsoon).Theythenobtainadietaryhistory,inwhicheachsubjecttriestorememberwhatsortoffoodheorshehaseatenoveragivennumberofyears.Ifthefocusofstudyis,forexample,theantioxidantsvitaminsCandEandbetacarotene,researchersthenestimatehowmuchofthesevitaminsthereporteddietwouldcontain.Theypartitionthesampleintoseveralgroups,takingdatafromthosewiththehighestlevelofintake(usuallytheupperfifth)andthosewiththelowest(usuallythelowestfifth).Researchersthenascertainthenumberofcasesoftheparticulardiseaseunderstudythathaveoccurredineachgroupatthetwoextremes,thehighestfifthandthe

lowestfifth.TheresultsmayshowthatthediseaseoccurslessofteninthegroupwithhighestvitaminEintakethaninthatwithlowestintake.ThiswouldappeartoindicatethatvitaminEprotectsagainstgettingthatdisease.

However,thismethodhasdrawbacks.First,itisdifficultformostpeopletoremembertheirdietovermanyyears.People'smemoriesaboutsuch

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mattersarenotoriouslyunreliable.Furthermore,experimentshaveshownthat,whenpeoplefilloutquestionnaires,theyoftenunwittinglyoverestimatetheirconsumptionoffruitsandvegetables.Theseconddrawbackisthe"uncontrolledvariable"problem.SubjectswithahighintakeofvitaminEmayalsohaveahealthierlifestyle-whichconsistsofengaginginmoreexercise,eatinglessfatanddrinkinglessalcohol,beingsubjecttolessstress,andsoon-thanthosewithalowintakeofvitaminE.Itmaybepreciselythatcombinationofalow-fatdiet,moreexercise,andlessstressthataccountsforthelowerdiseaserate,ratherthantheamountofvitaminEinthediet.Althoughatrialcanbedesignedtocontrolforobviousfactorssuchasalcoholandtobaccouse,thereisalwaysthepossibilityofsomeotherfactorthatresearchershadnotthoughtofbeingthemoresignificantreasonforthedifferenceindiseaseratesbetweentwogroups.

Prospectiveepidemiologicalstudiesalsooperateonaselectedpopulationofsubjects,butthistimeresearchersfollowthosesubjectsforanumberofyears,measuringtheirantioxidantintakeandsometimestheirantioxidantbloodlevels.Attheendofasetperiodoftime,researchersascertainhowmanymembersofthehighestandlowestintakegroupsoftheantioxidantunderstudyhavedevelopedaparticulardisease.Theadvantageofthismethodisthattheresearchersgetmoreaccuratereadingsofeachindividual'santioxidantintakelevelsanddonothavetodependonunreliablememories.Thedisadvantagesarethecostandthelongtimerequiredtocompletetheexperiment.Thismethodalsosuffersfromtheuncontrolledvariableprobleminthatonecannevereliminatetheeffectonthefinalresultsofabetterlifestyleandotherfactorsnotidentifiedwhentheexperimentwasdesigned.

Thebestwayofobtaininginformationisadouble-blind,placebo-controlledstudy,ofwhichtherearetwotypes,preventativeandtherapeutic.

Inapreventativestudyresearchersselectanumberofapparentlyhealthysubjectsusingcertainexclusioncriteria(e.g.,beloworaboveacertainagerange,thepresenceofotherillnesses,andsoon)anddividethemintotwoequalgroups,thetreatmentgroupandtheplacebogroup,matchedforage,sex,andanyotherfactorthatmightbesignificant.Ifallthesubjectsinthetreatmentgroupwereolderpeopleandallthesubjectsintheplacebogroupwereyounger,thenitcouldneverbeprovedthatanyapparenteffectofthetreatmentbeingtestedisnotsimply

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attributabletotheagedifferencebetweenthegroups.Oncethematchedgroupsareselected,thetreatmentgroupisgiventheantioxidanttobetestedandtheplacebogroupaplacebopillthatlooksandtastesthesameastheantioxidant;thesubjectsdonotknowwhichonetheyaretaking.Infact,nooneknowswhichtreatmentanindividualreceivesexceptforonememberoftheresearchteam.Theothermembersoftheteamthatperformtheclinicalevaluationsdonotknowthetreatmentgroupassignments.Neithertheevaluatornorthesubjectareintheknow-hencetheterm"double-blind."Thisexperimentaldesignensuresthatevaluationsarenotsubjecttobias.Attheendofthetrial,itisdeterminedhowmanysubjectsineachgroupdevelopthediseaseunderstudy(e.g.,heartdisease,cancer,orcataract)andhowmanyhavediedfromit.Ofcourse,thetrialcaninvestigatemorethanonedisease.

Atherapeutictrialentailsthesameprocedures,butthesubjectsalreadyhavethediseaseinquestion;thestudyisdirectedtowardfindingoutifthetreatmentimprovestheircondition,oratleastslowsdowntheprogressofthedisease.Theadvantageofthismethodisthelikelihoodthatanyresultsare,infact,attributabletothetreatmentandnottosomeotherfactor.Thedisadvantage,inthecaseofantioxidants,isthattheseagentshavealong-termcourseofaction.Thus,toberelevant,atherapeutictrialmustlastforyearsratherthanformonths.Clearly,ifadiseaseconditiontakestenyearstoestablishitself,thenaclinicaltriallastingonlyoneyearwillnotyieldanymeaningfulresult.Butlong-termtrialsareexpensiveandaburdenonboththeinvestigatorsandthepatients.Itisdifficulttofindsubjectswillingtowaitforyearsbeforetheycanbetoldwhattheyaretaking.Also,inaprotractedtrialitbecomeseasierforthedouble-blindstatustobecompromised-thatis,forsomeonetodiscoverinadvertentlywhichpilliswhich.

Onethingweknowaboutantioxidantsisthattheyaremorelikelyto

helppreventvariousdiseasesthantocurethemoncetheyhavestarted.Inaprotractedillness,suchasParkinson'sdisease,antioxidanttherapyismorelikelytobeeffectiveifitisstartedbeforetheaffectednervecellsinthebrainaredestroyed.However,suchtimingisdifficulttoachieveasthesecellsbegintodiefiveyearsbeforethefirstclinicalsymptomsofthediseasearemanifest.SincethereisnoexistingtesttotellwhichpeoplewilldevelopParkinson'sdisease,meaningfultherapeutic

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trialstostudytherelationshipbetweenantioxidantsandParkinson'sdiseasecannotbecarriedout.Afurtherproblemisthatmanyofthestudiesunderconsiderationinthisbooktestonlyone,orperhapstwo,antioxidants.Thisisapoorstrategy,becauseantioxidantsworktogetherasasynergisticteam.Astudyusinglargeamountsofjustoneantioxidantmayseriouslydisruptthissynergisticprocessandleadtounreliable,orevenundesirable,resultsasisdetailedlater.

Afinaldrawbacktotherapeutictrialsisthat,eveninadiseaseknowntobecausedinpartbyreactiveoxygenspecies,givingantioxidantsbymouthorbyinjectiondoesnotguaranteethattheywillevergettotheplaceatwhichtheyareneeded.Thebodyisnotasackfilledwithfluidinwhichmedicinessimplydiffuseeverywhere.Rather,thebodyhashighlyspecificmechanisms,calledpumps,thattightlycontroltheuptakeoftheantioxidantfromthegutintotheblood,fromthebloodintothetargetorgan,andonceintheorganontotherightplaceintherightpopulationofcells.Forexample,vitaminCissolubleinwater,butnotinfat.Therefore,itcouldnevergetinsidethefattycellmembranewherefatoxidationtakesplace.Ontheotherhand,vitaminEissolubleinfat,andsocanreachthesetargets.Tocircumventthisproblemsomepharmaceuticalcompaniesarebusytryingtomakefat-solublederivativesofvitaminC.Buteventhesewillnotsolveeveryproblem.Wherethecellulartargetisinawaterysurround,evenifsurroundedbyalipid(fat)barrier,water-solublevitaminCwillstillbeneeded.

measurementofoxidativestressIntheclinicBecausemostreactiveoxygenspeciesarehighlyreactivemolecules,theydonottravelfarfromwheretheyaremadebeforeattackingsome

biologicalmoleculesuchasfat,protein,orDNA.Oncethesereactiveoxygenspeciesgetattachedtothebiologicalmolecule,itisnolongerpossibletodetectthemwithoutremovingthebiologicalmoleculefromthebodyandanalyzingitfortracesoftheattachedreactiveoxygenspecies.Asitisnotpracticaltomeasurefreereactiveoxygenspeciesinbloodorbodytissuesinaclinicalsetting,indirectmethodsarenecessary.

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1.Underoxidativestressthemetabolismofthecellchangestoproducecertainstablesubstances.Thesecanbemeasuredinthebreathorinthebloodtodeterminethedegreeofongoingoxidativestress.Examplesarepentane,MDA(malonyldialdehyde),conjugateddienes,andlipidperoxides.Furthermore,oxidativeattackchangesthechemicalstructureofDNA,fat,andproteins.Thesechangescanbedetectedandmeasuredinthelaboratory.Examplesare8-OH¬GonDNA,conjugateddienesandMDA/TBAadductsonfats,andcarbonylsonproteins.

2.Duringoxidativestressthesmall-moleculeantioxidants,suchasvitaminsCandE,whenmoppinguptheexcessreactiveoxygenspecies,tendtobeusedupataratefasterthantheantioxidantscanbemobilizedandrushedtothesceneofaction.Thismeansthatthebloodlevelsoftheseantioxidants,especiallyofvitaminsCandEandbetacarotene,willtendtofallaslongasthedegreeofoxidativestressisgreaterthanthecapacityofthebodytomobilizeenoughantioxidantdefensestodealwiththesituation.Thebloodlevelsoftheseantioxidantscanbemeasured,thusindicatinghowthebattleisgoing.

3.Antioxidantenzymesaresynthesizedwhentheyareneeded.Forexample,underoxidativestress,levelsofSOD,CAT,andGSHpxtendtoriseinthebloodandbodytissues.Thisisbecausereactiveoxygenspeciesactdirectlyonthenucleusofthecell(viathetranscriptionfactorNF-KBmentionedearlier)tostartthesynthesisoftheseenzymes.Thus,thelocalandgeneralantioxidantdefenseswillbeincreased.However,insomecases,thediseaseprocessmaybeduetolowlevelsofoneormoreoftheseenzymesbecausesomethinghasgonewrongwiththecellularmachinerymakingthem-inwhichcasebloodlevelswillbelow,notelevated.

theroleofoxidativestressindiseaseOxidativestress-damageresultingfromanexcessiveproductionofreactiveoxygenspeciesand/orafailureoftheantioxidantdefenses-playsanimportantroleinmanydiseases.Logically,then,antioxidantscouldpotentiallyplayausefulroleintherapy.Duringtheinitialstageofoxidativestressthebody'sdefensesaremobilizedand

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levelsinthebloodandtissuesofantioxidantcompoundstendtorise.Ashasbeennoted,thisisinpartduetothefactthatreactiveoxygenspeciesdirectlystimulatethecelltomakemoreantioxidantenzymes.Iftheoxidativestressistooprolongedortoosevere,theantioxidantdefensestendtobeoverwhelmedbecausethesmallmoleculeslikevitaminsCandEsimplygetusedupandtheirbloodlevelsdecrease.Overwhelmingoxidativestressmayalsocausethereactiveoxygenspeciestoattacktheantioxidantenzymesthemselves-which,asproteins,arevulnerabletosuchanattack-andsodiminishtheireffectiveness.Asavailableantioxidantsareconsumedwithoutreplenishment,withcontinuedoxidativestressandthebuildupofreactiveoxygenspeciesmolecules,cellulardamagecanoccur,leadingtothedevelopmentofdisease.

Thissectiondescribesthosediseasesthoughttobeassociatedwithoxidativestress;itincludesanaccountoftheresultsoftreatmentofthesediseaseswithantioxidants.Itshouldbeemphasizedthatthetechnicalterm"oxidativestress"isnotthesamethingas"stress,"ascommonlyusedtodenotepsychologicalorlifestress.Butthetermdoesconveythesenseofthecontinualbattleinalllivingcellsbetweenpotentiallylethalreactiveoxygenspeciesandtheantioxidantdefenses.

Theorderinwhichthefirsttwelvediseasesispresentedcorrespondstoboththedegreeoftheirimpactonthepopulationatlargeandthedegreeofimportanceofoxidativestressintheiretiology.Therestaregiveninalphabeticalorder.

HEARTDISEASE

CoronaryarterydiseasecausesheartattacksandisthesinglemajorcauseofdeathintheUnitedStates.Itiscausedbytheslowbuildupofaformoforganizedbloodclot(calledanatheromatousplaque)inthe

wallsofthearteriesthatsupplytheheartwithblood.Manyfactorscombinetocausetheseplaques,includinggenes,excessanimalfatsandcholesterolinthediet,excesslow-densitylipoprotein(LDL,thebadformofcholesterol)intheblood,lackofexercise,smoking,andobesity.Butonemajorfactorrelatedtotheothersistheoxidationoffatsintheblood.Asaresultofthisoxidationthefatsintheblood(andelsewhereinthebody)become,sotospeak,rancid.WhatimplicatesLDL

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cholesterolincoronaryheartdiseaseisthefactthatitismoreeasilyoxidizedthanarenormalfats.Oxidizedfatssticktothewallsofarteriesandarethentakenupbycertainwhitebloodcellscalledmacrophages(Greekfor"bigeater").Typically,whenthesemacrophagestakeupanormal(non-LDL)fat,theybecome"full"andstopconsumingfat.Theythenmoveofftoallowanothermacrophagetotakeover.InthecaseofoxidizedLDLfats,thisprocessisaltered.WhenthemacrophagestakeupanoxidizedLDLfat,theswitch-offmechanismthatsignalsfullnessfailstowork;thecellsgoontakingupoxidizedfatandbecomeoverloadedandbloatedwithfattoform"foamycells."Thesefoamymacrophagesceasetooperateproperlyandremaininthearterywalltohelpformtheorganizedclot.Whentheclotblocksthenormalflowofblood,aheartattackislikelytoresult.

Itisnotonlythefailureofnormalmacrophageregulationthatleadstocoronaryheartdisease.Increased"stickiness"ofthewhitecellsandplateletsinthebloodisalsoinvolved.Thefattydepositsinthewallofthebloodvesselscausewhitebloodcells(includingfoamymacrophages)andplateletstosticktothem,whichstartstheprocessofclotformation.Anythingthatincreasesthisstickinesswillbeariskfactorforheartattack.However,ifthesebloodcellsarenotstickyenough,theywillfailtorepairsmalltearsinthevesselwallandhemorrhagemayresult.Aswithanyregulatedprocess,toomuchortoolittlestickinesscanleadtohealthproblems.VitaminEhasbeenshowntoreducestickiness,especiallyinthecaseofbloodplatelets,byamechanismindependentofitsantioxidantproperty.ItalsoprotectsLDLfatsagainstoxidativeattackbyitsantioxidantproperty.

Aheartattackitselfcausesprofoundoxidativestress,withreleaseofreactiveoxygenspeciesespeciallyduringthereperfusionstage,whenthebloodflowisreturningtothedamagedheartmuscle.Chandrasekaretal.haveshownthat,duringthereperfusionstage,the

levelsofmessengerRNAsforproinflammatorycytokinesintheheartareraised[32].Thiselevationmeansthatasignalwassenttothecellnucleustomanufacturemorecytokines(whichareproteins)bymeansoftheDNA-to-RNAsystemofproteinsynthesis,ofwhichmessengerRNAsareapart.Thepurposeofthiscytokineproductionissomewhatobscure,asproinflammatorycytokinesonlymakethingsworsebyincreasingtheblockageofthecoronaryartery.Atthesametimetheresearchshowsthatasignalwassent

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tothenucleusoftheheartmusclecelltomanufacturemoreofthekeyantioxidantenzymesCAT,SOD,andGSHpx(seepart1)soastoprotecttheheartmusclebycounteractingthedeleteriouseffectsofreactiveoxygenspecies.

Ifoxidationoffatsisoneoftheculprits,thenantioxidantsmaybepartoftheremedy.Ifantioxidantscouldslowdowntheoxidationofthefatsthatstartthispathologicalprocess,theymighthelppreventheartattacks.However,tobeeffectivetheseantioxidantswouldhavetobefatsoluble(seepart1)soastobeabletopenetratetowherethedamageisinthefat.

ManyexperimentsinanimalsandinthetesttubehaveshownthatvitaminEwillprotectcellsandfatsagainstfatoxidationinducedbyreactiveoxygenspecies.Heartmuscleisparticularlyvulnerabletooxidativestressbecauseofitsheavyworkloadanditsnormallowlevelofantioxidantdefenses[180].Soitislikelytobeadverselyaffectedbyanyinterferencewithitsbloodsupply,asinaheartattack.Inthecaseofanyorganthattemporarilylosesitsbloodsupply,muchofthedamageisdonebyreactiveoxygenspeciesduringthereperfusionperiod,whenthebloodisenteringtheorganagain.

CLINICALDATAANDMAJORRESEARCHSTUDIES.

Alookattheclinicaldatainhumansandareviewofthemajorresearchstudieswillhelpustounderstandwhetherantioxidantscanpreventoralleviatecoronaryheartdisease,whichIhenceforthterm"heartdisease"withtheunderstandingthatthisincludesonlycoronaryheartdiseaseandnotconditionslikeheartfailureorirregularitiesoftheheartbeat.Thedatafromthethirty-fourmostprominentstudiesontherelationshipbetweenantioxidantsandheartdiseaseispresented.Thesestudiesarenumberedforeaseofreference;thereadercanfollowtheanalysisofhowthesestudiesrelatetoeachother.Youwillnotethattherearedisagreementsinthesereportsbetweenthe

authoritieswhocarriedouttheresearches,andyoumaywonderwhy.Afterall,itdidnottakelongtodiscoverthatpenicilliniseffective.However,inthecaseofthesechronicandcomplicateddiseases,arrivingatfirmconclusionsismoredifficult.Reliablejudgmentsmustbebasedonalltheresearchworkthathasbeencarriedoutandontherecommendationsmadebyalltheexpertsinthefield.

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Inthefirsteightstudiestheinvestigatorsexaminedtherelationshipbetweenthelevelofingestionofantioxidantvitaminsandtheincidenceofheartdisease.

(1)IntheNurse'sHealthStudy,StampferandRimmmeasuredtheintakeofvitaminsCandEandbeta-carotenein87,245Americanfemalenursesoveranaverageperiodofeightyears-atrulyformidableundertaking[207].Theydividedthegroupintothefifthpart(quintile)withthehighestintakeandthefifthpartwiththelowestintake.TheaveragelevelofvitaminEtakenbythehighestquintilewas208mgperdayandtheaverageleveltakenbythelowestquintilewas2.8mgperday.TheyfoundthatthehigherlevelofintakeofvitaminEwasassociatedwitha34percentreductioninheartdisease.Ahigherconsumptionofbeta-carotenewasassociatedwitha22percentdecrease.Iftheintakeofboththeseantioxidantswashightherewasa50percentreduction.VitaminCsupplementshadnoeffect.TheyalsonotedthatvitaminEwaseffectiveonlyifitwasgivenasavitaminEsupplementandnotasmerelyoneingredientinamultivitaminpill.TheyexplainedthisonthebasisofthefactthatvitaminEsupplementstypicallycontainmorethan1oomgperdaywhereasthemultivitaminpillscontainonly30mgperdayorless.Thisisevidencethatthecurrentrecommendeddailyallowance(RDA)forvitaminEmaybetoosmalltoplayaroleinpreventingheartdisease.

(2)Thesameteamthenlookedatapopulationof39,910menoverafouryearfollow-upperiodusingthesamemethods[176].ThemedianintakeofvitaminEinthecaseofthehighestquintilewas419mgperdayandinthecaseofthelowestquintileitwas6.4mgperday.AgaintheyfoundthatthehigherlevelofvitaminEintakewasassociatedwithasignificantreductionintherateofdevelopmentofheartdisease;vitaminChadnoeffect.Inthisstudybeta-carotenewasalsoeffectivebutonlyinsmokers.Thisfindingwithbeta-carotenemighthavebeenduetotheshortertermofthisstudyascomparedwiththeir

firststudy.Thissuggeststhatthetherapeuticeffectsofbeta-carotenemaytakealongperiodoftimetodevelop.Theremayalsobeagenderdifferenceinvolved,sincethisstudyinvolvedonlymenwhereasthepreviousstudyinvolvedonlywomen.Theauthorspointout

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thatthe"healthierlifestyle"explanationfortheseresultswasunlikelytoberight,asthesubjectswhotookhighlevelsofvitaminCsupplementshadequallyhealthylifestylesasthosewhotookhighlevelsofvitaminEsupplements,butobtainednobenefit.Inalaterpaperthesameauthorsstatethatatleast100mgperdayofvitaminEintakeisrequiredtoproduceaneffectinloweringtherateofheartdisease[207].

(3)Thethirdstudywascarriedoutonapopulationof34,486postmenopausalwomenwhowerefreefromheartdiseaseatthestartofthetrial[114].Theinvestigatorsmeasuredtheintakeofantioxidantvitaminsandfoundthat,ifvitaminEwasobtainedfromfood(mainlyfromnuts,seeds,margarine,andmayonnaise),therewasastrongprotectiveeffectagainstheartdisease.Therewasnoprotectiveeffectifthevitaminwastakenasamultivitaminsupplement.TheauthorsexplainedthisresultalsoasowingtothefactthatthedoseofvitaminEinthemultivitaminsupplementsusedbythesesubjectswastoolow.Again,vitaminChadnoeffect.

(4)ThePhysician'sHealthStudyisanothermajorstudy,thistimeconfinedtobeta-carotene.Fortwelveyears,27,071Americanmalephysicianseachreceivedasmalldoseofbeta-carotene(equivalenttotwocarrotsperday)[82].Theinvestigatorsreportednobenefitforpreventingheartdiseasefromthislevelofbeta-caroteneintake.

(5)AsimilarstudycarriedoutinBasel,Switzerland,foundthateightyearsofbeta-caroteneintakeshowednoclinicalbenefit;butifthelengthofthestudywasincreasedtotwelveyears,therewasasignificantreductionintheincidenceofheartdisease[66].Theresearchersstressheartdisease'sslowrateofdevelopmentand,ifoneistogetatrueestimateontheeffectivenessofanyprocedure,theneedforlongtrialsratherthanshortones.

(6)IntheScottishHeartHealthStudyitwasfoundthatahighlevelofintakeofvitaminsEandCandbeta-caroteneappearedtoprotectmen,

butnotwomen,againstheartdisease[216].Thisstudyusedasophisticatedstatisticalmethod(multivariantdiscriminantanalysis)foranalyzingtheresults;theactuallevelsofvitaminEintakeinvolvedarenotmentioned.

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(7)TheLipidResearchClinics-CoronaryPrimaryPreventionTrialstudied1,899menaged40to59andmeasuredtotalcarotenoids(notjustbeta-carotene,whichcontributesonly25percentofthetotalcarotenoidintakeofthediet)[146].Theresultsshowedastrongprotectionagainstheartdiseaseformenwhohadneversmoked.Theauthorsalsostressthatthedurationofsuchstudiesmustbeatleasttenyearsforvalidconclusionstobedrawn.

(8)Oneofthelongestlongitudinaltrialseverconductedstudied1,556menoveraperiodoftwenty-fouryears[158].Theresultsshowedthathighlevelsofintakeofbeta-caroteneandvitaminCledtoa20-30percentdecreaseinthedeathratefrombothheartdiseaseandcancer.

Instudies9to13,theresearchersinvestigatedtherelationshipbetweenbloodlevelsofantioxidantvitaminsandtheincidenceofheartdisease.

(9)GeyhasreportedtheresultsoftheMONICAprojectcarriedoutbytheWorldHealthOrganization[65].ThisprojectstudiedtherelationshipbetweenbloodlevelsofvitaminEanddeathratesfromheartdiseaseinsixteenEuropeancountriesandfoundthatvitaminEhadastronglyprotectiveeffect.Whengiveninsufficientamounts,vitaminEworkedbetterincombinationwithseveralantioxidant''helpers"thanonitsown.Aswehaveseen,antioxidants(particularlyvitaminsB3ornicotinamide,E,andC)worktogetherasateamandneedtobegivenasateam,insufficientquantities,tobemosteffective.MostmultivitamintabletformulationscontaininsufficientamountsofvitaminE.

(10)Riemersmaetal.measuredbloodlevelsofvitaminsEandCinapparentlyhealthymiddle-agedmeninfourlocations-twoinFinland,oneinScotland,andoneinsouthernItaly[174].Inthefirstthreelocationsthereisaveryhighincidenceofheartdisease;insouthernItalyheartdiseaseislessprevalent.BloodlevelsofvitaminsCandE

werelowinScotlandandinoneoftheFinlandlocationsandhighinItaly.ItalianstypicallyeatanymorefreshfruitsandvegetablesthandoScotsandFinns.ButinKarelia,theotherFinlandlocation,vitaminClevelswerenotlow,yettherateofheartdiseasewas

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high.TheauthorssuggestthatthisapparentdiscrepancymightbeduetothefactthattheKarelianswereingeneralmoreobeseandhadhigherbloodpressurethandidtheotherthreegroups-bothfactorsthatpredisposetoheartdisease.Indeed,dietarystudiesshowthatFinnshavethehighestintakeoffatinEurope.Thisagainillustratestheimportantpointthatotherfactors(suchasbloodpressureandobesity)maycomplicatetheinterpretationoftheeffectsofantioxidants.

(11)Anotherstudycomparedtwogroupsofyoungpeople,onefromNaples,Italy,andtheotherfromBristol,England[161].TheItalianshadhigherbloodlevelsofvitaminEandmuchhigherlevelsofbetacarotene.Althoughthegroupsatethesamequantityofvegetables,theItaliansconsumedconsiderablymoretomatoesandoliveoil.TheItalianshadmuchlowerratesoffatoxidation(asmeasuredbyplasmalevelsofconjugateddienesandlipidperoxides,whichareproductsoflipidoxidation).Tomatoes,whichcontaintheimportantantioxidantlycopene,andoliveoil,whichalsocontainsmanyantioxidants,arekeyingredientsoftheMediterraneandiet,whichmanystudieshaveshownofferspowerfulprotectionagainstheartdiseaseandsomeformsofcancer.

(12)Singhetal.studiedimpoverishedindustrialworkerswhoateapoordietandhadhighexposuretotoxicfumesderivedfromdieselenginesandheavymetalssuchascopperandlead[196].ThosesubjectswhodevelopedheartdiseasehadlowerbloodlevelsofvitaminsEandCandofbetacarotenethandidthosewhodidnotdevelopheartdisease.

(13)Middle-agedmeninLithuaniahavefourtimesasmanyheartattacksasmiddle-agedmeninSweden.Tofindoutwhy,Kristensenetal.studiedonehundredpeople,fiftyfromeachcountry[111].Therewerenodifferencesbetweenthetwogroupsintheordinaryriskfactorssuchasbloodcholesterol,smoking,obesity,andhighbloodpressure.Butthereweretwosignificantdifferences:theLithuanians

hadlowdensitylipoproteins(badcholesterol)thatweremoreeasilyoxidized,andtheyhadlowerbloodlevelsofsomeantioxidants,suchasbetacarotene,lycopene,and,interestingly,gamma-tocopherol(arelativeofvitaminE).Levelsofalpha-tocopherol(vitaminE)werethesame.Theinvestigatorssuggestedthattheirresultsmightbeduetothefact

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thatLithuaniansingestedmorepolyunsaturatedfatsbutconcludedthattheirantioxidantstatuswasalsoimportant.TheauthorsquoteanotherSwedishstudythatshowedthatmenwithcoronaryheartdiseasehadlowbloodlevelsofgammatocopherolbutnormallevelsofalpha-tocopherol.Thisunderscorestheimportanceofgammatocopherolinthedietandsuggeststhat,infuture,suchstudiesshouldpayasmuchattentiontogammatocopherolastoitsmorefamousrelativealpha-tocopherol.

Studies14to16concentratedonvitaminCalone.

(14)TheFirstNationalHealthandNutritionExaminationSurvey(NHANES)cohortstudywasbasedonaten-yearfollow-uponthedietof11,348Americanadultsaged25to74[52].TheresultsindicatedthatahighdietaryintakeofvitaminCappearedstronglytoprotectmenagainstdeathfromheartdisease(aswellasdeathfromcanceranddeathfromallcauses);butwomenwereonlyweaklyprotected.However,thisstudyhasbeencriticizedontechnicalgroundsbyHerbert[83].Enstromhasrepliedtothiscriticism[51].

(15)Tooheyetal.studied172AfricanAmericanSeventh-DayAdventists(whosereligiouspracticeprohibitssmokingtobaccoanddrinkingalcohol)[217].TheresultsshowedthatahighintakeofvitaminCwasstronglyassociatedwithalowerrateoffatoxidation(probablybecauseofthewayvitaminC"helps"vitaminE,asdescribedinpart1).Theresearchersconcludedthattheirresultswereprobablynotduemerelytoeatingmorefruitsandvegetables,mainlybecausetheyfeltthattheyhadnoteliminatedthepossibilityoftheinfluenceofotherfactors,suchasabetterlifestyle.

(16)Nyyssönenetal.tested1,605menaged42to60inalong-termstudyinFinlandoftheeffectsofvitaminCdeficiency[149].Theapparentlyhealthysubjectsenteredthestudybetween1984and1989andwerefollowedupuntil1996.Someninetysubjectshadabloodlevellowerthanthecutoffpointthatindicatesadeficiencystateof2

mg/L.ThesesubjectsshowedahighlysignificantincreaseinthenumberofheartattackswhencomparedwiththerestofthesubjectswhohadnormalbloodlevelsofvitaminC.Thiswassoevenallowingforotherfactorssuchastheamountofsaturatedfats,carotene,

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fiber,andteaconsumed.However,furtherincreasesinthebloodlevelofvitaminCabovethelimitof2mg/Lconferrednofurtherprotection.ThissuggeststhatvitaminCsupplementsbythemselveswouldnothavebeenofhelp.However,itisamatterofconcernthatsomanyFinnsweredeficientinvitaminC.PhysiciansshouldbearinmindthepossibilityofapreviouslyundetectedvitaminCdeficiencywhenevaluatingasubject'sriskofhavingaheartattack.

Theprotectiveeffectofantioxidantswasestimatedinstudies11and15bymeasuringthelevelsoffatoxidationthatpredisposestowardheartattacks;intheotherstudiesitwasestimatedbymonitoringthedevelopmentofheartdiseaseitself.Wecansumuptheforegoingreviewofthemajorepidemiologicalstudiesasfollows.

INTAKESTUDIES

HighdietarylevelsofvitaminEaloneprotectedagainstthedevelopmentofheartdiseaseinthreestudies(1,2,and3).Therewerenostudieswithnegativeresults.

VitaminCwasprotectiveorpartlyprotectiveintwostudies(14and15)buthadnoeffectinthreestudies(1,2,and3).ItsmaineffectivenessmaybeinpeoplewhohaveanactualvitaminCdeficiencystate.

Beta-carotenewasprotectiveinstudy5butnotinstudy4.

ThecombinationofvitaminsEandCandbeta-carotenewasprotectiveinstudy6.

Totalcarotenoidswereprotectiveinstudy7.

Thecombinationofbeta-caroteneandvitaminCwasprotectiveinstudy8.

VitaminCwasprotectiveinvitaminCdeficientindividualsinstudy16.

Intwostudies(6,14)menwerereportedtohaveamorefavorableclinicalcoursethanwomen.

BLOODLEVELSTUDIES

HighbloodlevelofvitaminEalonewasprotectiveinstudy9.

HighbloodlevelsofvitaminsEandCwereprotectiveinstudy1o.

HighbloodlevelsofvitaminEandbeta-carotenewereprotectiveinstudy11.

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LowlevelsofvitaminE,vitaminC,andbetacarotenewereariskfactorinstudy12.

Lowlevelsofbetacarotene,lycopene,andgamma-tocopherolconstitutedariskfactorinstudy13.

Collectively,thisepidemiologicaldatastronglysupportsaprotectiveroleforvitaminEinthepreventionofcoronaryheartdisease,ifgivenatanadequatedose(over1oomgperday).ItisbettertoadministervitaminEtogetherwithitssupportiveantioxidants.Theevidenceforbetacarotene'sroleisweaker,buttotalcarotenesappeartobemoreeffectivethanbetacarotenebyitself.TheevidenceforanyprotectiveroleofvitaminCadministeredbyitselfisunconvincing,exceptinpeoplewhohaveanactualvitaminCdeficiency-possiblybecauseheartdiseaseistheresultoffatoxidationandvitaminC,awater-solubleantioxidant,doesnotpenetrateafattyenvironment.However,ifvitaminEisindeedprotective,thenvitaminCmaybeneededinitsroleasahelperofvitaminE.ThuswecanexpectvitaminCtobeusefulwhengiventogetherwithvitaminE,butnotwhengivenbyitself.

FIVEDOUBLE-BLIND,PLACEBO-CONTROLLEDSTUDIES

(17)Stephensetal.haverecentlyreportedoneofthefirstresultsofsuchatrial-theCHAOSstudycarriedoutinCambridge,England[200].Therewere2,002subjectswhowerestudiedforanaverageofseventeenmonths.HalfweregivenvitaminE(800mgperday),andtheotherhalfreceivedaplacebocapsule.InthetestgroupbloodlevelsofvitaminErosesubstantially,showingthatitwasbeingabsorbedadequately.TheresultsshowedasignificantfallinthenumberofheartattacksinthegroupthathadbeengiventhevitaminE.Thenumberofdeathsdidnotdecrease,buttheinvestigatorsnotedthatmostoftheseoccurredatthebeginningofthetrial,sothevitaminEmightnothavehadtimetowork.Otherstudieshavedemonstrated

thatbenefitsfromadministrationofvitaminEneedtimetodevelop.

(18)Anotherdouble-blindstudyshowedthatvitaminE(400mgperday)wasprotectiveagainstheartattacks[208].Theprotectionwasincreasedinthecaseofthosesubjectswhoalsotookaspirin(325mg)daily.

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(19)TheAlpha-tocopherol-beta-carotene(ATBC)study,whichwasprimarilyaninvestigationofcancer[5],alsoreportedontheincidenceofheartattacksamongthesubjects[170].Thestudyinvolved1,862malesmokersinsouthernFinland;eachhadhadoneheartattack.Thesubjectsweredividedintofourgroups.GroupAreceived50mgperdayofvitaminE;groupBreceived20mgperdayofbeta-carotene;groupCreceivedboth;andgroupDreceivedneither.AfterfiveyearsthesubjectsingroupA,whohadtakenonlyvitaminE,hadnodifferenceinfatalheartattacksascomparedwiththecontrolgroupD,butshoweda38percentreductioninnonfatalheartattacks.Butbothgroupswhoweregivenbeta-caroteneshowedsignificantincreasesinfatalheartattacks.InaneditorialintheissueoftheLancet[209]thatreportedtheresults,Stephens,amemberoftheCHAOSteam,pointedoutthattheATBCstudyusedonlyone-tenththedoseofvitaminEthattheCHAOSstudyhadused;moreover,theATBCinvestigatorshadusedsyntheticvitaminEwhereastheCHAOSgrouphadusednaturalvitaminE,whichischemicallydifferent(aswesawinpart1).StephensconcludedthatthebulkoftheevidencesupportstheuseofvitaminE,butnotbeta-carotene,totreatcoronaryheartdisease.Furthermore,instudy1oreportedabove,thesouthernFinnshadanaberrantresult,astheyhadhighbloodlevelsofvitaminCbutalsoahighlevelofheartattacks;inotherstudieshighbloodlevelsofvitaminCareassociatedwithalowincidenceofheartattacks.Theconfoundingfactorinthatstudymighthavebeenthesubjects'veryhighconsumptionoffat.Interestinglyenough,anotherstudyofLappslivinginnorthernFinlandshowedthattheyhadverylowlevelsofheartdisease[129]LappshaveaquitedifferentdietfromsouthernFinns'.TheresearchersattributedtheLapps'lowlevelsofheartdiseasetotheirdiet,whichprovidesrichsourcesofvitaminE,albumin,andselenium.

(20)TheEstablishedPopulationforEpidemiologicalStudiesinthe

Elderlyexaminedtheroleofantioxidantsupplementation(vitaminsEandC)inapopulationof11,178peopleaged67to105.SupplementsofvitaminEaloneweresignificantlycorrelatedwithalowermortalityratefromheartattacks[128].

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Asummaryofdouble-blind,placebo-controlledstudiesisasfollows:

VitaminEappearedtoreducethemortalityratefromheartattacksinonestudy(20)butnotintwoothers(17,19).

VitaminEappearedtoreducethenumberofheartattacksinallfourstudies(17-20).

VitaminCwasnottestedbyitself.

Beta-caroteneappearedtoincreasethemortalityfromheartattacksinonestudy(19).

Instudies21-26thesubjectswerepatientsactuallyundergoinganacuteheartattack.

(21)Singhetal.studied109casesofacutemyocardialinfarctionand182controls[197].TheyfoundthattheplasmalevelsofvitaminsA,C,andEandofbeta-carotenefellduringtheattack.Plasmalevelsofoxidizedfatsrose.

(22)Patientsfollowingaheartattackhadasignificantlyhigherdeathrateiftheirbloodtotal-antioxidantcapacity(excludingalbuminanduricacid)waslow[144].

(23)Inarandomized,double-blindcontrolledstudyof125patientswithamyocardialinfarction,63ofwhomweregivenantioxidants(vitaminA50,000internationalunits;vitaminCIG;vitaminE400mg;andbeta-carotene25mg)fortwenty-eightdaysand62ofwhomweregivenplacebo,thepatientswhoreceivedtheantioxidantshadlesssevereheartattacks(smallerinfarctsize,lesspain,improvedheartfunction,andlowerlevelsofoxidizedfatsintheblood)thandidthosewhohadreceivedplacebo[198].

(24)&(25)Chamiecetal.measuredtheeffectsofvitaminE(600mgperday)andvitaminC(600mgperday)ontheelectrocardiogram

(EKG)afteranacuteheartattackinaplacebo-controlledstudy[31].TheyfoundthattheplacebogrouphadanumberofsignsintheEKGtypicalofaheartattack.TheseEKGchangeswerenotseeninthevitamin-treatedgroup.Inasimilarstudyusinganotherantioxidant(N-acetylcysteineorNAC),thepatientsgiventheantioxidantsshowedlessimpairmentofheartfunctionandlessfatoxidationthandidthepatientsgiventheplacebo.

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THEEFFECTOFANTIOXIDANTSONPHYSICALCHANGESINARTERIES

(26)CoronaryangiographyisanX-raymethodoflookingatthearteriesoftheheart.Hodisetal.usedthismethodon56mengivensupplementsofvitaminsCandEaftercoronarybypasssurgery[88].TheresultswerethatinmildandmoderatecasesthevitaminsledtoasignificantslowingdownofthediseaseprocessinthearteriesasshownbytheX-raypictures.However,thiswasnottrueinseverecases.Theslowingdownofdiseasewaslargelyduetotheintakeofover1oomgperdayofvitaminE.

(27)Asimilarinvestigationwascarriedoutonthecarotidarteriesin1,187people[21].Theinvestigatorsusedultrasoundtomeasureinthelivingpersonthedegreetowhichatherosclerosishadblockedtheartery.HighbloodlevelsofvitaminEwereassociatedwithlessarteryblocking.Also,thereweremoresignsoffatoxidationinthebloodinthosepeoplewithlowbloodlevelsofvitaminE,selenium,andbetacarotene.TheinvestigatorsconcludedthattheirresultssupportaprotectiveroleofvitaminEinheartdisease.

Studies24-27yieldimportantfindingsthatprovidehardobjectiveevidenceofthebenefitsofantioxidanttreatmentinheartdisease.Furthermore,thestudiesinthissection(17-27)withoutexceptiondemonstratethatvitaminEatadosageofaround400mgperdayhelpstopreventheartattacksandlessenstheeffectsofanacuteheartattack.Again,vitaminCseemedtohavelittleeffectexceptasahelperofvitaminE.

(28)Patientsonrenaldialysishavefivetimesthenormalrateofheartattacks,possiblybecausethedialysisprocedureremovesthekeyantioxidantsvitaminCanduricacidfromtheblood.Suchpatientsurgentlyneedtoincreasetheirantioxidantintake.

AnimalstudieshaveshownthatvitaminQ10protectstheliningofthebloodvesselsintheheartagainstoxidativeattack[227].SeveralstudieshavefocusedontheantioxidantvitaminQl0inhumans,ofwhichtwoarereviewedhere.

(29)Kuklinskietal.studied61casesofacutemyocardialinfarction(heartattack)foroneyear[113].HalfweregivenvitaminQ10plus500µgselenium,andtheotherhalfplacebo.Intheexperimentalgroup

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noneshowedanyabnormalityoftheEKG,withnodeathsfromheartdisease.Inthecontrolgroupgivenplacebo40percentshowedanabnormalEKG,andthereweresixdeathsfrommyocardialinfarction.Theauthorsadviseantioxidanttreatmentforallcasesatrisk.

(30)AsimilarbutuncontrolledstudyshowedthatvitaminQ10(75-600mgperday)in424cardiacpatients(averagefollow-uptime,7.8months)wascorrelatedwithclinicalandelectrocardiographicalimprovement[116].Theseauthorsciteseveralpreviousdouble-blind,placebocontrolledstudieswhichshowvitaminQ10tobe"safeandeffective."

THEFRENCHPARADOX.

Nutritionalexpertshaverecognizedforyearswhattheycallthe"Frenchparadox."AlthoughtheFrenchhaveadietrichinfats,cholesterol,andallsortsofdeliciousfoodsthataresupposedtobeverybadforyou,theyalsohavealowrateofheartdisease.Somenutritionistshavesuggestedthatthisisbecauseoftheredwinethattheydrink[69,701].(Ofcourse,theyalsoeatadietrichinprotectivefruits,vegetables,herbs,garlic,andoliveoil.)Redwinecontainspowerfulantioxidantflavonoids(inparticularquercetin,rutin,reservatol,andcatechin).Whitewinecontainslesseramounts.Thesechemicalsarealsofoundintea,onions,andapples.However,itispossiblethattheFrenchparadoxmayalsobedueinparttothehigherintakeofvitaminE,especiallyintheformofsunflowerseedoil.

(31)Hertogetal.inZutphen,Holland,studied805menaged65to84forfiveyears[86].Theymeasuredthetotalflavonoidintake,65percentofwhichcamefromtea,13percentfromonions,and10percentfromapples.Theyfoundthatahighflavonoidintakewasassociatedwithalowerdeathratefromallcauses.ThreeotherstudiesreviewedbyHollmanetal.(theNetherlandsCohortStudy,whichinvolved120,850menandwomen,andtwostudiesinFinland,oneof

whichinvolved5,130menandtheotherwomenand550men)allshowedaprotectiveeffectofhighdietaryflavonoidintakeagainstheartdiseasebutnotagainstcancer[91].Ithasbeensuggestedthatifeveryonedranktwoglassesofredwineadaytherateofheartdiseasewouldfallby40percent.Thismaybe

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somewhatofanexaggeration,butcertainlyflavonoidsareimportantinthediet.Allfourstudiesonflavonoidsheredescribedfoundthemtobeprotectiveagainstheartattacks.

(32)Anotherrecentstudy,whichinvolvedresearchersintenEuropeancountries,hasshiftedthefocusofinterestontolycopene(themainantioxidantintomatoes)[110].Insteadoftheusualbloodlevelstheseresearchersmeasuredthelevelofvariousfat-solubleantioxidantsinthebodyfat(adiposetissue).Thisisalogicalplacetolookforcompoundsthataresolubleinfatratherthaninwateryblood.Theyfound,first,thatlycopeneandbetacarotenelevelsinbloodareaboutthesame,butthatfatcontainsmuchmorelycopene.Next,theyfoundthathighfatlevelsoflycopenewereassociatedwithalesserriskofheartattacks.Thiswasnotsoforalpha-orbetacarotene.Theyalsocommentthatlycopeneisamuchbetterantioxidantthanbetacarotene.Itispossible,therefore,thattomatoesaremoreprotectivethancarrots.

(33)Nitroglycerineisadrugthatiscommonlyusedinthetreatmentofangina.Oneofitsdrawbacksisthattolerancedevelopstoitsactionthatis,dosesthatareinitiallyeffectivedonotremainso.Onerandomized,double-blind,placebo-controlledtrialhasfoundthatvitaminEsupplementspreventthedevelopmentofthistolerance[227].TheresearchersthereforerecommendtheuseofvitaminEsupplementsinpatientswhotakenitroglycerine.

(34)AstudycomparingsmokersandnonsmokersreportsthatpeoplewhosmokecigaretteshavelowlevelsofvitaminsCandEbutnormalantioxidantenzymesintheirredbloodcells.Whensmokershaveaheartattack,theirbodiesrespondwithmoreseverechangesinantioxidantstatus(loweredlevelsofantioxidantenzymesSOD,GSHpx,andCAT,andantioxidantvitaminsA,C,E,andGSH)thanthoseofnonsmokers.Theauthorsofthestudyrecommendthat

smokerstakeantioxidantsupplements,inparticularvitaminsCandE.

BLOODPRESSURE.

Finally,therehasbeenonerandomized,double-blind,cross-overstudyoftheeffectofantioxidantsonbloodpressure.Some30percentofadultsintheWestsufferfromelevatedbloodpressure.

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Galleyetal.inScotlandselectedthirty-eightpatientswithhighbloodpressureandseventeenpatientsfromthesameclinicwithnormalbloodpressure[61].Eachpatientreceivedanantioxidantcocktail(orplacebo)foreightweeks,followedbyatwo-weekwashoutperiod,andthenplacebo(orantioxidantcocktail)foranothereightweeks.ThecocktailconsistedofvitaminC(500mgs),vitaminE(600mgs),beta-carotene(30mgs),andzinc(200mgs).Bloodpressurewassignificantlyloweredinbothgroupsofpatients,butmoresointhosewithhighbloodpressure.Thelattergroupalsoshowedanincreaseinurinaryexcretionofnitrite,ametaboliteofnitricoxide.Theresearchershypothesizedthatthebloodpressurewasloweredbecausetheantioxidantsprotectednitricoxide(whichlowersbloodpressurebydilatingbloodvessels)fromoxidationbythesuperoxideion.Sincehighbloodpressurepredisposestoheartdiseaseandstrokes,theresearcherssuggestedthatthisvitamincocktailmightbeeffectiveinreducingtheincidenceofthesediseases.AstudyoftheeffectsofvitaminQl0onhypertensionshowedthatithadapositiveclinicaleffect[117].Bloodpressurelevelwasreducedandtherewaslessneedforantihypertensivedrugs.

thesestudiesprovidestrongevidencethatvitaminEshouldbetakenatadoseofatleast400mgperdaybyanyonewishingtodecreasethelikelihoodofhavingaheartattack.Thisdosecannoteasilybeobtainedfromdietalone,asonewouldendupeatingtoomuchfat.TheevidenceindicatesthatthisdoseofvitaminEissafe,exceptinthecaseofpeoplewithcertainbloodcoagulationdisorders;itmayresultinasmallincreaseintheriskofhemorrhagicstroke,asdetailedinpart3.AlongwiththevitaminEoneshouldalsotakeanadequateamountofitshelperantioxidants.However,beta-carotenebyitselfshouldbeavoided,especiallybypeoplewhohavehadoneheartattack.WhyistheefficacyofthisdoseofvitaminEnotwidelyacceptedbytheauthorities,includingmanyphysiciansandother

healthprofessionals?Giventheevidence,itisrathersurprisingthatmanyexpertsstillmaintainthattheofficialRDAofvitaminEof20mgperday-twentytimessmallerthantheamountneededtoconferaprotectiveeffectagainstheartdisease-issufficienttocoverallourhealthneeds.Themotivationsandimplicationsofthecurrentpolicieswillbeconsideredlater.

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CANCER

Cancerscanoriginateinalmostallthecelltypesinthebody,andthedevelopmentofcancerisanenormouslycomplicatedprocessinwhichmanybiochemicalsystemsplayarole.Prominentamongthesesystemsarethosethatdamagethecell'sDNA.ManyagentscandamageDNA:ultravioletlight,radiation,cancer-producingchemicalssuchastar,andreactiveoxygenspeciesmolecules.Alargenumberofanimalexperimentsshowthatreactiveoxygenspeciescaninducecancersinvarioussystemsandthatantioxidantscanbeprotective.AlmostallcancercellshavelowlevelsoftheantioxidantenzymesCATandGSHpxandhaveanabnormalregulationoftheseenzymes[150].Asaconsequence,theyaremorevulnerabletooxidativestressandfurtherDNAdamagethanarenormalcells.Indeed,thecancercellsthemselvesshowmuchchemicalevidenceofoxidativestress.Withdefectiveantioxidantenzymes,thesecellscannotproperlyhandlehydrogenperoxide(H202),whichprocess,accordingtoresearchers,''offerstremendouspotentialforcancertherapy"[150].Itispossiblethatnewdrugsmaybedevelopedthatcandetoxifythehydrogenperoxide.Moreover,itispossible,butnotyetestablished,thatantioxidantsmayaffectbiochemicalmechanismsotherthandamagetoDNAthatareinvolvedintheformationandgrowthofcancers.Thesemayincludethecomplexmechanismsthatgovernthedifferentiationandgrowthofcells.

Whatisnowrequiredareexperimentsinhumansthatshowwhetherornotantioxidants,eitherinahealthydietrichinfruitsandvegetablesorgivenassupplements,actuallyhelptopreventoralleviatecancerinpeople.

TheWorkStudyGrouponDiet,Nutrition,andCanceroftheAmericanCancerSocietyhasestimatedthataboutone-thirdofthehalf-milliondeathseachyearfromcancerintheUnitedStatesarea

consequenceofdiet[236].Thus,morethan15o,000deathsayearcouldbepreventedbyasimplechangeofdiet,tosaynothingoftheresultingenormousreductioninhealthcosts.TheWorkStudyGrouprecommendsthefollowingstepstolowercancerrates:eatlessbutconsumeamorevarieddiet;eatmorefruits,vegetables,wholegraincereals,legumes,andnuts;lowerfatintake;drinklessalcohol;avoidsmoked,salt-cured,andnitritepreservedfoods;andtakeantioxidantsupplements(especiallyvitaminE)"incertaincases."

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Therehasbeenanenormousvolumeofclinicalresearchintotheroleofdietincancer.Blocketal.attheNationalCancerInstitutereviewed156epidemiologicalstudiesoftherelationshipbetweenadietrichinfruitsandvegetablesandvariousformsofcancer[17].Theyreportedthatformostcancerssuchadietcutsthecancerrateinhalf.Especiallyfavorablesitesarethelung(aftercontrolforsmoking),inwhich24outof25studieshadpositiveresults;esophagus,mouth,andlarynx(24outof25positive);pancreasandstomach(26outof30positive);colon,rectum,andbladder(23outof28positive);andcervix(11outof13positive).Clearly,fruitsandvegetablescontainsomeagentsthatprotectagainstcancer.Blocketal.concludedthatthehealthylifestylehypothesiswasunlikelytoaccountforthedata.Theyalsostressedthegreatimportanceofthehelpingactionofthelargenumberofdifferentantioxidantsinthediet.

TavaniandLaVecchiaoftheMarioNegriInstituteinMilan,Italy,havereviewedalargenumberofstudiesoftheeffectofdietinaMediterraneanpopulationandconcludedthatfruitsandvegetablesofferastrongprotectiveeffect(61-87percent)againstmanyformsofcancer(betterprotectioninthehigherrespiratoryanddigestivetractsthaninthelowertracts),butnoneagainstcancersofthelymphaticsystem[213].Theevidencesuggestedthatrawvegetableswerebetterthancooked,andvegetableswerebetterthanfruit.

Flaggetal.havesummarizedwhattheyconsideredtobealltheadequatelycontrolledandconductedstudiespublishedbetween1985and1992ontherelationshipbetweendietaryintakeandbloodlevelsoftheantioxidantsbeta-caroteneandvitaminsCandE,andvariousformsofcancer[55].Theyestimatedthestrengthoftheprotectionandwhethertherewasaconsistentrelationshipbetweenhigherbloodlevelsoftheantioxidantsandincreasedprotection(calleda"dose/response"relationship).Theresultsindicatedthattheantioxidantsprovidedgoodprotectionagainstcancerofthelungand

upperrespiratoryanddigestivetracts,someprotectionagainstcancerofthecolonandcervix,butnoneagainstbreastandprostatecancer.Itisgenerallythoughtthatbreastandprostatecancersaremainlycausedbyadisturbanceinhormonalcontrol;thus,thelackofprotectionaffordedbyantioxidantsisnotsurprising.However,onestudyof47,894subjectsinBoston,whichmeasuredcarotenoidsinthediet,found

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thatadiethighspecificallyinlycopene(fromtomatoesortomatopaste)seemedtoprotectagainstthedevelopmentofprostatecancerduringthefouryearsofthestudy[67].

Diplockhasalsoreviewedalargenumberofstudiesontherelationofantioxidantdietaryfactorsandcancer[43].Hefoundthatantioxidantswereprotectiveincancersofthelung,upperrespiratoryanddigestivetracts,stomach,bladder,pancreas,cervix,andovary,butnotincancersofthebreastandprostate.Healsoconcludedthatforcolorectalcancersomeingredientofthedietseemstobeimportant,butitmightbefiberratherthanantioxidants.

Somereportsofprospectivestudiesatfirstsightwouldappeartopaintalessoptimisticpicture.A1996issueoftheNewEnglandJournalofMedicinecarriedtwoimportantpapersandaneditorialthathavehadwidespreadrepercussions.ThefirstpaperrelatedtotheCARETstudy(beta-caroteneandRetinolEfficacyTrial)[154].Thiswasafour-yeardouble-blind,placebo-controlledstudyof18,314malesandfemaleswithahighcancerriskfromsmokingorexposuretoasbestos.Thedosageadministeredtosubjectswas30mgofbeta-carotene(equivalenttofourcarrotsaday)plus25,000internationalunitsofretinol(vitaminA).Theresultswerea28percenthigherincidenceinthetreatmentgroupthanintheplacebogroupoflung(butnotother)cancer,17percenthigherincidenceofmortalityfromallcauses,anda28percenthigherincidenceofmortalityfromheartdisease-leadingtoearlyterminationofthestudy.However,theauthorsadmitthattheycouldnottellwhetherthebeta-caroteneorthevitaminA(orthecombination)wastheculprit.Theyconcludedthatitwouldbeunwisetogivelargedosesofonlyonedietaryantioxidantasthismightleadtoaseriousimbalanceoftheimportanthelpingactionoftheotherantioxidants.Thisisquiteplausiblebecauseoftheimportantsynergisticactionoftheantioxidantvitamins.Theauthorsalsocriticizedmanyoftheepidemiologicalstudiesreportinganapparent

protectiveeffectoffruitsandvegetablesinthedietbecausetheyignore,orfailtocontrolproperlyfor,othervariables,suchasthelevelofintakeoffatsandredmeat,exerciselevels,lifestyle,andsoon,thatmightactuallyhavebeenresponsibleforthereportedresults.Manystudieshave,infact,donetheirbesttocontrolforsuchvariables.

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ThesecondpaperreportedonthecurrentstatusofthePhysician'sHealthStudy[82],whichhaslastedfortwelveyearsandhasinvolved27,071Americanmalephysicians(11percentsmokers;35percentformersmokers;54percentnonsmokers)givenasupplementofbetacaroteneequivalenttotwocarrotsaday.Theresultsshowednoevidenceofanybenefitforcancer,heartdisease,ordeathrate,but,unliketheresultsoftheCARETstudy,therewasnoincreaseoflungcancerevenamongthesmokers.Theconclusionwasthatbetacarotene(atthislowdose)byitselfisuseless,butthatevidencefromotherstudiesindicatesthatvitaminEremainspromising.TheinvestigatorsalsostatethattheincreasedlungcancerriskreportedbytheCARETandATBC(seebelow)studiesisnotconsistentwiththedietaryevidence,andthatthecancer-promotingaction(ifreal)ofbetacarotenemaybeconfinedtoheavysmokers.

Betacaroteneinducesbloodvesselstogrow;becausecancersneednewbloodvesselsinordertoexpand,thiscouldexplainwhyinsomecasesbetacarotenemightpromotetumorgrowth[191].Betacarotene,itisrecommended,shouldnotbegiventopeoplewhohaveahighcarcinogenintake,suchassmokers.Anotherhypothesishasbeendevelopedtoexplainwhybetacarotenemayleadtotheincreaseinlungandprostatecancerreportedbythestudiesreviewedabove[112].TheactiveformofvitaminDhasananticancereffectincertaintissues,whichincludelung,prostate,andcolon.BetacarotenecaninterferewithvitaminDsynthesis.Furthermore,betacaroteneisstoredintheskin,andthismayblockthestimulatingeffectofultravioletradiationonvitaminDsynthesisintheskin.IntheATBCtrialinFinland,345ofthesubjectsdevelopedyellowingoftheskin.Thissupportsthehypothesisthatgivingexcesslevelsofoneantioxidantmayinduceashortageinanotherantioxidant,thusunderliningonceagaintheneedtogivesuchantioxidantsinabalancedformula.So,insmokers,itmightbewisetoaddvitaminDtobetacarotene

supplements.IthasalsobeensuggestedthatthereasonwhybetacarotenedoesnotworkinsmokersisthatthesepeoplehavealowvitaminCstatusand,aswesaw,vitaminCisinvolvedinrecyclingvitaminE[20].Thus,onthishypothesis,smokersneedvitaminsCandEratherthanbetacarotene.

AthirdnegativepaperbytheATBC(Alpha-Tocopherol,BetaCaroteneCancerPreventionStudyGroup)inFinland,inwhich29,137males

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whowereheavysmokersweregiven20mgofbeta-caroteneand50mgofvitaminEperdayforanaverageofsixyearsinadouble-blind,placebo-controlledstudy,reportedan18percentincreaseintheincidenceoflungcancer,moreprostatecancer,andan8percentincreaseindeathsfromallcausesinthevitamingroup[5].However,alaterreportofthisstudyqualifiedtheseresultstosomedegreebyadmittingthattheirfindingsconflictwiththedietaryevidence[13].Additionalfindingsreportedinthisstudyshowedthatthosesubjectswithhigherserumlevelsanddietaryintakeofbeta-caroteneandvitaminEatthestartofthestudyhadalowerriskofdevelopinglungcancer.Furthermore,thevitaminEsupplementsappearedtoprotectagainstprostatecancer(down34percent)andcolorectalcancer(down16percent).Thepeoplewhogotlungcancertendedtobethosewhoalsodrankmoreheavily.Theresearchersconcludedthatlonger,evenlifetime,supplementationwillbeneededtocombatsuchaslowlydevelopingprocessascancer.

TheeditorialthataccompaniedthesereportsintheNewEnglandJournalofMedicineargues(i)thatbeta-caroteneasasolesupplementforcancerpreventioniscontraindicated,(ii)thatthevalueofantioxidantsupplementsingeneralremainsunclear,and(iii)thattheprotectiveeffectofdiet(especiallythestrongevidenceforfruits,vegetables,andgrains)remainsimportant.Buttheeditorialconcludedthatitisanopenquestionastowhethertheantioxidantsinthesefoodsareresponsible.TheconclusiondrawnfromthisapparentdebaclebytheDirectoroftheNationalCancerInstitute,whichfundedthesestudies,was:"Wedonotknowhowtoreplaceahealthfuldietandahealthfullifestylewithsimplepills"[74].

Bothoftheseeditorialcommentsseemtometobeoverreactions.Whenalltheevidenceisconsidered,ratherthanisolatedsectionsofit,severalpointsaboutantioxidantsbecomeclear.Aswehavealreadyhadcausetonoteseveraltimes,antioxidantsshouldnotbegiven

singlybecauseofthestrongevidenceoftheirteamaction.Becauseoverloadingwithonemayupsetthisdelicatebalanceandleadtobadresults,oneshouldbeskepticalaboutsingleantioxidantsforsaleonstoreshelves.Theevidenceclearlyshowsthatantioxidantsshouldnotbeconsumedsinglybutonlyaswell-balancedmixturesofmanyantioxidants.Butitisimportanttoensurethattheantioxidantmixturecontainsenoughofthekey

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antioxidants,inparticularvitaminsEandC.Manymixturesonsalecontaininsufficientquantitiesoftheseantioxidants.However,ifadoctormeasuresantioxidantsinapatient'sbloodandfindsthatoneortwoarelow,itisallrighttotakesupplementsoftheseunderthedoctor'sdirection(moreonthislater).InfairnessitmustbepointedoutthatthesefactswerenotknownadecadeorsoagowhentheNationalCancerInstitutetrialsweredesigned.Noonetodayshoulddesignaprospectivetrialbasedonjustoneoreventwoantioxidants.

Itwouldbewisenottogivebetacarotenebyitselftoheavysmokers.Itisalsounreasonabletoexpectthatantioxidantscouldreversethebadeffectsofmanyyearsofheavysmoking(anaverageofthirty-nineyearsintheFinnishstudy).Moreover,thesubjectsintheFinnishstudyweregivenonly50mgperdayofvitaminE(inadditiontothebetacarotene),whereastheeffectivedosewouldseemtobetentimesasmuch.Inaddition,theyweregivensyntheticvitaminE,whichischemicallydifferentfromnaturalvitaminE,aswesawinpart1.Itmustalsoberememberedthatbothheartdiseaseandcancerdevelopslowlyandprogressivelyoveralongperiod.Thevalueofantioxidanttreatmentcouldbetterbetestedbygivingitearlyoninthepathologyandmaintainingtheeffectivedosageforalongerperiod.OmennhasalsodrawnattentiontotheseflawsinallofthemajorATBC,PS,andCARETstudies:choiceofhighrisk-subjects,choiceofasingleantioxidant,toolowadose,andtooshortatrial[153].InatextbookonantioxidantsPackerandDiplockstatethatthisstudyshouldbe"viewedwithcaution"[155].AstheCarotenoidResearchInteractiveGroupconcluded,"Althoughcarotenoidsshouldnotbeconsidereduniversalpreventersofdisease,itisequallyinappropriatetodownplaybetacaroteneasa'passingfad'"[28].

In1996betacarotenehadapieceofgoodnewsforachange.Omageetal.gaveagroupofnormalwomenadietverylowinbetacaroteneforsixty-eightdays[152].Theyfoundthatthemeasuresforfat

oxidationintheblood(conjugateddienes)wereraisedsignificantlyattheendofthetrial.Theyconcludedthatthisresult"supportsthesuppositionthatbetacarotenemayhaveanimportantroleinantioxidantdefense."

Fourstudiespublishedinthe1990smeasuredbloodlevelsofantioxidantswithrespecttocancerrisk.

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(1)Knektetal.inHelsinkistudied36,265Finnswithaneight-yearfollow-up[107].TheyfoundthatlowplasmalevelsofvitaminEwereassociatedwitha1.5increasedriskforcancer,particularlygastriccancer.Inotherwords,highserumlevelsofvitaminEappearedtoprotectagainstcancer.

(2)Sthelinetal.,inaSwissstudyof2,974maleswithatwelve-yearfollow-up,showedthatlowlevelsofbetacarotenecorrelatedwithhigherrisksforlungandstomachcancer[205].Inthisstudybetacaroteneappearedtoprotectagainststomachcancer.

(3)InastudycarriedoutinMaryland,Comstocketal.tookserumsamplesfrom25,802peoplefrom1974to1975[35].Thesesampleswerekeptfrozenuntil1989,bywhichtime436oftheseindividualshaddevelopedcancer.Theirserumantioxidantlevelswerecomparedwiththoseof765matchedcontrolsfromthegroupwhohadnotdevelopedcancer.TheresultswerethathighbetacaroteneandvitaminElevelswereassociatedwithastrongprotectiveeffectagainstlungcancer.Lycopene(theantioxidantfromtomatoes)showedastrongprotectiveeffectagainstpancreaticcancer.However,thisstudywasbasedononlyoneblood-levelmeasurementofnutrients,andthesebloodlevelsareliabletofluctuateaccordingtothediettakenovertheperiodbeforethemeasurement.Inanotherstudyplasmalevelsofantioxidants(vitaminsCandE,urate,andglutathione)wereshowntobelowingastriccarcinomapatients,andthemeasuresoffatoxidationwerehigher.Butwecannotdeducefromtheseresultswhetherthelowplasmalevelsofantioxidantscontributedtothecauseofthecancerorwerearesultofit.

(4)Last,Ziegleretal.measuredthelevelsofsixcarotenesinapopulationofJapaneseHawaiiansinrelationtotheriskofdevelopingcancerofthelung,esophagus,larynx,throat,andmouth[244].Theyfoundthatlowlevelsofalpha-carotene,betacarotene,beta-

cryptoxanthin,andlycopenecorrelatedwithahighincidenceoflungcancer.Thiswasparticularlytrueinthecaseofalpha-carotene(morethanbetacarotene).Othercancerscorrelatedwithlowlevelsofalpha-carotene,betacarotene,andbeta-cryptoxanthin.Theyconcludedthatothercarotenoids,notonlythebetter-knownbetacarotene,appearedtobeimportant.

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Thus,tosummarizethesefourstudies:

VitaminEwasprotectiveintwostudieswhereitwasmeasured(1,3).

Beta-carotenewasprotectiveinthreestudies(2,3,4),althoughinstudy(4)othercarotenesweremoreprotectivethanwasbeta-carotene.

Twoleadersinthisfield-HelenWisemanandBarryHalliwellofKing'sCollege,London-havepublishedareviewofthemechanismsbywhichreactiveoxygenspeciespromotecancer[234].Theynotethat"itisincreasinglyproposedthatreactiveoxygenspeciesandreactivenitrogenspeciesplayakeyroleincancerdevelopment,especiallyasevidenceisgrowingthatantioxidantsmaypreventordelaytheonsetofsometypesofcancer."Antioxidantsmayhelppreventcancerdevelopmentby(i)preventingstructuraldamagetoDNA;(ii)affectingthemechanismbywhichcellscommunicatethroughchemicalsignals;(iii)affectingtheactivityofgenesandproteinsthatrespondtostressandthatacttoregulatethegenesinvolvedincancerouscellgrowth.

SOMEINDIVIDUALCANCERS

STOMACHCANCER.

Severalwell-conductedstudieshaveshownthatvitaminCsupplementshaveastrongprotectiveeffectagainstcancerofthestomachandesophagus.ButrecentdatasuggeststhatthismayhavelesstodowiththeantioxidantpropertiesofvitaminCandmoretodowiththefactthatvitaminCcanneutralizethepotentcancerproducingnitrosaminesfoundinthestomach.Nitrosaminesarederivedfromsmoked,cured,orspicyfoods,whichshouldthereforeeitherbeavoidedortakeninsmallquantities.Infouroutoffivestudies,

vitaminCsupplementsreducedthelevelsofnitrosaminesingastricfluid,reducedtheexcretionoftheirmetabolicendproductsintheurine,loweredtheabilityofthegastricfluidtoinducemutations(aprecancerousstep),andraisedthelevelofactivityofDNArepairenzymesthatprotectagainstcancer.

Bukinetal.havestudiedpatientswithintestinalhyperplasia,aprecancerousconditionofthestomach[25].Inthisconditionthestom-

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achtissuecontainsraisedlevelsofaprotooncogeneODC(ornithinedecarboxylase),whichplaysaspecificandimportantroleinpromotingtheformationoftumors.Theinvestigatorsconductedadouble-blind,placebo-controlledstudyoftheeffectonthetissuelevelofthisprotooncogeneofgivingvitaminE(400mgperday)andbeta-carotene(20mgperday)topatientsoveraone-yearperiod.BiopsiesofthestomachliningshowedthatvitaminEreducedODCactivityby65percentbytheendoftheyear,andbeta-carotenereducedODCactivityby50percent.Inthegroupreceivingplacebo,therewasnosuchreduction.ExaminationoftheareasofintestinalmetaplasiainthestomachrevealedthatvitaminEproducedsignificantshrinkageofthemetaplasticareasintenoutoffourteenofthepatientsinoneyear.Beta-caroteneproducedsignificantshrinkageinnineoutofeighteenpatients.Therewasnoshrinkageoftheseareasinthepatientstakingplacebo.Thisstudymayillustrateanimportantpoint,namelythatantioxidantsaremorelikelytobeeffectiveduringtheprecancerousstagethanduringthestageafterthedevelopmentofanactualcancer.

BREASTCANCER.

Mostofthestudiesinthisareahaveyieldedconflictingornegativeresults.AgoodreviewhasbeenprovidedbyKimmicketal.[104].Threeofspecialinterestwarrantdescription.Onestudy,inwhichtherewere262casesofbreastcancerand273normalcontrols,suggeststhatthetypeofbreastcancermaybeanimportantfactorindeterminingtheresponsetoantioxidanttherapy[4].Thecancerpatientsweredividedintotwogroups-thosewithnegativeandthosewithpositivefamilyhistories.TheintakeofvitaminsCandEandbeta-carotenefromdietaryhistorieswasestimated,anditwasfoundthatinthegroupwithanegativefamilyhistory,beta-caroteneappearedtobeprotective,whereasvitaminsCandEwerenot.Inthegroupwithpositivefamilyhistories,however,vitaminEseemedtobeprotective,whereasbeta-caroteneandvitaminCwerenot.

Freudenheimetal.studied297patientswithbreastcancerand311normalcontrols[58].Theinvestigatorsacceptedthenotionthatadietrichinfruitsandvegetablesprotectsagainstbreastcancerandsetouttodeterminewhichantioxidantsinthesefoodswereimportant.TheirresultsshowedthatadietrichinvitaminsCandE,andthecaroteneslutein

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andzeaxanthinaswellasfiberderivedfromfruitsandvegetables,reducedtheriskofbreastcancer,whereasbeta-cryptoxanthin,lycopene,andfiberderivedfromgraindidnot.Themostimportantfactorsinreducingriskwerethetotalamountoffruitsandvegetableseatenand,amongindividualitems,carotenes,lutein,andzeaxanthin.Theauthorsstressedthatalltheseindividualcomponentsprobablyhaveateameffectandthatthereareprobablyrelevantfactorsinfruitsandvegetablesofwhichwearestillunaware.

Lockwoodetal.carriedoutatwo-yearsurveyof32patientswithbreastcancerthathadspreadtotheaxillarylymphnodes[127].TheygavetheANICAprotocol-amixtureofantioxidantsandminerals(includingbetacarotene,vitaminsCandE,selenium,gamma-linoleicacid,and90mgofvitaminQ10)-andfoundthatnopatientsdied(theexpectednumberwasfour);noneshowedfurthermetastasesorweightloss;theneedforpainkillerswasreduced;andsixpatientsshowedapparentremission.Theauthorsrecommend300mgperdayofvitaminQ10toattainabloodlevelof20µg/ml.Thewidemixtureofantioxidantsmaybeakeytotheirapparentsuccess.

However,otherinvestigationshaveyieldedconflictingornegativeresults.Wecanonlyconclude,onthebasisofpresentevidence,thatbreastcancerdoesnotrespondconsistentlytodietarymanipulation,whichconfirmstheearlierdatafromepidemiologicalstudies.Thismaybebecausebreastcancer(aswellasprostatecancer)isgreatlyinfluencedbyhormonalfactors.Also,cancerislikelytobeagroupofrelateddiseaseswithdifferentpathologies.Clearly,morestudiesusingawidemixtureofantioxidants,likethoseofLockwoodetal.[127],shouldbeundertaken.Thisconclusionissupportedbyareviewthatstatesthathumanstudiesare"limitedbutpromising"andrecommendsthatantioxidantsshouldalwaysbegivenasacomprehensivemixture[104].

LUNGCANCER.

Ziegleretal.attheNationalCancerInstituteconcurthatthereisconvincingevidenceoftheprotectiveactionoffruitsandvegetablesagainstlungcancerbutnoconvincingevidenceastowhichindividualantioxidantsmaybeimportant[243-245].However,thesameresearchgroupinapopulation-basedstudyofcarotenesinsmokersfoundthatadiethighinfruitsandvegetableswassignificantlyprotectiveagainst

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lungcancer,buttheyconcludedthatbetacarotenewasnotthedominantfactor[246].Intakesofalpha-carotene,yellowandorangevegetables,anddarkgreenvegetables(whichcontainluteinandzeaxanthin)wereeachmorepredictiveofreducedlungcancerriskthanwastheintakeofbetacarotene.TheNetherlandsCohortStudyonDietandCancer,aprospectivestudyofmorethan100,000Dutchmenandwomenovera6.3-yearperiod,showedasignificantcorrelationbetweentheamountofvegetablesinthediet(excludingpotatoes)andalowlungcancerrate[71].Themostprotectivevegetableswerecauliflower,endive,andlettuce.Alowconsumptionoffruit(especiallycitrus)wasassociatedwithincreasedlungcancerrisk.

Thecomplexityofthisfieldisillustratedbytworeportspublishedina1997issueoftheAmericanJournalofEpidemiology.Thefirst,byYongetal.,wastheprospectiveepidemiologicalNHANESIstudyof3,968menand6,199womenaged25to74yearswithamedianfollow-upofnineteenyears[238].TheymeasuredtheintakeofantioxidantvitaminsduringthistimeandfoundthatvitaminCwashighlyprotectiveagainstlungcancer.ThequarterofpeoplewiththehighestintakeofvitaminC(computedfromananalysisofthediet)hadsignificantlylowerratesoflungcancerwhencomparedwiththequarterofpeoplewiththelowestintake.However,noadditionalprotectionseemedtobegainedbytakingsupplements.VitaminEandcaroteneswereprotectiveonlyamongpeoplewhowerecurrentsmokers.TheauthorsadmitthattheirfindingcouldbeexplainedbytheusualcomplicationthatpeoplewhotookmorevitaminCintheirdietalsowerethosewithgenerallyhealthierlifestyles,andthatitwasperhapsthelatterfactorthatwasprotectiveagainstthedevelopmentoflungcancer.However,theresearchersalsofoundthatwhenvitaminsCandEandcarotenoidsweretakentogether,theprotectiveeffectwasmuchincreased.Itseemsunlikelythatpeoplewhotakeallthreevitaminswouldhaveamuchhealthierlifestyleascomparedwith

thosewhotakeonlyoneantioxidantasasupplement.Thus,itseemsmorelikelythattheprotectiveeffectisgenuineandexemplifieswhathasbeenstressedsoofteninthisbook-theimportanceoftakingabalancedmixtureofantioxidants.

ThesecondreportwasbyKnektetal.fromFinland[1o8].Theystudied9,959Finnishmenandwomenaged15to90whowereinitially

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cancerfree.Adietaryhistorywasobtainedwithafollow-upperiodoftwenty-fouryears.Duringthistime997ofthegroupdevelopedcancer,andofthese151noapparentprotectiveeffectbyvitaminsCandEorbetacarotene,butaverystrongprotectiveeffectbyflavonoids.Thisprotectiveeffectwasforlungcanceronly.Themainsourceofflavonoids(inthiscasequercetin)intheFinnishdietisapplesandonions.(Finnsdrinklittleteaorredwine.)TheresearchersnotedthatapplesareapoorsourceofvitaminCandbetacarotene.TheyalsonotedthatFinnsingeneralhadaverylowintakeofflavonoidsascomparedwithpeopleelsewhere.Oddly,thebenefitseemedtobegainedfromapplesandnotonions.Aswehavealreadyseen,Finns,atleastsouthernFinns,seemtoreactdifferentlythandootherpopulations[5,174,175].Theirveryhighintakeoffatsandalcoholmaybeimportantcomplicatingfactors.

AnotherstudyonsmokersfoundthataddingvitaminE(100-200mg),withorwithoutvitaminC(500mg),hadnoeffectontheincreasedrateofexcretionintheurineofachemicalderivedfromoxidativelydamagedDNA[166].Theinvestigatorssuggestedthatcancer-protectingeffectsoffruitsandvegetables(atleastinsmokers)mayresultfromotheranticanceragents,suchasflavonoidsandpolyphenols,inthesefoods.Itisthereforeencouragingthatcompanieswhomakeantioxidantsupplementshavestartedaddingflavonoidsandpolyphenolstotheirpills.

COLORECTALCANCER.

Kampmanetal.studiedtheeffectofvegetablesandanimalproductsoncoloncancerriskinDutchmenandwomen[99].Theyfoundthatvegetablesreducedtheriskinbothmenandwomen,whereasredmeatincreasedtheriskinwomen.Otherstudiesoncolorectalcancerhavefailedtoachieveconsistentresultswithindividualsupplements.Someotherfactororfactorsotherthanantioxidants,suchasfiberinadiet

highinfruitsandvegetables,mayaccountforthereductionofincidenceofcolorectalcancers.

UTERINECANCER.

Again,thedatarelatingtothevalueofindividualsupplementsisconflicting.Moreover,loweringserumestrogens,achievedthroughavegetariandiet,maybemorerelevantthanantioxidantactiononestrogen-relatedcancers(e.g.,breastanduterus).Theepidemiologi-

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calevidencethatadiethighinfruitsandvegetablesappearstobeprotectiveagainstthedevelopmentofcervicalcancerwasquotedearlier[17,43]

ORALCANCER.

AreviewbyGarewalandDiplockstatesthat''allavailableevidencesupportsasignificantroleforantioxidantnutrientsinpreventingoralcancer"[62].Theyrecognizethatalcoholandtobaccouseaccountforsome75percentoforalcancerintheWest.Inepidemiologicalstudiesoftheroleofcarotenoidsinlaryngealcancer,fouroutoffourwerepositive;inoropharyngealcancernineoutofninewerepositive.Insimilarstudiesoftheprecancerousconditionofleukaplakia,eightoutofeighttrialsyieldedpositiveresults.Inaclinicaltrialusingdailydosesofbeta-carotene(30mg),vitaminC(IG),andvitaminE(800mg)in79patientswithoralcancer,55percentreportedclinicalimprovement[101].Gridleyetal.oftheNationalCancerInstitutestatethatvitaminEprotectsagainstoralandpharyngealcancer[75].

CONCLUSIONONCANCER.

Thereisavastbodyoflaboratorydata,invitroandinanimals,showingacloseconnectionbetweenreactiveoxygenspecies,oxidativestress,andtheinitiationandprogressofcancer.AsstatedbyFrankeetal.,"evidencefortheinvolvementofendogenouslygeneratedfreeradicalsandoxidantsincarcinogenesisandotheragingrelateddiseasesiscompelling"[57].Althoughthereisgeneralagreementthatadietlowinsaturatedfatsandhighinfruitsandvegetablesisofcrucialimportanceinthepreventionofmanyformsofcancer,thereisstillagreatdealofdisagreementastowhattherelevantagentsinfruitsandvegetablesare.Thereisalsowidespreaddisagreementaboutthevalueofantioxidantsupplements.However,throughallthismurkageneralpicturearises.Somecancers-oral,upperrespiratorytract,lung,andhighergastrictract-seemtobemore

amenabletopreventionbydietarymeansthanothers-breast,uterus,prostate,andbloodcell.Moreover,dietarymechanismsotherthanantioxidantactionappeartobeimportantinsomecases-forexample,theantinitrosamineactionofvitaminCinthecaseofstomachcancerandtheactionofdietaryfiberincolorectalcancer.Butitremainsclearatthistimethatadietrichinavarietyoffruitsandvegetableswinshandsdownoveranyvitaminsupplements.Such

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adietprobablyprovidesmanyanticanceragentsbesidesantioxidantsaboutwhichweasyetknowlittle.Tobenefitfromtheprotectiveeffectsofdietarychemicalsitisbesttodowhatyourparentstoldyou-eatyourvegetables.

DISEASESOFTHENERVOUSSYSTEM

Thebrainisparticularlyvulnerabletooxidativestressforseveralreasons:

1.Itusesoxygenatafasterratethananyothertissue.

2.Itscellularmembraneshavehighlevelsofeasilyoxidizablefat.

3.IthasnaturallylowlevelsofthetwoantioxidantenzymesCATandGSHpx.

4.Nervecellsthatarekilledcannotbereplaced,unlikeothercellsinthebody.

5.Severalofthebrain'schemicals,calledneurotransmitters,thatareusedassignalsbetweennervecellsinducebiochemicalreactionsthatleadtothereleaseofreactiveoxygenspecies.

VitaminC(alsoknownasascorbicacidorascorbate)hasmanyfunctionsinthebrainunrelatedtoitsvitamineffectinpreventingscurvy(whichhastodowithbuildingupconnectivetissueintherestofthebody).ThebrainhasveryhighlevelsofvitaminCandaspecificmechanismforpumpingitoutofthebloodintobraincells.BrainvitaminCplaysaroleinthesynthesisandreleaseofmanyneurotransmitters,anditalsohasanimportantroleasthemainwater-solubleantioxidantinthebrain.

Thefollowingbraindiseasesareassociatedwithoxidativestress.

STROKE.

Astrokeresultsfromtheblockageofanarterytothebrain.Atfirstthebrainsuffersfromlackofoxygen.Thisiscalledtheischemicstage.Then,whenthebloodreenterstheaffectedregionofthebrain(calledthereperfusionstage),moredamageiscausedbylargequantitiesofreactiveoxygenspeciesthatarereleased.Theseareprimarilyresponsibleforthebraindamagesufferedbythestrokevictim.Itisthereforepossiblethatantioxidants,iftheycanbegivensoonenough,maypreventsomeofthisdamage.

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DOWN'SSYNDROME.

Down'ssyndromeisassociatedwiththeoverproductionofoneformofreactiveoxygenspecies-hydrogenperoxide-owingtoageneticfaultintheantioxidantenzymesuperoxidedismutase(SOD)(seepart1)thatmakeshydrogenperoxide.ThesepatientshaveanextracopyofthegeneforSODonchromosome21.Thismayseemparadoxical-whyshouldanantioxidantenzymemaketoomuchofanoxidantlikehydrogenperoxide?TheansweristhattheSODactsonthestronglyoxidantsuperoxideionandturnsitintoweaklyoxidanthydrogenperoxide.Thelatteristhendetoxifiedbythesecondenzymecatalase(CAT),whichthusactsintandemwithSOD.InDown'ssyndrome,thebrainleveloftheenzymethatdetoxifieshydrogenperoxide-CAT-isincreasedinresponsetotheSOD-inducedoverproductionofhydrogenperoxide.ButevenwiththeelevatedCATactivity,theoverallexcessofhydrogenperoxideisharmfultobraintissue.

ALZHEIMER'SDISEASE.

ThebraininAlzheimer'sdiseasehastwoneuroanatomicalabnormalitiesvisibleunderthemicroscope.Onetypeconsistsofroundblobscalledplaques,theotherofmassesofproteinfilamentscalledneurofibrillarytangles.

TherearetwomaintypesofAlzheimer'sdisease,onewithageneticbackgroundandtheotherwithout.SomecasesofAlzheimer'sdiseasearecausedbyadefectivegeneonchromosome14thatcodesfortheproductionofaproteincalledpresinilin-I.Thisproteinformsanintegralpartofnervecellmembranes.Cellscontainingthisabnormalgenearemuchmorevulnerablethannormalcellstooxidativestress.

ThebraininAlzheimer'spatientsshowsevidenceofoxidativestress,withdamagetobrainproteinsbeingpronounced[73].Anabnormaltoxicbrainprotein-beta-amyloid-concentratesinplaquesandistoxic

tonervecellsbyareactiveoxygenspecies-basedmechanism.Thismechanismincludesactivationoftheenzyme(calledprostaglandinHsynthase)thatstartsthesynthesisofinflammation-producingprostaglandins.Levelsofthisprostaglandin-producingenzymearegreatlyraisedinsidethedamagednervecellsinthedisease.Inresponsetothis,thelevelsoftheantioxidantenzymeglutathioneperoxidase(GSHpx)inthebrainisraisedtocombattheincreasedoxidativestress.Butanotherantioxidantdefense-beta-carotene-getsoverwhelmed,soitslevelsfall.Inthe

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cerebralcortexofthebraininAlzheimer'sdiseasethereisalsoevidenceofincreasedfatoxidation.Thus,thebraininAlzheimer'sissubjecttoanintenseinflammatoryprocessmediatedinpartbyexcessproductionofreactiveoxygenspecies.

Thereisnowconsiderableevidencetosuggestthatnonsteroidalanti-inflammatoryagents,suchasaspirinoribuprofen,maypreventordelaytheinitialonsetofsymptomsofAlzheimer'sdisease.Outofsixteenstudiesonthistopic,fifteenhadpositiveresults.McGeeretal.conductedananalysisofseventeenepidemiologicalstudiesandfoundasignificantcorrelationbetweentheuseofanti-inflammatorydrugsandprotectionagainstAlzheimer'sdisease[133,1341].Thediscoveryofthiscorrelationwasmadebyaccident.Aseriesofpatientswithrheumatoidarthritiswerebeingtreatedinalong-termstudywithanti-inflammatoryagents.ThephysiciansweresurprisedtodiscoverthatfewerofthesepatientsdevelopedAlzheimer'sdiseasethanwasexpected.Manypeopletakeanaspirinaday,asthishasbeenshowntoreducetheriskofheartattack.Itnowseemslikelythattakinganti-inflammatoryagentsmayalsoreducetheriskofgettingAlzheimer'sdisease.Anti-inflammatoriesinhibittheenzymethatmakestheinflammation-producingprostaglandins;thisreactionisalsoapotentproducerofbrain-damagingreactiveoxygenspecies.Thus,itisreasonabletosuggestthatantioxidantsmayhelphere,too,althoughfurtherstudiesareneeded.InthecaseofapatientwhowasunfortunateenoughtohavebothAlzheimer'sdiseaseandaformofcancerknownasmultiplemyeloma,thepowerfulimmunosuppressantsandanti-inflammatoryagentsgiventohimforthetreatmentofhiscancerproducedasignificantimprovementinhisAlzheimer'sdiseasefortwoyears,untilhisdeathfromthecancer[102].

TheNewEnglandJournalofMedicinereportedtheresultsofadouble-blind,placebo-controlled,randomizedtrialofvitaminE(2G

perday),orthedrugselegiline(whichcutsdowntheproductionofreactiveoxygenspeciesinthebrain),oracombinationofthetwo,in341casesofmoderateAlzheimer'sdiseaseinamammoth,twenty-three-centerstudyovertwoyears[183].Practicalindicatorsweremeasuredsuchastheneedforhospitalization,lossofabilitytoperformtheactionsneededfordailyliving,developmentofseveredementia,anddeath.TheresultsshowedasignificanttherapeuticeffectforbothvitaminEandforselegilinein

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preventingthefurtherdevelopmentoftheillness.However,thecombinationofthetwodidnotconferanyaddedbenefit.Inthesameissue,DrachmanandLebercommentedonthispaper,pointingoutsomecaveats.TheyagreedthatitisnowjustifiedtotreatthisstageofAlzheimer'sdiseasewitheithervitaminEorselegiline(butnotboth).ButthestudydidnotaddressthequestionastowhethervitaminEwouldpreventordelaythesubsequentdevelopmentofAlzheimer'sdiseasewhengiventoyounger,apparentlynormalpeople.Anydouble-blind,placebo-controlledstudydesignedtoanswerthisquestionwouldbeenormouslydifficultandexpensivetocarryout.ThisstudysuggeststhatvitaminEmaybeofbenefitincasesofestablishedAlzheimer'sdisease,presumablybecauseofitsantioxidantproperties.Thereisnowabundantevidenceofpowerfuloxidativestressinthedisease.Sincethereiseveryscientificindicationthatantioxidantsaremoreeffectivewhengivenbeforetheoxidativestresshasproducedactualcellulardamage(seealsothesectionondiabetes),thenmedicalcommonsensesuggestsgivingpeopleatriskforAlzheimer'sdiseasevitaminEsupplements(ataround400-800mgperday).Thislevelwilldothemnoharmifsomeelementaryprecautions,relatingtovitaminKandhemorraghicstroke(seepart3),arefollowed.

PARKINSON'SDISEASE.

Parkinson'sdiseaseiscausedbythedestructionofcertainnervecellsinapartofthebraincalledthesubstantianigra(or"blacksubstance,"socalledbecausethesenervecellscontainlargeamountsoftheblackpigmentneuromelanin).Thesecellsuseachemicalcalleddopamineastheirneurotransmitter.Withinthecellsofthesubstantianigra,dopamineiseasilyoxidizedtoformaredsubstancecalleddopaminochrome,which,inturn,formsneuromelanin.Thisprocessreleasesalargeamountofreactiveoxygenspecies.Inaddition,dopaminochromeishighlytoxictonervecells.Atbirththecellsof

thesubstantianigracontainnoneuromelanin;rather,itgraduallyandsteadilyaccumulatesduringlife.Normallyneuromelaninisusefulinthatitgetsridofthetoxicdopaminochrome.Italsobindsandneutralizestoxicheavymetalatomssuchasironandmanganese.However,inexcess,ititselfbecomestoxicanddestroysthenervecell.Whenacriticalmassofthecellsinthesubstantianigrahavebeendestroyed,Parkinson'sdisease

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results.Inthisdisease,thereissevereoxidativestressinthesubstantianigrawithexhaustionofglutathione.(Recallfrompart1thatglutathioneisthemainantioxidantinsidethecellsofthebrain,whilevitaminCisthemainantioxidantinthewateryfluidbetweenthecells.)Hydrogenperoxidealsointerfereswiththestorageofdopamineinsidethecellsinthesubstantianigra[48].Dopamineinsideitsstoragevesiclesisprotectedbyantioxidantsfromoxidation;butdopamineoutsidethesevesiclesismoreliabletooxidation,becauseinthislocusithaslessantioxidantprotection.Glutathionescavengeshydrogenperoxide,so,whenitslevelfalls,hydrogenperoxidelevelsriseanddopaminecannotbestoredproperly.Itthusbecomesmorevulnerabletoconvertbyoxidationtodopaminequinones,poisonouscompoundsthatdamagethecells.Becausethecellsofthesubstantianigracontainthemajorpartofthedopamineinthebrainandsupplyittotherestofthebrain,theirdestructionleadstothesymptomsofdopaminedepletion.Thesearetremor,rigidity,andmentalimpairment-thesymptomsofParkinson'sdisease.

ThecurrentprincipaltreatmentofParkinson'sdiseaseistoadministerL-DOPA,theprecursorofdopamine.Inthebrain,L-DOPAistakenupandturnedintodopaminetoreplacethedopaminemissingintheParkinsonianbrain.However,thebeneficialeffectsofL-DOPAtreatmentlastonlyashorttime:thebasicdestructiveprocesscontinues,withthedopaminecellsinthesubstantianigrabeingkilledoffatasteadyrate.AfteraboutfiveyearsthediseaseprogressestoaconditionasprofoundasifL-DOPAhadneverbeenadministered.Clearlywemustdeveloptherapydesignedtopreventthekillingofthesecellsandnotmerelysupplybyartificialmeanstheproduct(dopamine)thattheymake.Aswithdiabetes,forwhichthemaincurrenttherapyisinsulin,thetreatmentstrategysupplieswhatismissingbutdoesnotaddressthemainproblem,whichistopreventthedestructionoftheinsulin-producingbeta-cellsofthepancreasthat

causedthediseaseinthefirstplace.

IfParkinson'sdiseaseisdueinparttooxidativestress,itwouldbelogicaltotryantioxidanttherapyinanattempttodelayorpreventParkinson'sdisease.Moreover,L-DOPAitselfisalsometabolizedinthebraintothetoxiccompounddopachrome,whichcanfurtherdamagethebraincells.Forthisreason,Menaetal.advocatevitaminCsupplementsduringL-DOPAtherapy[140].Parkinson'ssufferersalsohaveahigherinci-

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denceofheartdiseasethandonormals,possiblybecauseofthesameraisedlevelofoxidativestress.

PeoplewithParkinson'sdiseasetypicallyhavenormalbloodlevelsofvitaminsA,C,andE,andScheideretal.haveclaimedthatthereisnocorrelationbetweenthediseaseandthepreviousintakeofantioxidantvitamins[188].AcontraryresultwasobtainedbydeRijketal.[41]inastudyof5,342subjectsaged55to95.Asemiquantitativefood-intakequestionnairewasgivenfrom1990to1993.Thirty-onesubjectssubsequentlydevelopedParkinson'sdisease;theyhadasignificantlylowerintakeofvitaminE,butnotvitaminCorflavonoids,thandidthosewhodidnotdevelopParkinson'sdisease.AnothersuchstudyinHawaiiproducedthesameresult.

TherehavealsobeensomestudiesoftreatmentofcasesofestablishedParkinson'sdiseasebyantioxidants,buttheresultshavebeeninconclusive.However,thedamagetothepigmentedneuronsofthesubstantianigrastartsatleastfiveyearsbeforetheearliestclinicalsymptomsofParkinson'sdiseaseshowthemselves.Therefore,givingantioxidantstopatientsalreadywithsymptomsmaybeacaseofshuttingthestabledoorafterthehorsehasgone.AsthereisatpresentnowaytoidentifywhichpeoplewilldevelopParkinson'sdiseasefiveyearslater,theonlywaytoapplythisstrategywouldbetoraisetheantioxidantintakeforeveryoneovertheageof40.

MOTORNEURONDISEASE.

Motorneurondiseasegoesbyseveralnames.ManyknowitasLouGehrig'sdisease;themedicaltermisamytrophiclateralsclerosis,orALS.ThephysicistStephenHawkingsuffersfromALSandhasbeenalong-termsurvivorofthedisease.Mostpatientsdiewithinthreetofiveyearsofdiagnosis.Itiscausedbyaselectivedeathofthelargemotornervecellsinthespinalcord.Withoutthetransmissionofmotorsignalstothemuscles,widespreadparalysisresults.Thereare

twoformsofthedisease,geneticandsporadicornongenetic.Intheformertype,thegeneatfaultistheoneformakingtheantioxidantenzymeSODandisfoundonchromosome2.Thebraininthesecasesshowslowerantioxidantdefensesandchemicalsignsofincreasedfatoxidation.

ReiderandPaulsontelltheinterestingstoryofhowvitaminEwasusedsomefiftyyearsagototrytotreatALS[173].Thepatientsincluded

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thefamousbaseballplayerLouGehrig,alaswithoutbenefit.However,theseresearcherssuggestthat,nowthatsomecasesofthediseasehavebeentracedtoageneticallyabnormalantioxidantenzyme(SOD),thesemayrepresentasubtypeofthediseaseandthatfurthertrialsareindicated.

HUNTINGTON'SDISEASE.

Huntington'sdisease,alsoknownasHuntington'schorea,ischaracterizedbyprofounddementia,abnormalemotionalreactions,disturbedbehavior,andinvoluntarymovementscalledchorea.Itiscausedbyamutationinadominantgeneandischaracterizedbyseverenerve-celllossinthebasalgangliaandpartsofthecerebralcortex.Thebasalgangliaarestructuresinthebrainthatcontroltheprogrammingofvoluntarymovements.Withintheaffectedbraintissues,theenzymesinthemitochondriathatprovidetheenergythecellneedsareseverelyaffected.DNAremovedfromanaffectedpartofthebrainofapatientwithHuntington'sdiseaseshowsanabnormalchemicalchangethatwasbroughtaboutbyattackbyareactiveoxygenspecies[23].

SCHIZOPHRENIA.

Thisisasevereillnessthataffectsoneineveryhundredpeople.Itischaracterizedbyhallucinations,delusions,paranoia,andemotionaldisturbances.Itusedtobethoughtofasapsychologicalillness,butwenowknowthatitisanorganicdiseaseofthebrain[202].Therearetwotypesoftheillness.TypeIshowsacute"positive"symptomssuchashallucinationsandexcitement.Ithasastronggeneticcomponent,respondswelltotreatmentwithantipsychoticdrugs,andthebrainshowsnosignsofphysicaldegenerationonascan.TypeIIischaracterizedby"negative"symptomssuchassocialwithdrawalandapathyandrespondspoorlytomostmedicinesexceptclozapine,anatypicalantipsychoticdrug.IntypeIIcasesthereisnogenetic

componentbutthebraintypicallyshowssignsofphysicaldamageonascan.

ModerntechniqueshaveshownatthemicroscopiclevelthatthebrainintypeIIschizophreniahasbeendamaged.Inmanybrainregionstherearefewernervecellsthannormal;inafewareasthereappeartobetoomany;and,inotherkeyareas,thereisalossoftheinterconnectionsbetweencells.Becausethejobofthebrainisconductedmainlybyneuronssendingeachothersignals,lossofpartofthenetworkthatcarriesthesesignalscanhaveseriousconsequences.

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Inthissystem,ifthenumberofconnectionsbetweenneuronsisreducedbelowacertainlevel,neuralcomputationscannotproceednormally,andphenomenacalledparasiticfocidevelopinwhichacertaincomputationentersintoaviciousrepetitivecyclethatcannotbechangedbyexternalinfluences;inthehumanbrainaffectedbyschizophrenia,delusionsandhallucinationsresult.

Howarethesekeyconnectionslostinschizophrenia?Inordertounderstandthemechanism,wemustdiscusssomespecificsofwhathappensattheseconnectionsbetweenneurons.Thegapbetweentheendofoneneuralprocess(oraxon)andthenextneuroniscalledasynapse.Thechemicalthatcarriesthemessagefromoneneurontothenextacrossthisgapiscalledaneurotransmitter.Neurotransmitterscaneitherbeexcitatoryorinhibitory.Excitatoryneurotransmitters,whenreleasedacrossthesynapse,causethesecondneurontofire.Inhibitoryneurotransmitters,whenreleased,causeittostopfiring.InthebrainintypeIIschizophreniathereisa50percentlossofexcitatorysynapses.

Themainexcitatoryneurotransmitterinthehumanbrainisachemicalcalledglutamate,morefamiliarasthemonosodiumglutamateusedinmuchAsiancooking.Glutamateisaverytoxicmolecule,anditisremarkablethatthebrainusesitforsuchakeyroleinneurotransmission.Yetthistoxicityhasafunction.Glutamateexertsitstoxicactiononnervecellsbymeansofthereactiveoxygenspeciesitgeneratesinthesecond(postsynaptic)neuron.Thisprocessisoneofthewaysinwhichtheglutamatesynapsecangetridofunwantedsynapses.Synapses,evenintheadultbrain,areinaconstantstateofflux.Newsynapsesarecontinuallybeingformedandoldonesdeleted.Weareconcernedherewiththemechanismthatleadstosynapsedeletion[201].

Atsynapticconnectionswhereglutamateistheneurotransmitter,there

arethreetypesofreceptors.OneoftheseiscalledtheNMDAreceptor.Activationofthisreceptorresultsinaninflowofcalciumionsintothenervecell,whichstartsacascadeleadingtoactivationoftwoenzymes.OneoftheseisprostaglandinHsynthase(orPGHsynthase),whichwehaveseenbeforeastheenzymethatinitiatesprostaglandinsynthesis.TheactivationofPGHsynthaseleadstothereleaseoflargequantitiesoftoxicreactiveoxygenspecies,includinghydrogenperoxide.Hydrogenperoxideitselfisnotveryreactivebutitcandiffusewidelyinandoutofcells.

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Undercertainconditions,especiallyinthepresenceoffreeiron,itcanformmoretoxicreactiveoxygenspeciessuchasthehydroxylradical.

TheotherrelevanteffectoftheNMDAreceptoristoactivateanotherenzymecallednitricoxidesynthase,whichmakesnitricoxide(NO).Nitricoxideisagascapableofdiffusingwidelyfromitspointoforigin.Thereisevidencetoshowthatboththesecompounds-hydrogenperoxideandnitricoxide-haveimportantfunctionsinthebodyassignalingmolecules.Moreover,theybothhavepro-oxidantproperties,and,beingfreelydiffusiblemolecules,theycanentertheglutamatesynapseitself.Heretheycanactuallyeliminatethesynapse.Oneimportantfactorthatdetermineswhetherasynapseismaintainedordeletedisthebalanceinthesynapsebetweenneurotoxicoxidants(hydrogenperoxideandnitricoxide),whichwilltendtodeletethesynapse,andneuroprotectiveantioxidants,whichwilltendtomaintainit.

Theantioxidantdefensesatthesynapseconsistofthreemaincomponents.ThefirstisvitaminC,whichisreleasedbytheaxonterminalduringtheprocessinwhichtheactionofglutamateisterminatedbypumpingitbackintothesynapticterminal,whereitcanberecycledtobeusedagain.Thus,thebrainveryneatlyarrangesforafloodofprotectivevitaminCtobepumpedintothesynapsejustwhenthedamaginghydrogenperoxideisdiffusingbackfromthepostsynapticsite.Thesecondisanantioxidant-carnosine-whichisfoundinglutamatenerveterminalsandreleasedtogetherwiththeglutamate.Thethirdisthemostinteresting.Attachedtothesideofmostglutamatesynapsesisadopamineterminal,whichistriggeredwhenanyactivityoftheorganismisrewardedbywhatwecallpositivereinforcement-thatis,foodorsomeotherpleasurablestimulus.Someofthedopamineitreleases,wheneversuchastimulusisreceived,enterstheadjacentglutamatesynapse.Dopaminehappenstobeapowerfulantioxidant-akeyfactdiscoveredbytwoscientistsin

Japan,JiankangLiuandAkitaneMori[125].Dopamineherewillincreasetheantioxidantstatusofthesynapseandtiltthebalanceofsynapsegrowthanddeletioninthedirectionoftheformer.Thismaybeoneofthebiochemicalwaysinwhichconditionedreflexesarebuiltupandlearningtakesplace:ittendstostrengthenthosebehaviorsthatleadtopositivereinforcement,becausethecircuitsthatunderliethatbehaviorarestrengthenedbygrowingmoresynapses.Likewise,iflessdopamineis

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released,thebalanceinthesynapsetiltstheotherway,andtheprobabilityincreasesthatthatsynapsewillbepruned.

However,usingdopamineasanantioxidantinthiswaycarriesarisk.For,intheabsenceofsufficientlevelsofotherantioxidantsinthesynapse,dopamineeasilyconvertsspontaneously(byoxidation)totoxicquinones,includingdopaminochrome.Furthermore,undertheseconditionsofloweredantioxidantdefenses,nitricoxidewillalsoconverttopoisonouscompoundscalledreactivenitrogenspecies(suchasperoxynitrite),whichwillattackdopamineandhastenitsconversiontothetoxicquinones.Thesereactivenitrogenspeciesanddopaminequinoneswillattackthesynapseandcandestroyit.

EvidencesuggeststhatitmaybethissystemthatgoeswrongintypeIIschizophrenia:

1.Antioxidantsmopuporotherwiseinactivatethereactiveoxygenspeciesthatwouldotherwisedeletethesynapse.Antioxidantsalsoslowdowntheproductionofquinonesfromdopamine.Theseantioxidantmechanisms,particularlythoserelatingtovitaminCandtoGSHpx,arefaultyinschizophrenia.

2.Theblackpigmentinthebrain,neuromelanin,whichismadefromthetoxicquinones,isameansoftakingthemoutofcirculation.Thereispreliminaryevidencethatneuromelaninisabnormalinsometypesofschizophrenia.

3.Somebraindopamineisnormallyturnedintoacompoundcalled5-cysteinyldopamine,whichisinitselfagoodantioxidant.Thisprocessalsopreventstheformationofthetoxicquinones.Levelsofthiscompoundareelevatedintheschizophrenicbrain.However,thiscompoundcanitselfleadtotheproductioninthebrainofneurotoxicderivatives(calledbenzothiazines)thathavebeenimplicatedinthecauseofParkinson'sdisease.

4.Anotherdefenseagainsttheformationoftoxicquinonesfromdopamineaprocesscalledtransmethylation,convertsthemintoharmlesscompounds.Inthisprocessamethylgroup(composedofoneatomofcarbonandthreeofhydrogen)isattachedtoanactivesiteonthemoleculeandrendersitnontoxic.MyworkwithLelandTolbert,JohnKelso,andothershasshownthatthisreactionisalsoweakinschizophrenia.

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Directchemicalevidencenowexiststhatthequinonesderivedfromdopaminearepresentinthehumanbrain.Indeed,theymustbe,becausetheylieonthechemicalsyntheticpathwaybywhichneuromelaninismade,andneuromelaniniscertainlypresentinthebrain.

Epinephrineanddopaminearecloselychemicallyrelated-infact,epinephrineismadeoutofdopamine.In1954Hoffer,Osmond,andIdiscoveredthatthequinonederivativeofepinephrine,adrenochrome,whengiventonormalpeopleproducesinthemmanyofthesymptomsofschizophrenia[89].Thisexperimentwasconfirmedbythreeothergroupsofscientists,oneintheUnitedStates,oneinGermany,andoneinCzechoslovakia.Epinephrineisusedinthebrainasaneurotransmitterbyonlyonesmallsetofnervecells.Itismorelikelythatcloserelativesofadrenochrome-thequinonesderivedfromdopamineandnorepinephrine-areinvolvedintheschizophrenicprocess.Norepinephrineisfoundinanucleusofthebraincalledthelocuscoeruleus;thenervecellsherealsocontainneuromelanin,indicatingthatnorepinephrine,too,ismetabolizedinthebrainbythequinonepathway.Thereisevidencethatthenervecellsofthenorepinephrinepathwayarealsodamagedinschizophrenia,andthisdamagemaybesimilarlyaffectedbyreactiveoxygenspeciesandthequinonederivativeofnorepinephrine.Noonehasasyettestedtheeffectofthesequinonesderivedfromdopamineandnorepinephrinegiventonormalpeople,butitmaywellbethattheyactashallucinogens,liketheircloserelativeadrenochrome,thequinonederivedfromepinephrine.

Thus,tosummarize,reactiveoxygenspeciesandoxidizedderivativesofbraindopaminecalledquinonesmaybeinvolvedinschizophrenia,ontheevidencethattheyareagentsthatmayprunesynapsesandinschizophreniadefensesagainstthem(antioxidants,O-methylation,andneuromelaninformation)arefaulty.Itisthereforeworth

investigatingwhetherboostingantioxidantdefensesand/orcuttingdownreactiveoxygenspeciesproductionisofbenefitintheillness.

Peoplewithschizophreniaarelowinantioxidantdefenses.PlasmalevelsofvitaminCarelow,andmorevitaminCthannormalisneededtoraisebloodlevelstoagivenlevel,suggestinganincreasedusageincombatingoxidativestress[211].Glutathionelevelsinbloodarealsolow,andthereisastrongcorrelationbetweenlowlevelsoftheantioxidantenzymeGSHpxandtheraisedlevelsofbraindamageinschizophrenia.

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MyworkwithHofferandOsmondhasdemonstratedthatschizophreniamayalsobeassociatedwithadiminishedcapacityfordealingwithtoxicmetabolitesinthebrainproducedfromtheoxidationofepinephrine,dopamineandnorepinephrine.Manyantischizophrenicdrugs,suchaschlorpromazine,arepowerfulmoppers-upofthetoxichydroxylradicalandinhibitorsoffatoxidation.Thepotentantischizophrenicdrughaloperidolactsdifferently:itmopsupanotherkindofreactiveoxygenspeciescalledhypochlorousacid.Thus,itispossiblethatthebeneficialeffectsofthesedrugsinschizophreniamaybedueinparttotheirantioxidantproperties.ReportshaveindicatedthatantioxidantssuchasvitaminCbenefitschizophrenicpatients[1oo].Moreworkinthisareaseemstobecalledfor.

PSYCHOLOGICALSTRESS

Someexperimentswithratshaverecentlyshownthatseverepsychologicalstressinrats(inducedbyrestrainingtheanimalforeighthours,whicharatfindsexceedinglystressful)leadstosevereoxidativestress.Theoxidativestressischaracterizedbyexhaustionofantioxidantdefensesandanelevatedlevelofoxidizedfats.Theprincipaldamagingagentinthistypeofstressisthehydroxylradicalthatproducesstomachulcersinratsunderthesecircumstances[39].Suchulcersmaybepreventedbyantioxidants.Thereareasyetnohumanexperimentsdesignedtoinvestigatethepossiblerelationbetweenpsychologicalstressandoxidativestress,buttheresultsofsuchatrialwouldbeinteresting.

DIABETES

Thisdiseaseiscausedbyadefectinsugarmetabolismowingtoalackofinsulin.Evenwithinsulintreatment,itstillremainsamajorcauseofblindness,kidneyfailure,disordersoftheheart,brain,andvascular

systems,andlimbamputations.TypeIdiabetes,alsocalledinsulin-dependentdiabetes,ischaracterizedbymarkedlackofinsulin,itsearlyageofonset,itsseverity,andtheneedtotakeinsulininjections.Insulinisproducedbythebeta-cellsofthepancreas.TypeIdiabetesisanautoimmunediseaseinwhichthebody'simmunesystem

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mistakesitsownbeta-cellsinthepancreasforforeignintrudersandproceedstodestroythembyamechanismthatincludesanattackbyreactiveoxygenspecies.Beta-cellsnormallyhavealowlevelofantioxidantprotection.Levelsofreactiveoxygenspeciesarealsogenerallyincreasedthatis,notonlyinthepancreas-becausethediabetic'swhitecellsproducemorereactiveoxygenspeciesandmoreprostaglandinsaresynthesized.(Youwillrememberfrompart1thattheprocessofmakingprostaglandinsreleaseslargeamountsofreactiveoxygenspecies.)Moreover,twomechanismsthatinvolvetheabnormalmetabolismofbloodsugar-glucose-alsoyieldreactiveoxygenspeciesasaby-product.Thereisalsoevidencethatfreeironandcopperionsarereleasedfromthestoreswheretheyareusuallykeptfromdoingharm.Freeironandcoppercirculatinginthebodyfluidsareextremelytoxicoxidants.Thus,indiabetestheincreasedlevelsoffreeironandcopperionsaddstothelevelofoxidativestress.

Animalstudiesshowthatantioxidantscanpreventoralleviatevariousformsofexperimentallyinduceddiabetes.Indiabeticratsthesyntheticantioxidantprobucolprotectstheheartagainstoxidativestress.Inhumandiabetes,bloodlevelsofmarkersforoxidativestressareincreasedandlevelsofprotectiveantioxidantsdecreased(inparticularuricacidandvitaminC)[133].VitaminsCandEinhibitfatoxidationindiabetics.Noninsulin-dependentdiabeticshavesignificantlyloweredlevelsofvitaminCintheblood[133].TestsofvitaminCinhumandiabeticshaveshownthatitimprovesvascularperformance,leadingtoafallinbloodlevelsofLDL(bad)cholesterolandariseinprotectiveglutathionelevels[160].DiabeticsalsohavebeenreportedtohaveloweredbloodlevelsofvitaminA,glutathioneperoxidase,anduricacid,aswellashavingsignsofoxidativedamagetotheDNAinbloodcells[78].Inothertestsnicotinamide(vitaminB3)atadosageof3Gperdayreducedtheneedtogiveinsulintodiabetics.VitaminB3isoneofthehelpersoftheantioxidantactionof

vitaminEasdescribedinpart1.Santinietal.concludefromtheirstudiesthatininsulin-dependentdiabetesoxidativestressisincreasedandantioxidantdefensesaredefective''regardlessofduration,metaboliccontrolorpresenceofcomplications"[184].

Chaseetal.reportedaninitialnegativeresultinapreliminarytestofnicotinamideindiabeticchildrenandadolescents[33].Thoughthis

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wasdisappointing,theyreasonedthatbythetimeactualdiabetesdevelops,thedamagetothepancreaticbeta-cellshasalreadybeendone.Therefore,theysuggestedthatantioxidanttherapybestartedintheprediabeticstage.Theytestedthistheoryinafurtherstudyoftwenty-twochildrenathighriskfordevelopingdiabetes.Thesechildrenhadafirst-degreerelativewithdiabetes,aswellasantibodiesintheirbloodagainstbeta-cellsandimpairedinsulinrelease.Theygaveeightchildrenplaceboandfourteenchildren3Gperdayofnicotinamide.Alleightofthechildrenonplacebodevelopeddiabetesbytheendofthestudy,butonlyoneofthechildrenonnicotinamidedid.Theauthorsfeltthatthisresultwasmostpromisingandagainstressedthatthenicotinamidemustbegivenbeforethebeta-cellsaredestroyed.

Thesyntheticantioxidantsilymarinhasbeentestedindiabeticpatientswhohadcirrhosisoftheliver[223].Thirtypatientsweregiveninsulinonlyandtheotherthirtyweregiveninsulinplussilymarin.Aftertwelvemonthsthepatientswhohadhadthesilymarinshowedsignificantclinicalimprovementascomparedtothecontrols.Indicesusedincludedfastingbloodglucoselevels,glycosuria,fastinginsulinlevels,insulinrequirements,andMDAlevels.

Inastudyofeightydiabeticswithdamagetotheretinaandperipheralnerves,twentypatientsweregiventheantioxidantlipoicacid,twentyreceivedvitaminE,twentyweregivenselenium,andtwentyreceivedplacebo[156].Thefirsttwogroupsshowedasignificantimprovement,asmeasuredbylessfatoxidation,betterlegsensation,improvedreflexes,andlessalbuminintheurine.TheantioxidantlipoicacidiscurrentlybeingusedinthetreatmentofdiabeticnervedamagebyDr.Packer'sgroup.Lipoicacidcrossestheblood-brainbarrier,whichN-acetylcysteinedoesnot.Adouble-blind,placebo-controlledstudyhasbeencarriedoutontheeffectsoflipoicacidonadisorderofheartfunction(cardiacautonomicneuropathy)thatoccurs

asacomplicationofdiabetes[241].Thirty-ninepatientsreceived800mgperdayoflipoicacidandthirtyfourothersreceivedplacebo.Theinvestigatorsreportedamodestbutsignificantimprovementinheartfunctioninthegroupthatreceivedthelipoicacidwhencomparedwiththosethatreceivedtheplacebo.Therewerenosideeffectsnoted.Anotherdouble-blind,placebo-controlledtrialoftheantioxidantaminoacidL-arginineinhumandiabetesfoundthat

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itstronglyreducedthelevelsoffatoxidation.Thecomplexinteractionsbetweenfatintakeandantioxidantstatusindiabeticshasbeenillustratedbyastudyinwhichasimplechangeindiet(lessfat,morecarbohydrate)ledtoanincreaseinbloodlevelsofvitaminsCandE[6].Thisisbecausethelowerfatintakeproducedlessoxidativestress,thussparingtheantioxidantvitamins.

PregnantdiabeticratsfedeitherthesyntheticantioxidantBHT(butylatedhydroxytoluene)orvitaminEhadalowerincidenceofoffspringwithcongenitalabnormalitiesthandiduntreateddiabeticrats.ThiswasconfirmedbyasecondstudyinratsusingacocktailofvitaminE(400mgperday)andtwocompoundsreportedtobedeficientindiabetesarachidonicacidandmyo-inositol[172].Theuntreateddiabeticratshadahighincidenceofabnormaloffspring,includinga23.7percentrateofneuraltubedefects,ascomparedwith4percentofnormalrats.Thetreatmentreducedtheincidenceofneuraltubedefectsinthediabeticratstonormallevels.Theseabnormalitiesarethoughttobeduetohighblood-sugarlevelsindiabetesthatmayinterferewiththetransportofthekeyantioxidantglutathioneinthebody.Inhumans,thebirthdefectsassociatedwithdiabetescanbepreventedbyastrictadherencetoatreatmentanddietaryregimendesignedtolimitraisedblood-sugarlevels[171].Antioxidantsupplements,however,maymakethistreatmentmoreeffective.Nohumanworkhasasyetbeendonetotestthishypothesis.Theconclusionisthatantioxidanttherapyseemspromisingindiabetes,especiallyiftheprediabeticstagecanbediagnosedandtreated.

EYEDISEASES

CATARACTS.

Thetransparentcrystallineproteinsoftheeye,unlikemostproteins,

arenotcontinuallyreplaced.Theyarealsoatriskforoxidativedamagefromultravioletlight.InanimalexperimentsvitaminsCandEandsomesyntheticantioxidantsprotectedthelensagainstoxidativestress.TheimportanceofvitaminCisindicatedbythefactthatthereisanactivetransportsystem(pump)foritinthewateryhumorandthelens.Severalepidemiologicalstudieshavesuggestedaprotectiveroleforantioxidantsagainstcataractformation.

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(1)Hankinsonetal.carriedoutastudyofmorethan50,000nursesforaneight-yearfollow-upperiod[77].Theymeasuredtheintakeofantioxidantsinthedietandcomparedthelowestintakegroupwiththehighestintakegroupforcarotenesandfounda39percentreductionincataractsinthelatter.VitaminsCandEandriboflavininthedietwereineffective.Spinachratherthancarrotswasthemosteffectivevegetable.DietaryvitaminChadnoeffectnordidmultivitamintablets.However,vitaminCsupplements(averagedoseof50-500mgperday)takenfortenormoreyearsledtoa45percentreductionincataracts.Theauthorsquotethreepreviousstudiesthatobtainedthesameresultandonethatfailedtodoso.WhydidthestudybyHankinsonetal.findthatdietaryvitaminCwasnotprotectivewhereasvitaminCsupplementswere?Probablybecauseofthehigherdoseinthecaseofsupplements.

(2)Inacarefullycontrolledtrialinvolving152subjectsand152controls,vitaminCsupplements(300-600mgperday)overfiveyearsappearedtoreducethecataractrateby70percent[178].VitaminEsupplements(400mgperday)forfiveyearsappearedtoreducetherateby55percent.

(3)Astudyof1,380ophthalmicoutpatientsagedfortytoseventy-nineindicatedthattheregularuseofvitaminsupplementssignificantlyloweredtheincidenceofcataract[21].

(4)Afifteen-yearfollow-upstudycomparedforty-sevenpatientswithcataractsandninety-fourmatchedcontrols[106].Lowserumlevelsofbeta-caroteneandvitaminEcorrelatedwithmorecataractformation.Therewasathreefolddifferenceintheincidenceofcataractsbetweentheone-thirdofsubjectswhohadthehighestserumlevelsandtheone-thirdwhohadthelowest,indicatingthattheseantioxidantsprotectedagainstcataractformation.LevelsofvitaminCwerenotmeasured.

(5)Jacquesetal.,inastudyof247femalesaged56to71,showedthatvitaminCsupplementsreducedtheincidenceofearlylensopacitiesby77percentandofmoderatelensopacitiesby83percent.However,thevitaminChadtobegivenforaminimumperiodoftenyearsforthebenefittobeobtained.Shorterperiodsshowednoeffect.Theresearchersconcludethat"long-termconsumptionofvitaminC

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supplementsmaysubstantiallyreducethedevelopmentofagerelatedlensopacities"[97].

Thesestudiescanbesummarizedasfollows:

VitaminEappearedtobeprotectiveintwostudies(2and4).

VitaminCappearedtobeprotectiveinsixstudiesandnotinone(1,2,5,andthosequotedby1).

Carotenesappearedtobeprotectiveintwostudies(1and4).

Vitaminsupplementsappearedtobeprotectiveinonestudy(3).

However,whenonetakesintoaccountthattherearethreetypesofcataract-nuclearsclerosis,corticalopacities,andpostsubcapsularthingsgetmorecomplicated.Therehavenotbeenenoughstudiesasyettodeterminereliablywhichsubtypesrespondordonotrespondtoantioxidanttherapy.

Thereactionoftheexpertstoallthisinformationhasbeenmixed.Christenconcludesthattheepidemiologicaldataare"wildlyconflicting"withmanyuncontrolledconfoundingvariables[34].Gershoffsaystheyare"promisingbutunproven"[63].Taylorbelievestheconsensusisimpressiveandsuggeststhattheoptimumlevelsofnutrientsforthedelayofcataractshouldbedefinedassoonaspossible[214].OptimumlevelsforvitaminEwill,hesuggests,probablyrequiresupplements.

Diplockclaimsthat"thelaboratoryandepidemiologicalevidenceisnowsostrongthatitisessentialtoensurethatthepopulationisadequatelysuppliedwithE,Candbeta-carotene"[43].

MACULARDEGENERATION.

Inthecaseofadvancedage-relatedmaculardegeneration(adiseaseinwhichthecenteroftheretinadegenerates),onelargemulticenter

studyof356patientsand520normalcontrolshasshownthatahigherdietaryintakeofcarotenoidswascorrelatedwitha43percentreductionofmaculardegeneration,butvitaminsCandEwereineffective[192].Theparticularcarotenoidsmostlikelytobeinvolvedwerenotbeta-carotenebutluteinandzeaxanthin,whicharefoundindarkgreenleafyvegetablessuchasspinach,collardgreens,kale,andturniptops;carrotsareverylowinthesetwocompounds.However,thisresultmayhavelittletodowithantioxidants.Luteinandzeaxanthinhappentobe

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thetwodominantyellowpigmentsinthemacula(center)oftheretinathatfilteroutthedamagingbluelight.Beta-caroteneandlycopene(fromtomatoes)areabsentfromthemacula.Increasingtheserumlevelsoflutein,bydietarymanipulation,leadstoincreasedluteininthehumaneye.Thusluteinandzeaxanthinemayacttoprotecttheretinadirectlybytheirfunctionasnaturalpigmentsagainstlightdamage,ratherthanasgeneralantioxidants.However,anotherstudyof167casesofmaculardegenerationimplicatedlowlevelsoflycopeneratherthanluteinandzeaxanthininthedisease[131].RedbloodcellsincasesofmaculardegenerationhavebeenreportedtohavesignificantdecreasesinlevelsofSODandglutathioneperoxidase[148].Landrumetal.suggestthatlong-termsupplementationforindividualshavinglowlevelsofmacularpigmentcouldbeofbenefit[115].Adietrichindarkgreenleafyvegetablesand/orsupplementswithluteinandzeaxanthin,andwithtomatoesand/orsupplementsoflycopene,mayhelpprotectagainstthisformofblindness.

RESPIRATORYDISEASES

Thelungisatriskofoxidativestressbecauseofthelargeamountsofoxygenthatpassthroughitwhenwebreathe.Oxidativestressinthelungleadstodamagetothecellmembranes,inflammation,andbronchoconstriction.

ASTHMA.

Asthmaisachronicrespiratorydisorderthatresultsinconstrictionofthebronchianddifficultyinbreathing.Itisassociatedwithoxidativestressbecausethewhitecellsintheepithelialliningofthebronchiproducemorereactiveoxygenspeciesthannormal.RiskfactorsforasthmaincludelowdietaryintakeofvitaminsCandEandselenium,highbodyiron,andexposuretoenvironmentaltoxinssuchaslead,

whichpoisonsseveralenzymesinthebodyonthepathwaymakingtheimportantantioxidantglutathione.Ithasbeenshownineightoutoftenstudiesthatthechildrenofsmokershaveanincreasedincidenceofasthma.Oxidantexposureininfancymayleadtoasthmainlaterlife.AsthmaticshavelowbloodlevelsoftheantioxidantenzymeGSHpxandlowlevelsofthetracemineralselenium,whichisapartofthisenzymecomplex.Thisleadstoincreasedoxidativestressfromreactiveoxygenspecieslike

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hydrogenperoxide,whicharenormallyneutralizedbyselenium.NewZealandhaslowlevelsofseleniuminthesoil,andNewZealandershaveahighincidenceofasthmaandahighmortalityfromthedisease.

AlargeepidemiologicalsurveyconfirmedthatalowdietaryintakeofvitaminCiscorrelatedwithasthmaandthatthesymptomsofasthmaaremadeworsebyenvironmentaloxidantsandbetterbyvitaminC[79].VitaminCisthemajorantioxidantinthefluidthatcoversthesurfaceofthelungwhereitprotectsagainstenvironmentaloxidants,includingtoxicnitrogenoxidesinsmog.Antioxidantdefensesareparticularlylowduringanacuteasthmaticattack.Thecurrentevidencesuggeststhatantioxidantsshouldprotectagainstasthmaandalleviateitssymptoms.Interestingly,beta-blockers(suchasisoproterenol),whicharewidelyusedinasthma,arealsopotentantioxidants;theauthorsofonestudysuggestthatthismaycontributetotheirtherapeuticeffectinasthmabymoppinguptheexcessreactiveoxygenspeciesfoundinthedisease[68].

AstudycarriedoutinruralChinafoundthatincreasingtheintakeofvitaminCby1oomgperdayimprovedlungfunctionasmeasuredbyforcedexpiratorytests[92].Theimprovementwasestimatedtoequaloneyearofaging-relatedlossoflungfunction.Astudyof393nonsmokersfoundthatbloodlevelsofvitaminCwereinverselyrelatedlevelsofachemicalmarkerforfatoxidation[190].ThissuggestedthatvitaminCwasprotectiveagainstfatoxidation.Arecentdouble-blind,placebo-controlledstudyofseventeenasthmaticadultsshowedthatsupplementationwithvitaminE(400mgperday)andvitaminC(500mgperday)ledtoareductionintheirsensitivitytoozonethatwasmostmarkedinthesixmostseverecases[223].

ACUTERESPIRATORYDISTRESSSYNDROME(ARDS).

InARDStheantioxidantdefensesinthebloodarelowered,andthereisafallintheprotectiveelementsoftheplasma.Inonestudythirty-

twopatientswithARDSweretreated,halfwithconventionaltreatmentandhalfwithantioxidants(vitaminsCandE,selenium,andN-acetylcysteine)[186].Themortalityrateinthefirstgroupoverfourweekswas71percent,inthesecondgroup37percent-averysignificantdifference.InasecondclinicalstudythesyntheticantioxidantEUK-8wasfoundsignificantlytoprotectagainstthetypeofacutelunginjurythatoccursduringshock.Inadouble-blind,

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placebo-controlledprospectiveclinicaltrialinvolvingfiveintensivecareunitsintheUnitedStatesandCanada,ARDSpatientsweregiventheantioxidantsN-acetylcysteineandprocysteine[13].Therewasnoeffectonoverallmortality(possiblybecausethesamplesizewassmall),buttherewasasignificantimprovementinlungandheartfunction.

RESULTOFCIGARETTESMOKING.

Anotherlungconditioninwhichreactiveoxygenspeciesplayaroleistheresultofexposuretocigarettesmoke-bothactivesmokingandpassiveexposuretosmoking.Cigarettesmokingisthesinglelargestcauseofprematuredeathinindustrializedsocietiesandofcourseaffectsmanyothersystemsbesidesthelungs.Tobaccosmokehashighlevelsofreactiveoxygenspeciesandpro-oxidantoxidesofnitrogen,aswellasavarietyofcancer-producingchemicals.Everypuffofcigarettesmokeinhaledcontains1015(1followedby15zeros)moleculesofreactiveoxygenspecies.Insmokersindicesofoxidativestressareraised,whereasthelevelsofvitaminCandtheantioxidantenzymeCATarereducedinthefluidliningtheirlungs.GlutathionelevelsarereducedinthelungcellsthemselvesandplasmalevelsofvitaminC(butnotvitaminE)arealsoreduced.Smokersalsoexcreteinthebreathexcessiveamountsofthegasethane,whichisaproductoffatoxidation.Themorecigarettestheysmokethemoreethanetheyexcrete.VitaminEreducesfatoxidationinbothsmokersandnonsmokers.Inonethreeweekstudytensmokersweregivenanantioxidantcocktailthatincluded6mgofbeta-carotene,200mgofvitaminE,and250mgofvitaminC[8].Thereresulteda29percentreductionintheamountofethaneexcreted.Smokersexcretefourtotentimesthenormalamountof8-OH¬G(ameasureofoxidativeattackonDNA)thannormals.

Brownetal.studiedfiftysmokersandfiftynormalcontrolsina

double-blind,crossovertrialofvitaminE(280mg)versusplacebo[22].Theymeasuredthesensitivityoftheredbloodcellstooxidativestressinducedbythepro-oxidanthydrogenperoxide,aswellaslevelsofkeyantioxidantenzymes.TheyfoundthatvitaminEprotectedtheredbloodcellsagainstoxidativestressinbothsmokersandnonsmokersandraisedthelevelsofsomeantioxidantenzymes.Lykkesfeldtetal.,usingnewandaccuratemethods,measuredtheamountofvitaminCandoxidizedvitaminCinthebloodofsmokers[130].TheyfoundthatlevelsofordinaryvitaminCwere

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belownormal,whereasthelevelsoftheoxidizedformofvitaminCweremuchabove(18times)normal.WhenvitaminCrecyclesvitaminE,thevitaminCisturnedintooxidizedvitaminC(seepart1).ThiswasevidenceofsevereoxidativestressanddepletionofvitaminC.TheyrecommendedthatallsmokersneededtomaintaintheirbloodlevelsofvitaminCatabout70µL/L.Thiswouldrequireanintakeofatleast200mgperdayofvitaminC.Lehretal.saythatthereisnowenoughexperimentalandepidemiologicalevidencetowarrantclinicaltrialsofvitaminCindiseasesassociatedwithcigarettesmoking,suchaspulmonaryemphysema,chronicobstructivepulmonarydisease,andatherosclerosis[120].Itwouldseemlogicalthereforethatsmokerswhocannotstopsmokingshouldincreasetheirantioxidantdefenses.

EXPOSURETOSMOG.

Nitrogendioxide(NO2)isaprominentandpowerfuloxidantpresentinsmog.InhumanplasmaexposedtoNO2,thereisarapidfallinlevelsofvitaminsCandQ10andaslowerfallinvitaminE,bilirubin,andprotectiveproteingroups.HumansexposedtoexcessivelevelsofNO2(suchasglasscraftsmenandbraziers)showgreatlyexcessivelevelsoffatoxidation(uptoonehundredtimesthenormal)andareinspecialneedofantioxidantprotection.Thesamemaybetrueofpeoplewholiveinsmog-ladencitiessuchasLosAngelesandMexicoCity,butspecificstudiesneedtobecarriedouttodeterminethisrelationship.

Dieseloilfumescontainasmuchasonehundredtimesasmuchtoxicnitrogenoxidesasdogasolinefumes.Ifbloodplasmaisexposedtodieseloilfumes,thereisaprofoundfallinvitaminCanduratelevelsandalesserfallinvitaminElevels.Thebloodproteinsalsoshowsignsofoxidativedamage.

AGING

Agingisnotadiseasebutanormallifeprocessthatinvolvesphysicalandbiochemicalchangesinthebody.Itisgenerallyagreedthattheonlyreliablewaytoincreaselifespanthroughdietistoeatless(knowninthefieldascaloricrestriction).Thisinsightisrelatedtoacorrelationbetweenincreasedfoodconsumptionandoxidativestress.Astudyofratsfedasmuchastheywantedandratsgivenarestricteddietshowedthattheincreasedcaloriesinthedietledtoraised

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measuresoffatoxidationintheblood.CaloricrestrictionlowersreactiveoxygenspeciesproductionandlevelsofproteinandDNAoxidation.ItalsoreducesthenormalfallwithageoftheantioxidantenzymeCATinblood.Themechanismforthiseffectisunknown,butitmayinvolvetheenzymesandsmallmoleculesresponsiblefortheremovalofreactiveoxygenspecies.

Thereissomeevidencetosuggestthatincreasedoxidativestressandadeclineinantioxidantdefensesplayaroleinaging.Therearereportsofhighlevelsofreactiveoxygenspeciesanddecreasedantioxidantactivityinelderlypeople,particularlyintheadrenalglandsandinthebrain[81].Theagingbraincontainshigherthannormallevelsofoxidizedfats.Moreover,theagedhaveimpairedimmuneresponsesthatrendersthemmoresusceptibletoinfectionslikeinfluenzaandpneumonia.Increasedintakeofsomeantioxidantnutrients-especiallyvitaminE-improvestheimmuneresponse[141].

Leewenburghetal.claimthatagingisassociatedwithafallinbothenzymaticandsmall-moleculeantioxidantdefensesinmanyimportantorgans(liver,brain,heart,kidney,butnotmuscle)[118].Antioxidantdefensesintheadrenalglanddecreasewithage,which,inturn,leadstoadeclineintheproductionofadrenalcorticalhormones[7].Theadrenalsofyounganimalsarewellprotectedagainstoxidativedamage,andhavehighlevelsofseveralantioxidants,includingvitaminsCandE,andshowlowlevelsoffatoxidation.AdietdeficientinvitaminEleadstoincreasedfatoxidationintheadrenalsanddecreasedproductionofadrenalhormones.ArecentstudyinHollandfoundthatbeta-caroteneappearedtoprotectagainstage-relatedlossofcognitivefunction.However,Calsetal.haveconcluded,followingastudyinParis,thatagingbyitselfdoesnotleadtooxidativestressaslongasgoodgeneralhealthandgoodnutritionaremaintained[27].

Thereisasyetnoevidencetoshowwhetherantioxidantsupplementswillactuallyslowtheagingprocessinhumans.Furtherstudiesareneeded.Butthisremainsapossiblebenefittobehopedforbypeoplewhoattendconscientiouslytotheirantioxidantintake.However,whetherincreasedoxidativestress,weakenedimmunefunction,anddecreasedantioxidantdefensesarethehallmarksofnormalagingorareduetotheimpairednutritioncommonamongmanyelderlypeopleisstillanopenquestion.

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HIVINFECTIONANDAIDS

AIDSpatientsareunderpowerfuloxidativestressfromtwosources.Oneistheexcessiveproductionofreactiveoxygenspeciesbytheirwhitebloodcells.Theotheristheexcessiveproductionofcertainproteins,calledcytokines,thatcontroltheimmunesystem.Manycytokinesalsostimulateprocessesthatresultinoxidativestress.Thesepatientsshowdeficienciesofzincandselenium(twodietarymetalsthatareessentialfortheproperfunctionofantioxidantenzymes)andoftheantioxidantglutathione.Asthediseaseprogresses,reactiveoxygenspeciesproductionandlevelsoffatoxidationincreaseasaresultoftheattackoftheHIVvirusontheimmunesystem.Thisresultsinaprogressiveloweringofantioxidantdefenses,inparticularbloodlevelsofglutathione,zinc,selenium,vitaminE,carotenoids,andGSHpx,whichareexhaustedbythehighlevelofcontinuingoxidativestress.AIDSpatientsshowexcessfatoxidation.Levelsoffatoxidationstarttoriseearlyinthediseasebeforeanysymptomsdevelop.

SomeexpertsrecommendthattreatmentofAIDSshouldincludetherapiesaimedatrestoringdepletedglutathionelevels.OnesuchagentisNAC,whichhasbeensafelyusedinmedicinefortwenty-fiveyears.TheonlyproblemisthatNACisincompatiblewithtrypsin,chymotrypsin,andmanyantibiotics.ThereshouldbeagapofatleasttwohoursbetweentakingNACandanyofthese.IthasalsobeensuggestedthatNACmayexertpartofitsreportedtherapeuticactionbyraisingbloodcystinelevels,whicharelowinthedisease.Theselowlevelsleadtocomplicationssuchasmusclewastingandreducedimmuneresponses[46,47].Otherpromisingdrugsofthesametypearealphalipoicacidandglutamine,whichthebodyusestomakeglutathione.

AcontraryopinionisexpressedbyAilletetal.oftheInstitutPasteur

[2].Followingtest-tube(invitro)studiesofsomeantioxidants,includingNAC,onthereplication(growthandspread)oftheHIVvirus,theinvestigatorsfoundthattheantioxidantswereonlypartlysuccessfulinblockingHIVmultiplicationinonetypeofwhitebloodcellandunsuccessfulinothertypes.Moreover,theyfoundthatthehighdosesofantioxidantsneededtoproducethismoderateeffectcausedanunwantedblockadeofotherimportantbloodcellscalledmonocytes.Theyconcludedthatthese

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antioxidantscannotcountertheintenseactivityofthemultiplicationoftheHIVvirusbutmayaggravateimmunedisturbancesinHIVpatientsbythemonocyteblockade.Moreover,inHIVpatientslowdosesofantioxidantsmayhaveaparadoxicaleffectofincreasingHIVmultiplication.ThisisunwelcomenewsforthemanyAIDSpatientswhocurrentlytakelargeamountsofantioxidantssuchasNAC.

Theeffectsofbeta-caroteneandseleniumsupplementationhavebeentestedinpatientsinfectedwithHIV.Althoughmeasuresofoxidativestresswerereduced,itwasdisappointingthattherewasnopositiveclinicaleffectnoted.Everalletal.havefoundthatvitaminCslowsthegrowthoftheHIVvirusintest-tubeexperiments[54].Moreover,thelevelofvitaminCisloweredinthebrainofpatientswhodiedofAIDS.TheinvestigatorssuggestthatvitaminChastworolesinAIDS:thefirstistoraisetheleveloftheantioxidantdefenses,andthesecondmaybetokilltheHIVvirus.

AIDSpatientswithlowlevelsofvitaminsA,beta-carotene,B6,andB12haveapoorprognosis,andsupplementsofthesevitaminsincreasethesurvivalrate[212].AnotherstudyhasshownthatHIV-infectedpatientshavealowerriskofdevelopingactualAIDSiftheymaintainahighintakeofvitaminE[I].However,ahighintakeofzincincreasesthedeathrate.Inthecaseofbeta-carotenetheoptimumamountisabout10mgperday.Toomuchisharmful.TheseresultsmaybeduetotheeffectoftheBvitaminsontheimmunesystem.

RecentlyDrögeetal.suggestedthatAIDSpatientsmustbetreatedonanindividualbasis,adjustingthedosetotheneedsofthepatientasisdoneinthecaseofinsulintreatmentofdiabetes[46].Bloodlevelsofcystine,cysteine,andglutamineneedtobemonitored.Thiscreatesdifficultiesforattemptstocarryoutdouble-blind,placebo-controlledtherapeutictrialsusingonlyonedoseofNAC.Clearly,muchmoreresearchneedstobedoneinthisfield.

SHOCK

Shockisanacutemedicalemergencycausedbyinjury,bloodloss,severeburns,infection,andsoon.Septicshock,duetoabacterialinfection,istheleadingcauseofdeathinintensivecareunits.Thebacteriumreleasesatoxinthatprovokesanoverproduction

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ofcytokinesandreactiveoxygenspecies.Septicshockpatientshaveincreasedfatoxidationratesandexhaustedantioxidantdefenses.Inanimalexperimentsantioxidants(vitaminE,NAC,andSOD-ifthisisgivenbeforethesepsisstarts)haveproventooffereffectivetreatment,buttherearestillconflictsintheliterature.Inhumanstherehavebeentwotherapeuticstudies,onewithNAC,andonewithacombinationofvitaminsEandC,NAC,andselenium.Bothstudieshadpositiveresults.

Otherformsofshock-duetobloodlossandburns-arealsocharacterizedbysevereoxidativestress.Inanimalexperiments,antioxidantswereeffectivetreatmentsofshockduetobloodlossandburns.InthesestudiesnewsyntheticantioxidantssuchasZ-103andEbselenhavebeenused.Preliminarytestsinhumansareunderway.

ISCHEMIA/REPERFUSION

Inanycondition-suchasstroke,heartattack,orduringorgantransplants-inwhichthebloodflowtoanorganisinterruptedforawhileandisthenrestarted,severeoxidativestressresults.Duringaperiodoflossofnormalbloodflow,calledischemia,evenforaperiodofafewminutes,thetissuesbecomedamagedbythelackofoxygen.Butthemaindamageoccursduringreperfusion,therestorationofthebloodflow.Alargereleaseofreactiveoxygenspeciescausedbybiochemicalchangesinthereperfusedtissueresultsinsevereoxidativestressandaloweringofintracellularglutathionelevels.Inastudyofexperimentalischemiaoftheheartinrats,antioxidants(SOD,CAT,vitaminE,anddesferoxamine)offeredeffectiveprotection,butthebestwasthesyntheticagentH290/51,whichis1ootimesaspotentasvitaminEininhibitingfatoxidation.Inkidneytransplantsischemia/reperfusioninjurycanbereversedbyantioxidants.However,LehrandMessmerhavecomplainedthat,inspiteofthestrongscientificevidencethatoxidativestressplaysakeyroleintransplant

surgery,''littleattentionispaidtotheantioxidantstatusofpatientsundergoingorgantransplants"[119].Thisisanexampleoftheslowpaceatwhichthemedicalprofessioningeneralisactuallyputtingthesenewinsightstouse.

Inthrombolytictreatmentforacuteheartattacksinhumans(inwhichthebloodclotinthecoronaryarteryisdissolvedviaacatheter

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insertedintotheheart),patientsdevelopariseinfatoxidationandafallinvitaminEandretinoids-signsofreperfusionoxidativestress.Thus,theremaybearolefortheuseofsomeofthefaster-actingantioxidantsinthrombolytictreatment.VitaminEactstooslowlytoperformthistask.AstudyofcoronaryarterybypasssurgeryshowedthatpreoperativeadministrationofvitaminEforfourweeksresultedinfewerabnormalitiesintheelectrocardiogramandfewerinfarctions(heartattacks)aroundthetimeoftheoperation[189].

Patientswithblockedlegarteriesdeveloppainduringexercise,calledintermittentclaudication,becauseofthelackofbloodflowtosupporttheexercise;theysufferfromrepeatedischemia/reperfusiondamageeverytimetheygoforawalk.Inthesecases,afteraperiodofexercise,thereisasignificantdropinantioxidantcapacityintheblood.Suchpatientsmayneedantioxidantsupplementation.

Thereisalsoevidencethatreactiveoxygenspeciesareafeatureincerebralvasospasm(contractionofthearteriesofthebrain).Inanimalsantioxidantswereeffectiveinreducingvasospasm,particularlyifappliedlocally.Thismighthavesomeapplicationinneurosurgery.

However,awarningnotehasyetagainbeenstruck.PallerandEaton,intheirstudyofreperfusionoxidativedamagetothekidney,found,quiteunexpectedly,thatglutathioneandonetypeoftheantioxidantenzymeSODwereprotectiveifgivensinglybuthighlytoxicifgivenincombination[157],whereasglutathioneandanothertypeofSODgiventogetherweresynergistic.Theyadvisethat"greatcaremustbeusedindesigningandinterpretingstudiesemployingcombinationsofantioxidants."Thisappliesparticularlywhentheseagentsareadministeredintravenously.

CYSTICFIBROSIS

Incysticfibrosis,themostcommonlethalinheriteddiseaseintheUnitedStates,ageneticmutationleadstoabnormallystickysecretionsbythemucousglands.Thesecretionsgumupthelungs,resultinginchronicinflammation.Excessiveactivityofthewhitebloodcellsresultsinanincreaseinreactiveoxygenspecies,which

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inturnpromoteexcessiveproductionoffibroustissueinthelung.MalfunctionofthepancreasresultsinaninabilitytoabsorbvitaminEproperlyfromtheintestines,whichnotonlyimpairsthegeneralantioxidantdefensesofthebodybutalsoleadstoliverdamage.Moreover,thelungsofthesepatientsgetinvadedbyabacterium(pseudomonasaeruginosa)thatisaproducerofreactiveoxygenspecies.

CysticfibrosispatientshaveverylowbetacaroteneandvitaminElevelsandhighlevelsofoxidizedfats.Givingsupplementsofbetacarotenehelpsnormalizethelevelsoffatoxidation.Thelowerthelevelsoftheprotectivebetacarotene,thehigherthelevelsofoxidationofthefats.Therefore,supplementscontainingbetacarotenecouldbeoftherapeuticvalueincysticfibrosis.Thereisalsoaneedtodevelopnewsyntheticantioxidantsthatcanbeabsorbedinspiteofpancreaticfailure.Ramseyetal.saythat"everypatientwithcysticfibrosiswilleventuallyrequiresupplementationwithfatsolublevitamins"[69].ThepotentantioxidantNACcanbegivenadequatelybymeansofanaerosolspray.Winklhofer-Roobetal.haveshownthatpatientswiththisdiseasewhohavelowbloodlevelsofvitaminCalsohavehighbloodindicesofinflammation(MDAandTGF¬levels),whereasthosewithhighlevelsofvitaminChave"clearlylowervalues"oftheseindicesofinflammation[232].TheseresearchersseethesemeasurementsasevidencethatvitaminCisprotectiveincysticfibrosis,buttheywarnthat,owingtothepossiblepresenceoffreeiron,furtherstudiesareneededtodeterminewhethervitaminCsupplementsaresafe.Freeironmightbeanimportantconstituentofthefluidliningtherespiratorytractincysticfibrosis,inwhichcasevitaminC,whichbecomesapotentoxidantinthepresenceoffreeiron,mightbetoxic.

VanderVlietetal.offeranotherwarninghere[222].Itistheoreticallypossiblethatantioxidantsbenefitthebacteriummorethanthepatient.

Thebacteriumalreadyproducesoneantioxidantitself(slimyalginate),whichmightinterferewiththeoxidantattackusedbythewhitebloodcellstokillthebacterium,ashappensinacuteeyeinfections.TheseinvestigatorsalsowarnaboutthepossibledangerpresentedbytheinteractionofvitaminCandfreeiron.Researchersdevelopinganantioxidanttherapyforcysticfibrosismustbearthesecaveatsinmind.

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THECOMMONCOLD

Twenty-fiveyearsagoNobelLaureateLinusPaulingcausedafurorbyclaimingthatvitaminCcouldalleviatethesymptomsofthecommoncold.Althoughthemedicalestablishmentgreetedthisclaimwithderision,manypeopletodaycontinuetoreachforthevitaminCbottleassoonassignsofacoldstarttodevelop.However,wenowknowthatmanyofthesymptomsofacoldareduenottothecoldvirusitselfbuttoanoverlyenthusiasticresponseofthebody'sownimmunesystemtothevirus.Duringacoldthemucousmembraneliningofthenosebecomesfilledwithwhitebloodcells,whichsecretelargeamountsoftheirmostpowerfulweapon,reactiveoxygenspecies,aimedatkillingthevirus.Unfortunately,thereactiveoxygenspeciesproducedbythemacrophagesoftheimmunesystemalsoattackthecellsofthemucousmembranethemselves,leadingtoarunnynoseanddiscomfort.Thus,thestrategyofgivingantioxidantsduringacoldisnottokillthevirus,buttoweakenthisattackbyreactiveoxygenspeciesonthebody'sowntissues.However,vitaminCdoesalsohavesomeactioninboostingimmuneresponses[40,103].

HemilandHermanhaverecentlyreexaminedthefindingsofalltwenty-oneplacebo-controlledtrialscarriedoutonthistopicsince1970inwhichIGormoreofvitaminCadaywasgiven[81].Theyfoundthatineverystudytherewasnochangeinthenumberofcolds;buttherewasasignificantfallinthedurationandseverityofthesymptoms.TheycriticizeasinadequatesomepreviousreviewsthatconcludedthatvitaminCdidnothingforacold.Althoughthereisasyetnodirectevidencetosupportthishypothesis,itisscientificallypossiblethatvitaminCcouldreducethesymptomsofacoldwhilehavingnodirectactiononthecoldvirusitself.

ACUTEINFECTIONS

Antioxidantsarenot,ofcourse,cure-alls.Eyeinfectionscausedbybacteriaaremadeworsebyantioxidants,whichinterferewiththebactericidalactionofthereactiveoxygenspeciesproducedbythemacrophages.Thismaywellapplytootheracuteinfections.

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Onecertainexceptionispneumococcalmeningitis.Inastudyofrats,theantioxidantNACprotectedagainstthisinfection[109]byreducingthebrainedemaandincreasedintracranialpressureproducedbyreactiveoxygenspecieswhosebrainlevelsareincreasedbytheinfectionandwhichareamajorcauseofdeath.TheNACdidnotinterferewiththewhitecells'useofreactiveoxygenspeciestokilltheinvadingbacteria.Inthecaseofnonbacterialeyeinflammation,animalexperimentsshowthatantioxidantsareprotective.However,itwouldbewisetotakeantioxidantsduringthecourseofanacutebacterialinfectiononlyontheadviceofadoctor.

BETA-THALASSEMIA

Thisdiseasecausessevereanemia;consequently,patientsmustundergorepeatedbloodtransfusions,whichleadtosevereironoverloadanddamagetomanyorgans.Theexcessironinducessevereoxidativestress.Livreaetal.studiedforty-twopatientsandfoundthatbloodindicesofoxidation(conjugateddienes,MDA/TABadducts,andproteincarbonyls)wereraisedtwofold[126].Bloodlevelsofmanyantioxidantswerereduced(vitaminCby44percent,vitaminEby42percent,vitaminAby44percent,beta-caroteneby29percent,andlycopeneby67percent),presumablybecausetheywereusedupbytheiron-inducedoxidativestress.Thetotalantioxidantpotentialwasreducedby14percent.Theresearcherssuggestedthatthisoxidativestressmightbethecauseofthemyocardialdamagethatisthemajorcauseofdeathinthedisease.Theyconcludedthatadministrationofantioxidantcompounds,butnotvitaminC,couldbebeneficial.ApreviousattemptwasmadetotreatthisdiseasewithvitaminE.Rachmilewitzetal.treatedeightpatientswhohadlowvitaminElevelswith750-,1,000mgperdayofvitaminEforsixteenmonths[161].Theyfoundthatthereweresomechangesinantioxidantmeasures,butthetreatmenthadnoclinicaleffect.They

concludedthatvitaminEbyitselfmightnotbeenough.

CIRRHOSISOFTHELIVER

Cirrhosisoftheliver,whichfollowsfromexcessiveintakeofalcohol,maybedueinparttofatoxidationandliverdamagefromreactiveoxygenspecies.OnetrialofvitaminEsupplements

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inestablishedcirrhosiswasineffective,butthismayhavebeenanothercaseofshuttingthestabledoorafterthehorsehadgone.

EFFECTSOFSTRENUOUSEXERCISE

Moderateexercise,plusalow-fat,highcarbohydrate,andhigh-fiberdiet,leadstoadramaticdecreaseinLDL(badcholesterol)oxidation.However,ithasbeenshownthatextremelystrenuousexerciseleadstooxidativestressandcompensatoryrisesinantioxidantenzymesandglutathione.Thisisbecauseextremeexerciseleadstomuscleischemia/reperfusionandagreatlyincreaseduseofoxygen.AthleteshavehigherlevelsofvitaminEintheirredbloodcellsandvitaminCintheirwhitebloodcellsthandononathletes.Senhaswrittenagoodreviewofthistopic[193].Heconcludedthatphysicalexerciseisprotectiveagainstoxidativestressinanumberofways.However,overdoingitcanbeharmful.AccordingtoSen,people'sphysiologicalantioxidantstatusvarieswidelyandthusaperiodicassessmentofone'ssusceptibilitytooxidativestresswouldbedesirable.Afterareviewofthemethodsthathavebeenusedtocombatoxidativestressduringexerciseandtheirresults,heconcludedthatglutathioneisineffectiveprobablybecauseitdoesnotgettowhereitisneeded.NACisconvertedintoglutathioneinthebodyandmaybeeffective,butinformationislackingontheeffectsofvitaminsCandE.Onlytwotestshavebeencarriedouttoseewhethertakingantioxidantsactuallyincreasesathleticperformance.Thefirst,onswimmers,hadanegativeresult.However,atrialofvitaminEinhigh-altitudemountaineeringshowedimprovedperformanceatlowoxygenlevels.Atpresentweknowonlythatathleteshavebetterantioxidantdefensesthandononathletes.Onewondersifathleteswhotakeantioxidantsupplementswouldcomeunderthebanonartificialaidstoimproveathleticperformance!

HYPERTHYROIDISM

Hyperthyroidismisassociatedwithincreasedoxidativestress,leadingtoincreasedfatoxidationandlowerserumvitaminElevels.Thyrotoxicmuscleandheartlesionsmaybedueinpartduetooxidativestress.Therehavenotasyetbeenanyreportsoftheuseofantioxidantsinthedisease.

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INFLAMMATORYBOWELDISEASE

Lih-Brodyetal.havestudiedbiopsiesfromtheintestinesofpatientswithtwosuchdiseases-Chron'sdiseaseandulcerativecolitis[124].MeasuringindicesofproteinandDNAoxidationaswellaslevelsofreactiveoxygenspeciesandtheantioxidantenzymeSOD,theyfoundevidenceofsevereoxidativestress.InChron'sdiseasetheyfoundraisedlevelsofreactiveoxygenspecies,iron,andSOD,aswellasthepresenceofproteincarbonyls(evidenceofoxidativedamagetoproteins)andoxidativelydamagedDNA.Inulcerativecolitistherewereraisedlevelsofreactiveoxygenspecies,proteincarbonyls,andironnotonlyintheinflamedsitesbutinnormalareasbetweentheinflamedsites,showingthattheraisedlevelswerenotjustaresultofinflammation.Inulcerativecolitisthereisfreeironoverloadfromthebleeding,sovitaminCmustbeusedwithcaution.

MALARIA

Oxidativestressisinvolvedintwowaysinmalaria.First,duringanacuteattackagreatdealofpro-oxidantfreeironisreleasedfromtheredbloodcellsdestroyedbytheparasite;second,thedefensivemacrophagesreleasemanyreactiveoxygenspecies.Stimulatingtheformationofnewbloodcellsrichinantioxidantenzymesisnecessarytoreplacethoselostduringseverehemolysisinseveremalaria.

Ontheotherhand,themalarialparasiteitselfisverysusceptibletooxidativestress.Thus,newpro-oxidantantimalarialdrugshavebeendevelopedbasedonthetraditionalChinesefolkmedicineqinghaosu.

Furthermore,adiethighinfishoilsrapidlyproducesavitaminEdeficiency,whichresultsinslowergrowthofthemalarialparasite;this,too,hasbeenusedintherapy.

MITOCHONDRIALDISEASES

Defectsinpartsofthecellcalledmitochondria,whichprovidetheenergythecellneedstofunction,manifestasmuscleandbraindisturbances.Anopentrialofantioxidants(whichincluded2GperdayvitaminCand400mgperdayofvitaminE)producedencouragingresults[163].Thepatients"appearedto"survive

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longerwithlessdisabilityandfewermedicalcomplications.Moreover,nosideeffectswerereported.Inanotherstudynicotinamide(theantioxidantvitaminB3)wasgiventogoodeffect.

MYOTONICDYSTROPHY

Thisdiseaseismarkedbyraisedplasmalevelsofreactiveoxygenspeciesandoxidizedfatsandloweredantioxidantdefenses.Notrialsofantioxidantmedicationhavebeenconductedasyet.

NEONATALOXIDATIVESTRESS

Birthresultsinoxidativestresstothenewborninfant,whopassesrapidlyfromalowoxygenpressureintheuterustoahighoneassoonasheorshestartstobreatheair.ArecentstudyofnewbornratscomparedtheinfantsofmotherratsgiventheantioxidantNACwithcontrols.Inthecontrolmotherratstheoxidizedglutathionelevelsinplasmaincreasedelevenfoldafterbirth;intheNAC-treatedgroupthelevelincreasedonlytwofold.Evidently,muchoftheactiveformofglutathionewasbeingdepletedbytheoxidativestressandconvertedintotheoxidizedform.ThisconversionwassloweddownbytheNAC.Humanstudiesinthisareaareawaitedwithgreatinterestbecausethebirthprocessisfraughtwithdangertoinfants,manyofwhomsufferbraindamageinwhichoxidativestressmayplayapart.Givingmothersantioxidantsinthelaterstagesofpregnancymayprotecttheinfantfromoxidativestressatbirth.

PANCREATITIS

Inflammationofthepancreasisoftenaresultofdigestionoftheglandbyitsownhighlypotentdigestivejuices.Thereare20,000casesofthissyndromeintheUnitedStateseveryyear.Insixteenoutoftwenty-fouranimalexperiments,antioxidantsalleviatedacuteexperimentalpancreatitis.Inhumans,fivestudieshaveshownthat

thisdiseaseisassociatedwithsevereoxidativestressanddepletionoftheantioxidantdefensesbeta-caroteneandvitaminsCandE.OneclinicaltrialofNAChasproducedpromisingresults.

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PREECLAMPSIA

Thiscomplicationofpregnancy,theleadingcauseofmaternalmortalityintheWest,ismarkedbyhighbloodpressureandedema(swelling).Inbothplasmaandcerebrospinalfluid,thetotalnumberofantioxidantsisabovethenormallevelsseeninuncomplicatedlabor.Thisismainlybecauseoftheraisedlevelsoftheplasmaantioxidanturicacid,togetherwithsomeasyetunidentifiedagents.Weightforweight,thepredominantantioxidantinbloodisuricacid,whereasinthecerebrospinalfluiditisvitaminC.ThereisalsoincreasedconsumptionofvitaminCbythebodybutnotvitaminE[93].SerumlevelsoftheantioxidantenzymeGSHpxaredecreased,togetherwithsignsofincreasedlipidoxidation[164].Oxidativestressmayplayaroleinpreeclampsia,butasjustoneofanumberoffactorsinvolved.

RENALDIALYSIS

Theredbloodcellsinpatientsundergoingdialysissufferoxidativestress,withreducedlevelsoftheantioxidantenzymesSOD,CAT,andGSHpx.Thisresultsintheredbloodcells'dyingbeforetheyshould,becausetheyhavemorerigid(andthusbrittle)cellmembranesandaresubjecttoincreasedfatoxidation.Antioxidantsaddedtotheperfusionfluidwouldbeexpectedtobeadvantageous.Anotherkidneyailment,glomerularnephritis,isassociatedwithoxidativestress[219].Undialyzedpatientswithchronicrenalfailureshowafailureintheirantioxidantdefensesthatworsensastherenalfailureincreaseswithtime[29];subsequentdialysisworsensthecondition,whichmayaccountforthehighrateofatherosclerosisinthesepatients.

RHEUMATOIDARTHRITIS

Thisisanautoimmunediseaseinwhichtheimmunesystemmistakesthejointliningsforforeigninvadersandproceedstolaunchanattack

uponthembyreactiveoxygenspecies.Thefluidintheaffectedjointsinthesepatientshaselevatedlevelsofreactiveoxygenspeciesandfreeiron.Themoreseverethediseasethehigheraremeasuresoffatoxidationintheblood.ManypatientswithrheumatoidarthritisaremarginallydeficientinvitaminsCandE.Alowbloodlevel

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ofvitaminE,beta-carotene,andseleniumisassociatedwithaneightfoldincreaseintheriskforthedisease[11].Panettaetal.oftheLillyResearchLaboratoriesarecarryingoutastudyofnewsyntheticdrugs,suchas4-thiazolidinone,whichhavepotentantioxidantandantiinflammatoryactionsinthisdisease[159].

SYSTEMICSCLEROSIS

Thisisaconnectivetissuedisease(alsocalledscleroderma)duetooverproductionofcollagenthatleadstovasculardamageandRaynaud'ssyndrome(repeatedattacksofvascularspasmleadingtogangreneoftheextremities).Itismarkedbyrepeatedischemiaandreperfusioninthetissueswithresultingoxidativetissuedamage.Manyorgansareinvolved,includingtheheart,lung,intestines,andkidneys.ThesepatientshavelowplasmalevelsofvitaminCbutnormallevelsofvitaminE.ItisnotclearifthelowplasmalevelsofvitaminC-duetoneitherdietarydeficienciesnormalabsorption-isacauseorresultoftheoxidativestress.Antioxidantsmightwellbeeffectiveinthisdisease.

TUBERCULOSIS

Theinterestingfacthasbeenunearthedthatthebacteriumresponsibleforthediseasehasadefectinoneofthegenesthatregulatesitsantioxidantdefenses.Thus,intuberculosis,thesedefensesarelow.Thisexplainswhytheoxidantdrugisoniazidissoeffectiveintreatingtheillness.Relatedorganismsthatdonothavethisdefectivegenearenotsensitivetoisoniazid.

clinicaldataonantioxidants

FLAVONOIDS

SOY.

Inseventeenoutoftwenty-fiveanimalstudies,genistin,acomponentofsoy,showedanticanceractivity.InChinaandJapan,wheresoyconsumptionishigh,therearelowratesofcancerofthebreast,prostate,andcolon.However,epidemiologicalstudieslookingatthecorrelation

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betweenhighsoyintakeandcancerratehavebeeninconsistent.Outoftwenty-sixstudies,tenreportedpositiveresults,fifteennoeffect,andoneanegativeeffect.Soatleastthebalanceisinthepositivedirection.

REDWINE.

Goldbergexpressestheopinionthat,ifwealldranktwoglassesofredwineaday,theincidenceofcoronaryheartdiseasewouldfallby40percent[69,70].However,drinkingwineinexcessmayleadtocirrhosisoftheliver,and''theuseofalcoholforcardiovascularpurposesshouldnotbeencouragedasapublichealthmeasure"[36].Moreover,alcoholitselfisapro-oxidant,andLDL(badcholesterol)ismoreeasilyoxidizedinbeerdrinkers.

Askepticalnotewasintroducedbyareportfromacountrywithhighbeerconsumption(Holland).DeRijkaetal.gavetwenty-fourhealthypeoplewithnormalbloodfatsredwinesupplementsforfourweeks[42].Thelevelofplasmaantioxidantsandfatswasunchanged.However,thistrialwasprobablytooshort.AcontraryreportstatesthatconsumptionofredwinedoesreducethesusceptibilityofLDLstooxidation[59].

TEA.

Inonestudyamixtureofantioxidantsfromgreenteahadapotentinhibitoryeffectonthegrowthofmammarycancersinrats.Astudyofover1oo,000peopleinHollandshowedthatconsumptionofblackteaformorethanfouryearsdidnotlowertheincidenceofstomach,colorectal,orbreastcancer.However,blacktea(butnotgreentea)alsocontainstannins,whichcanpromotetumors.Aprospectivestudyof35,369womenintheIowaHealthStudyfoundthattheintakeoftwocupsof"nonherbal"teaaday(equivalent,inamountofantioxidantstherein,toonehelpingoffruitorvegetables)wasrelated

toasignificant40to70percentreductionintheincidencerateoftwotypesofcanceronly-digestivetractandurinarytract[240].Theauthorsofthestudyquoteanumberofotherstudiesshowingprotectionbyteaagainstoral,pharyngeal,andnasopharyngealcancers.Theysuggestthattheflavonoidsinteamayblockthecancer-producingnitrosaminesintheintestines.Theyalsomentionthatthekidneymightconcentratetheflavonoids,whichwillresultinhigherurinarylevelsofflavonoidsandtherebyhelpinfightingtumorsintherenaltract.Theywarn,however,thatdrinkingteathatistoohotmightincreasetheriskofesophageal

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cancer.TheprotectiveeffectofthelargeteaconsumptioninJapanmayberesponsibleforlowerlungcancerratesintheJapanese,despitetheirhigherrateofsmokingthanAmericans'.AnepidemiologicalstudyinJapanreportedthatcancerpatientswhodrankmorethantencupsofgreenteaadayhadanincreasedlifeexpectancy(by4.5yearsformenand6.5yearsforwomen)ascomparedwithcancerpatientswhodrankfewerthanthreecupsaday[60].

InthecaseofcoronaryheartdiseaseastudyinWaleshadanegativeresult[87].Theinvestigatorsselected1,900malesinCaerphillyandfollowedthemforfourteenyears.Therewasnocorrelationbetweentheamountofblackteadrunkandtheincidenceofheartattacks.Infact,thosepeoplewhodrankmoreteahadanincreasedgeneralmortalityrate.

FurtherresearchshowedthatteadrinkinginWalesisassociatedwithalesshealthylifestyle(obesity,smoking),whichwastheprobablecauseoftheincreaseddeathrate-anexampleofaconfoundingvariableatwork.However,theWelshstudydidfindaprotectiveeffectofonions,whichalsocontainprotectiveflavonoids.

GARLIC.

LaboratorytestshaveshownthatgarlicextractsprotectLDLsagainstfatoxidationandhaveantiviral,antimicrobic,andanticancerproperties.Experimentsinanimalsshowthatgarlicextractsslowthedevelopmentofatherosclerosis[50].Garlicalsoprotectsagainstirregularitiesintheheartbeatandpreventsthedevelopmentoffattystreaksoncoronaryvessels(apreludetoatherosclerosis)inrabbitsfedlargeamountsofcholesterol.

Fiveepidemiologicalstudies(inChina,Italy,Poland,Australia,andtheUnitedStates)haveshownthatadiethighinalliumvegetables

(i.e.,garlic,onion,chives,shallots,etc.)thatcontainallicinandrelatedantioxidantsprotectedagainststomachandcoloncancerbutnotagainstbreastandlungcancer.

Inanexperimentalstudyofischemicbraindamageinrats,garlicextractreducedthesizeoftheresultingbraindamageandreducedbrainreactiveoxygenspeciesproductioninthetreatedratsascomparedwithcontrols.

Thebacterium(Helicobacterpylori)responsibleforgastricandduodenal(peptic)ulcersisverysensitivetotheantibacterialeffectofgarlic

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[200].Theauthorssuggestthatcasesofpepticulcerthatareresistanttotheantibioticsnowusedtotreatthediseasemightbenefitfromtheequivalentoftwosmallclovesofgarlicaday.

OLIVEOIL.

Trichopoulousuggeststhatoliveoilmayoffera"modestprotection"againstbreast,ovarian,andlungcancer,mainlybecause,inadditiontoantioxidants,itcontainsmonounsaturatedfats,whicharemoreprotectivethaneithersaturatedanimalfatsorpolyunsaturatedfatsfoundinmanyvegetablesources[218].

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part3thesafetyofantioxidantsandrecomendations

thefirstruleforphysiciansHippocrateslaiddownwas"Thoushaltdonoharm."Therefore,itisofprimeimportancethatwefindoutifantioxidantsareharmlessbeforeweprescribethemtoourpatients.Thefirstsectionofpart3examinesthisquestionindepth.Thesecondsectiondiscusseswhatkindofdietisindicatedbythedata,whetherpeopleshouldorshouldnottakesupplementsofantioxidantsinadditiontowhattheygetinthediet,and,iftheydotakethem,underwhatcircumstancestheyshoulddoso.

safetyofantioxidantsJusthowsafearethecommonantioxidantsincurrentuse?Opinionsvarywildlyfromthebeliefthattheyarecompletelysafetoprotestationsthatundercertainconditionstheycanbehighlydangerousandevenlethal.Whatfollowsaretheactualdataonthesafetyofantioxidantsandadiscussionoftheopinionsofferedbyvariousexperts.

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BETACAROTENE

Severalauthoritieshavejudgedbetacarotenetobesafeorminimallyhazardous.However,itisclearfromtheresultsoftheCARETandATBCtrialsreviewedabovethatbetacarotenesupplementsgivenbythemselvesshouldnotbeusedinsmokers,inwhomthesupplementshavebeenreportedtoraisethedeathratefromlungcancer,heartattacks,andotherconditions.Norshouldtheybeusedinpeoplewhohavehadaheartattack.Animalstudiessuggestthatbetacarotenecanalsoincreaseliverdamagecausedbyalcohol.Itshouldthereforebegivenwithcautiontopeoplewhodrinkalotofalcohol.Furthermore,raisingbetacaroteneintakelowerstheserumlevelsoftheimportantantioxidantcarotenoids,lutein,andzeaxanthin.Thisisespeciallyrelevantintheeyediseasemaculardegeneration(seethesectiononeyediseases),becausebetacaroteneisnotfoundintheretina,whereasluteinandzeaxanthinareessentialforproperretinalfunction.Givingbetacaroteneinthisconditionwouldtendtodeprivetheretinaofgettingtheluteinandzeaxanthinitneeds;thelattertwoshouldbeaddedtoanyvitaminsupplementformula.Anotherpointtonoteisthatcanthaxanthinsupplements,takeninlargeamountsforalongtime,cancausecrystalstoformintheretinathatinterferewithvision.Fortunately,thecrystalsareabsorbeduponstoppingthesupplement.

Theyellowingoftheskincausedbybetacaroteneisbenignandcompletelyreversible,andinanycaseitlooksmorelikeagoodsuntanthanjaundice.

VITAMINC

BecausePaulingmademegadosesofvitaminCnotorious,therehasbeengreaterconcernaboutthepossibletoxicsideeffectsofvitaminCtakeninlargedosesthanoftheotherantioxidants.Inmostpeopledosesupto500mgperdayseemtobeperfectlysafe,yettheremay

besomeexceptions.

Oneproblemisoxalatekidneystones.ThechiefmetaboliteofvitaminCisoxalicacid,themainingredientinthemostcommontypeofkidneystoneintheWest(80percent).Chalmersetal.gaveseventeenkidneystonepatientsandelevennormalcontrols2GperdayofvitaminCbymouth,andreportedthattheformergroupexcretedmoreoxalateandlessvitaminCintheirurinethandidthecontrols[30].Whenthe

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vitaminCwasgivenintravenously,thisdidnotoccur.TheauthorssuggestthatthestoneformersarenotabletoabsorbvitaminCaswellasnormalscan;vitaminCtakenorallythusremainsintheintestineslonger,formingmoreoxalate,whichisabsorbedassuch.TheyadvisethatpeoplewhoformoxalatestonesshouldnottakevitaminCsupplements.Urivetskyetal.,whosestudyoffifteenkidneystonepatientsgiven2GperdayofvitaminCrevealedatwofoldincreaseintheexcretionofoxalateintheurine,concludedthatthechronicadministrationofvitaminCsupplementsmadethemmoreliabletoformstones[220].Theyadvisethatsuchpeopleshouldnottakemorethan500mgperdayofvitaminC.RiversagreesthatvitaminCposesnoproblemtonormalpeople,butthatoxalatestoneformersshouldnottakevitaminCsupplements[177].Goldfarbdoesnotagreewiththis,contendingthatnormallythemetabolicpathwayfromvitaminCtooxalateisworkingatfullblastanyway,sothatanyincreaseinvitaminCintakedoesnotleadtoanyincreaseinoxalateexcretionintheurine[77].TheexcessvitaminCissimplyexcretedasvitaminCintheurine.However,inafewsusceptibleindividualsamarkedincreaseinurinaryoxalatecanfollowtheingestionof1-2GofvitaminC.Schmidtetal.gavefourpatientsaverylargedose(10Gperday)ofvitaminCandfoundthatthemeanoxalateexcretionincreasedfrom50mgperdaytoonly87mgperday[189].Theyconcludedthatthiswasequivalenttothemagnitudeofeffectthatasimplechangeofdietcouldproduce.Diplockstatesthatthe"stonestory"hasprovenoncriticalexaminationtobe"withoutfoundation"[44].IfexcessvitaminCisingested,itisexcretedassuch,notasoxalate.Heattributesearlierstudies'apparentfindingsthatincreasingvitaminCintakeledtoincreasedoxalateoutputtotechnicalerrorsintheestimation,suchasallowingtheurinetobecometooalkaline.Infact,heconcludesthatvitaminCinthedosesnormallyusedinsupplementsisentirelyfreefromsideeffects.CertainlyIhavenotseenanyreportsofacaseinwhichakidneystone,inreallifeas

opposedtotheory,couldbetracedtovitaminCsupplements.Nevertheless,highdosesofvitaminCshouldbegiventoknownoxalatestoneformerswithcautionandonlyatthediscretionoftheindividualphysician.

AnotherpossibleproblemwithvitaminCisthat,inthepresenceoffreeiron,itbecomesapro-oxidantandshouldthereforenotbegiventopeoplewhomayhavefreeironthatmightreactwiththevitaminC.

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Normally,ironinthebodyissafelystoredinsidevariousproteins,andfreeironlevelsareextremelylow.Thisisjustaswell,asfreeironisexceedinglytoxic.Itthuscausesnoproblemsinthisregardinnormalpeople.Butsomeexperts(particularlyHerbert[83-851)advisethatvitaminCsupplementsnotbetakenbypatientswithironoverload,asinhemachromatosis,sideroblasticanemia,andthalassemia.HerbertsuggeststhatvitaminCsupplementsshouldnotbetakenifthebloodlevelofferritin,aniron-bindingprotein,isover120µg/L.Incontrast,otherauthoritiesstatethatironisalwayssafelyboundtoprotein;sovitaminCinfact,asopposedtotheory,neverinteractswithfreeirontoproducepro-oxidanteffectsinreallife[14,38,45,147].HerbertreferstoasubmissionpapermadebyM.KrikkertoanFDAcommitteethatmentions"severaldeathsinathletesduetothiscause."Iamnotawareofanysuchinteractionreportedinanyscientificpaper.HealsostatesthatpatientsinastudyontheeffectsofvitaminConcancerbyMoerteletal.[145]attheMayoClinicdid"muchworse"onvitaminC.Ihavereadthelatterpaperandwasunabletointerpretitinthisway.Infact,theMayoClinicgrouptreated1ooterminallyillcancerpatientswith10GperdayofvitaminCforuptoeighteenmonths(averagefourmonths)butthetreatmenthadnoeffectofanysort,goodorbad.ThestudywascarriedouttorefutetheclaimmadebyCameronandPaulingthatlargedosesofvitaminCproducedmarkedbenefitinsuchcases.Moerteletal.cametotheconclusionthatthisclaimwasbasedonasimpleerrorinthedesignofthetrial[145].DailyandZemel,inaneditorialintheAmericanJournalofClinicalNutrition,characterizeHerbert'scontributiontothedebateas"polarizinghyperboleandgrandstanding....WhatiscertainisthatthecontinuingdebateisnotwellservedbybeingreducedtothetypeofdiatribeevidentinHerbert'scommentary"[37].InapaperreadtoameetingoftheOxygenClubofCalifornia,GladysBlockpresentedevidencetoshowthatvitaminC,eveninthepresenceoffreeironinlivinghumans,actuallyinhibitsfatoxidation.

However,BartonandBertolipointout(asHerberthasclaimedovertheyears)thathemachromatosisisamuchmorecommondiseasethanisgenerallyrecognized[10].OnemillionAmericansarehomozygousforthegeneresponsibleandoneineightofthepopulationareheterozygous.Ironoverloadproblemsarecommonlyclinicallyoverlookedand

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screeningtests[49]shouldbemuchmorewidelyused[10].Suchtestswouldthereforeseemtobeadvisablebeforeadoctor'srecommendinghighdosesofvitaminC.

ThereareconflictingreportsastowhethervitaminCsupplementsmayinduceorimprovecataractsinelderlypatientswithdiabetes.Inmostpeople,aswesawearlier,vitaminCappearstoprotectagainstcataractsandagainstdiabetes.Elderlydiabeticsmayproveanexceptiontothisrule.

Toavoidhemolysis,vitaminCshouldnotbegivenintravenouslytopatientswithaconditionknownasglucose-6-phosphatedehydrogenasedeficiency[122].BendichandLangsethstatethatsomepreviousanecdotesclaimingtheallegedtoxicityofvitaminChavebeenexaggerated[12].IncontrolledtrialsithasbeenshownnottodestroyvitaminB12,itisnotmutagenic,itdoesnotcausereboundscurvyorabnormalpsychologicalreactions,anditdoesnotimpaircopperutilization-allofwhichhadbeenclaimedpreviouslyonananecdotalbasis.However,itcaninterferewithanumberofclinicalandlaboratorytests[143],includingbloodleveltests.Thetestsforglucose,uricacid,creatinine,alkalinephosphatase,andinorganicphosophategivefalselyhighlevels.Thetestsforbilirubin,lactatedehydrogenase,carbondioxide,potassium,catechol-o-methyltransferase,monoamineoxidase,cholesterol,creatinekinase,anddopa-ß-hydroxylasegivefalselylowlevels.Thetestforoccultbloodinfecesgivesafalsenegativeresult.Testsforacetaminophengivesfalsepositiveresults.AnumberoftrialsoflargedosesofvitaminC(forexample,thosebyPaolissoetal.[160],whogave1Gperdayforfourmonthstoforty-ninepeople;Busseyetal.[25],whogave3Gperdayfortwoyearstoforty-ninepeople;andMcKeowen-Eyssenetal.[136],whogave400mgperdayfortwoyearstoninety-sixpeople)havereportednosignificantsideeffects.

InanimalexperimentsvitaminCcanhaveeitheranticancerorcancer-promotingeffects,dependingoncircumstances.VitaminCdepressesDNA,RNA,andproteinsynthesis(i.e.,cellgrowthanddivision)insomecancer(neuroblastoma)cellsthathavehighironlevels,butitdoesnotdosoinnormalcells.ThehighironlevelscausethevitaminCtohaveapro-oxidanteffect.ThissuggeststhatvitaminCmightbeapowerfulenhancerofsomeantitumordrugsusedinthetreatmentofneuroblastoma.VitaminCcausesDNAdamageinneuroblastomacellsbutnotnormal

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cells.Benzathione(apowerfulcarcinogen)toxicityinguineapigsisreducedbyvitaminC.

Inonestudy,whereasanantioxidantmixtureofbeta-carotene,vitaminsCandE,andglutathionewaseffectiveinpreventingtheproductionoforalcancersbycancer-producingchemicalsinhamsters,vitaminCgivenbyitselfactuallyincreasedthecancerrate[194].TheresearcherssuggestedthisresultmightbeduetotheproductionoftoxicderivativesofvitaminCthatarenormallymoppedupbyvitaminEandtheotherantioxidantsinthemixture.Withoutthismopping-upoperation,vitaminCbyitselfprovedtobeharmful.Thisresultstressesonceagaintheenormousimportanceoftheteamactionoftheantioxidants.ThisisfurtherstressedbyPrasadandKumar,whostatethatmultipleantioxidantadministrationisessentialforthemaximumreductionofcancerincidenceinahigh-riskpopulationandthattheuseofjustoneortwoantioxidantsislikelytobeineffectiveandevenharmful[165].

However,astudybyJacquesetal.suggeststhatthisisnotanabsoluterule[96].TheymeasuredtheeffectsonbloodlevelsoftheraisedintakeofonlyoneofeithervitaminC,vitaminE,orcarotenoids;givingonlyoneledtoraisedbloodlevelsofoneorbothoftheothertwowithoutanyimpairmentofantioxidantstatus.Theyexplainedthisresultbypostulatingvariousinteractionsbetweenthedifferentantioxidantsatseverallevelsduringthepreparationoffood,inthegastrointestinaltract,inthecell,andbysparing.Forexample,theraisedvitaminClevelmayconvert,byitssynergisticaction,moreinactivatedoxidizedvitaminEtotheactiveformofvitaminE.

VITAMINE

ThereareonlytworecognizedcomplicationsofvitaminEtherapy.Thefirstisthatitcanworsenthecoagulationdefectcausedbyvitamin

Kdeficiency,whichisdueeithertomalabsorptionofvitaminKfromtheintestinesortoanticoagulanttherapy.Thesecondisthat,whereasvitaminEcertainlylowersbloodplateletcounts,thismaynotalwaysbebeneficialincertainpeople,asitmayincreasetheriskofhemorrhagicstroke.Therefore,solongasthesearerecognized,vitaminEtherapyisconsideredsafebymostauthorities[53,138,187,226].ByersandBowman,however,worryaboutpossibleasyet

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unknownsideeffectsoflong-term,high-dosevitaminEtherapy[26].ThisworrydoesnotseemtobejustifiedinviewofthefactthatmanyhundredsofthousandsofpeoplehavetakenvitaminEsupplementsoverthelastdecadewithoutanyreportsofsuchcomplications.However,raisingthelevelofintakeofalpha-tocopherol(vitaminE)lowersthelevelofitscloserelativegamma-tocopherol.Gamma-tocopherolismorepotentthanalpha-tocopherolindetoxifyingnitrogendioxide(thepotentoxidantinsmogandcigarettesmoke);thus,gamma-tocopherolshouldbeaningredientinanyantioxidantprogram.

recommendationsWhatconclusionscanwedrawfromthismassofdata?Giventhatmanyoftheinvestigationsandexperimentshavehadcontradictoryandconfusingresults,clearlymuchmoreworkneedstobedonetoclearupsomeoftheissues.However,certainthingshavealreadybeenclearlyestablished.

Itcannowbetakenasafactthattoxicreactiveoxygenspeciesplayasignificantroleinmanyacuteandchronicdiseasessuchasinflammation,coronaryheartdisease,cancer,diabetes,cysticfibrosis,rheumatoidarthritis,Alzheimer'sdisease,Parkinson'sdisease,andmanymore.Furthermore,theyplayanimportantroleinmanynormalbodilyprocesses,suchascontrolofgeneexpression,immuneresponses,controlofbrainsynapses,theactionofwhitebloodcellsinkillingbacteria,andothers.Wenowknowquitealotaboutthenatureofthebody'sdefensesagainstreactiveoxygenspecies.Morethantwentyimportantantioxidantsystemsinthebodyhavebeenidentified.

Itisalsonowbeyonddisputethatahealthydietshouldbedesignedto

haveaplentifulandvariedsupplyoffruitsandvegetables,aswellasaproperattentiontotherightandwrongsortsoffat,reducedsalt,andalowalcoholandlowcalorificintake.However,eventoday,ithasbeenestimatedthatonlyopercentoftheU.S.populationfollowthisadvicewithregardtofruitsandvegetables.Dietaryhabitschangeslowly.Inmanyareasfruitsandvegetablesareexpensive,andsomepeoplecannotaffordthem.ManyrestaurantsintheUnitedStatesaredieteticdisasterareas,withredmeat,saltypotatoes,andbutterybreadsasthestaplefoods.InSanDiego,California,theYellowPageslistonlyeightvegetarianrestaurants.

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Inhomekitchensmanyvegetablestendtobeovercooked,whichdestroystheirvitaminC.Howmucheasiertobuyabottleoftabletslabeled''antioxidantvitamins"andtrustthatwilldothetrick!

Furthermore,thegeneralpubliciscurrentlymuchconfusedbyallthecontradictoryreportsthathavebeenpresentedbythemedia.Onedaybetacaroteneisin,thenextitisout.Onedaymargarineisrecommendedinsteadofbutter;thenextdayadifferentadviceisgivenfollowingtentativeresearchreportsbyscientists.Manybookswrittenforthegeneralpubliconthistopicareuncriticalandmisleading.

Asitisnowclearthatantioxidantsworkasateam,itispointlesstodesignlargeandexpensiveclinicaltrialsofjustoneortwooftheantioxidants.Theantioxidantmixturetobetestedshouldcontainalltheprominentantioxidants,bothwater-solubleandfat-soluble,variouscarotenesandflavonoids,andpossiblyagentsdesignedtoraiseglutathionelevelsinthebody.

Mostexcessmineralsaddedtothesupplementaresimplynotabsorbed,exceptincasesofmineraldeficiencyfromthepreviousdiet.Seleniumisanexception,butseleniumoverdosageistoxic.However,calciumandmagnesiumarebeneficentevenwhennotabsorbed,astheyformveryinsolublesaltswithdeleteriousfattyacidsintheintestinesandsopreventtheirabsorptionfromtheintestines.Thismayhelptopreventcolorectalcancer.Calciumisalsorequiredbysomepeopletoguardagainstosteoporosis.

Furthermore,thereisnowaverystrongcasethatantioxidantsareneededinthemedicaltreatmentofspecificconditionssuchasischemia/reperfusion,acutemyocardialinfarction,asthma,shock,ARDS,cysticfibrosis,diabetes,Alzheimer'sdisease,andsoon.FurtherresearchmayadddiseaseslikeParkinson's,schizophrenia,ALS,andAIDStothislist,astheevidencealreadylookspromising.

Thepresentmajordisagreementcentersonwhetherantioxidantsupplementsshouldberecommendedforthegeneralpopulationinanattempttowardoffthedevelopmentofchronicdiseasessuchasheartdisease,cancer,cataract,andParkinson'sdisease.Inotherwords,shouldweraisetheRDAsforthekeyantioxidantvitamins?

Thefollowingisanaccountofthemostup-to-daterecommendationsmadebyrecognizedexpertsinthefield,beginningwiththosewhoadviseagainstraisingthepresentRDAs.

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MeyersandMaloleyrequire"clearproof"ofefficacyandthelackoflong-termtoxicitybeforetheycanrecommendsupplementsofvitaminsCandE[143].Theymaintainthatmanyoftheresearchreportsthatsuggestthatsuchsupplementsareneededareflawedbynottakingintoaccountotherriskfactorsforheartdiseaseandothercomplicatinghealth-consciousbehaviors(healthylifestyles)bythesubjects.However,aswehaveseen,manypositivetrialscannotbeexplainedonthehealthy-lifestylehypothesis.MeyersandMaloleyestimatethat,inspiteoftheiradvice,some25percentofAmericansself-medicatewithvitaminsupplementsonaregularbasis.

IllingworthagreeswithMeyersandMaloleyandoffersthiscaveat:"Intheabsenceofmoreconvincingclinicaltrialdataitseemsprematuretoadvocatesupplementationwithantioxidantvitamins[topreventcoronaryheartdisease]exceptinselectedhighriskpatients"[94].

Oliversays"thereisasoundscientificbasisandrationaleforincreasingtheintakesofvitaminEandCtoreduceoxidationofLDL"topreventcoronaryarterydisease,butheconcludesthatitisstilltooearlytorecommendsupplements."Thebestpossibleadvice"istoeatfoodshighinvitaminsCand/orE,includingcerealoils,nuts,freshcitrusfruits,freshvegetables,andpotatoes-manyofwhichareexpensive[151].Potatoes,whichareaffordable,arelackinginantioxidantsotherthanvitaminC,andfoodsourcesrichinEareallfatty.

RautalahtiandHuttunenofFinland'sNationalPublicHealthInstitute,Helsinki,adviseagainstantioxidantsupplementsforthepreventionofcancerbecauseofthelackofagreementintheclinicalresearchbase[171].However,thetrialstheymentionarehardlyafairselectionofthedatabase.Theyselecttwonegativetrials,oneinmelanomaandtheothertheflawedATBCtrialinFinland,wherewehaveseenthat

inadequatedosesofsyntheticvitaminEwereusedinthehopelesstaskoftryingtorollbacktheeffectsofheavycigarettesmokingoverhalfalifetime.ThepositivetrialtheyciteistheLinxiantrialinChina,inwhichthesubjectswerenutritionallydeprivedanyway[18].Theyshouldhaveusedabetterandwiderdatabase.

Maxwell[132]andHoffmanandGarewal[90],inreviewsofatherosclerosis,saythatthoughresearchtodatehasyieldedpromisingandexcitingresultstheycannotadvocateantioxidantsupplements-againlargelyonthebasisoftheflawedATBCtrial.

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Diplocksaysweneedtolookatthreelevelsofevidence[143]:

1.epidemiologicalstudiesoftherelationbetweenlevelsofintakeofnutrientsanddiseaserates,

2.prospectivestudiescomparingplasmalevelsofnutrientsanddiseaserates,

3.double-blind,placebo-controlledinterventiontrials.

Heconcludesthatthereisampleevidencefromlevels1and2tolinkantioxidantsandcoronaryheartdiseaseandsomeformsofcancer.Butthereisasyetlittleevidencefromlevel3.

ThedisagreementamongdoctorsonthismatteriswellillustratedinthepagesofthetwentietheditionoftheprestigiousCecil'sTextBookofMedicine,publishedin996.Inhischapterentitled"CancerPrevention,"GilbertOmennhardlymentionsantioxidants.InhisdiscussionofdiethementionsonlytheroleoffatandfiberandignorestheextensiveliteratureIhavequotedontheroleofantioxidants.Inhisdiscussionoftestsofsupplementsofantioxidantvitaminsincancer,hementionsonlytheFinnishATBCtrial,butnotitsmanydefects.Incontrast,WilliamBlot,inhischapteron"TheEpidemiologyofCancer,"givesprominencetotheroleoffruitsandvegetablesandsaysthatcarotenoidsaswellasvitaminsCandEcanreducetheriskofgettingcancer.JoelMason,inhischapteron"ConsequencesofAlteredMicronutrientStates,"alsostatesthatbeta-caroteneandvitaminEareprotectiveagainstsomecancers.RolandWeinsier,inhischapterondiet,statesthat"unprescribeddailyuseofsupplementsinamountsexceedingtherecommendeddailyallowanceshouldbeavoided.''Iagreeherewiththeword"unprescribed."Thecomplexitiesofantioxidanttherapyaresuchthatitshouldnotbeusedwithoutmedicaladvice,asIexplainlaterinthissection.

Argumentsfortheotherposition-thatRDAsshouldbechangednow

andthatantioxidantsupplementshaveaplaceintreatment-havecomefromsomeequallyeminentauthorities.

InaneditorialintheJournaloftheAmericanCollegeofNutrition,Blumbergexpressesthecontrarypositionforcefully[19]:"Itisunrealisticandunnecessarytowaituntiltheclinicaltrialsarecompletebeforeapplicationsfordiseasepreventionareendorsed."Hesaysthattheevidenceshouldbejudgedintotoandnotjustonthestandardsappliedto

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newdrugs-thatis,prospective,randomized,double-blind,placebocontrolledtrials.Healsocommentsthatantioxidants"appearremarkablybenignevenathighsupplementaryintakes"andthattheyareinexpensivetoboot.Heconcludes:"Recommendationtowaituntileveryconceivablestudyhasbeendesignedandconductedtoachievealevelofabsolutecertaintywillresultinthecontinuingcostofthediseasetotheindividualandsociety."

GeyagreesthatanupdatedprudentdietshouldcontainmorethanthecurrentRDAsofvitaminsCandEandbeta-caroteneplussupportingplantantioxidants[64].TheintakeofvitaminCneededtopreventscurvyis1mgperkgofbodyweightperday,whereasmostotheranimalsmakevitaminCatamuchhigherrate(40-275mg/kg/day,or3-19G/dayforahumanweighing70kg!).Moreover,ithasbeenestimatedthatourStoneAgeancestors,wholivedbyhuntingandgathering,hadavitaminCintakeofabout325mgperday.ItisthereforelikelythatevolutionhasproducedahumanbodythatneedsthisamountofvitaminC.

Mehraetal.state,"Itshouldberecognizedthat'definitivedata'isoftennotavailabletosupportalldecisionsinmedicalpractice"[138].Theyroutinelyrecommendantioxidantsupplements(beta-caroteneandvitaminsCandE)fortheprimaryandsecondarypreventionofatherosclerosis.Buttheystressthatthisisnotasubstituteforarigorousprogramofreductionofalltheotherknownriskfactors.Leskeetal.givesimilaradviceforcancerprevention[121].WeisburgeroftheAmericanHealthFoundationsaystheconceptofRDAs,withitsfocusontheavoidanceofdeficiencydiseases,isoutofdate[231].Hesaysthatitshouldbereplacedbythenewconceptofoptimalnutritiontoavoidchronicdiseasesandtoprotectagainstenvironmentaltoxins.ByersandBowmansay"betterdietaryadvice,possiblefortificationoffoodsupplies,andtheuseofrationallyformulatednutritionalsupplementsmaysoonemergeaspublichealth

strategiestohelppreventchronicdiseases"[26].

However,optimallevelsofintakehaveyettobedefined.OnthispointTengerdysays,inthecaseofvitaminE,thattheoptimumdosedependsonmanyfactorsandneedstobedeterminedforeachperson[215].Inparticular,becauseofthedemonstratedeffectofvitaminEinboostingimmuneresponses,herecommendsvitaminEsupplementationforthreetofourweeksbeforevaccination,providedthebloodlevelofthevitamin

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ismonitoredandanadequateseleniumintakeisassured.An"updatedprudentdiet,"accordingtoGey,shouldcontainImgofvitaminA,6-15mgofbetacarotene,60-250mgofvitaminC,and60-100mgofvitaminEsupportedby"plantantioxidants"[64].ToxiclevelsareestimatedbyVanderHagenetal.asover150,000IUforbetacarotene,1GforvitaminC,800mgforvitaminE,and500µgforselenium[221].Theseauthorssupporttheuseofsupplementsforthepreventionofeyedisease.BarberandHarrisadvisethefollowinglevelsofintakeofantioxidants:betacarotene15-30mg;vitaminC100-500mg;vitaminE200-800mg;selenium1o-1ooµg[9].Hathcocksaysthattoinhibittheformationofcancer-producingnitrosaminesinthestomachcompletely,oneneeds1GperdayofvitaminC[80].HealsonotesthatveryhighlevelsofingestionofvitaminCcansuppresstheabsorptionofcopperandthathighlevelsofzincingestion(100-300mgperday)canraiseLDLandlowerHDLlevels.

Inresponsetothosewhorecommendrelyingentirelyongettingpeopletochangetheirdiet,Johnsonsaysthatexperiencedcliniciansknowthatpeoplerarelychangetheirdietaryhabits;therefore,thisapproachis"likelytobetheleastacceptable,orpossible,orsuccessfulformanyhigh-riskindividuals"[98].ThissentimentissupportedbyWeisburger,whorecommendsvitaminsupplementationforpeoplewhodonot,willnot,orcannotaffordtoeattheirthreeservingsofvegetablesandtwooffruitaday[230].

Levineetal.pointoutfiveflawsinthecurrentmethodfordeterminingtheRDAofvitaminCandlisteightcriteriaastohowitshouldproperlybedone[122].TheystatethatthecurrentRDAsdonotreflecttheoptimumdosage,butwedonotyetknowenoughtosayexactlywhattheoptimumamountshouldbe;theysuggestprovisionallybetween200-500mgperdayofvitaminC,asmuchaspossiblefromfruitsandvegetables.Aswesawearlier,thedietofour

Paleolithicancestorshasbeenestimatedtocontainaround325mgofvitaminCperday.Themaximumamountobtainablefromanormaldietisaround500mgperday.

AnimportantpaperbyLevineetal.providesthestrongestevidencetodatethattheRDAforvitaminCshouldberaised[123].TheystudiedsevenhealthyvolunteersoversixmonthsonvariousdosesofvitaminC-

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from30to2,500mgperday-andmeasuredhowmuchvitaminCinthedietisneededtoobtainamaximumbloodlevel.TheyfoundthatthepresentRDAof60mgperdaydoesnotdothis;1oomgperdayarerequiredtosaturatethebloodcells(redandwhite),whichshowaconcentrationfourteentimesthatofplasmalevels.But200mgperdayareneededtoachievesatisfactoryplasmalevels.SotheyrecommendthattheRDAforhealthyyoungmenberaisedto200mgperday.Theystatethatanyintakeover500mgperdayissimplyexcretedintheurineandthereforewasted,butthatlevelsupto1Gperdayaresafe;abovethatleveloxalateanduratelevelsintheurineincrease.However,theystressthattheserecommendationsapplyonlytohealthyyoungmen;differentlevelsmaybeneededforwomen,smokers,thesick,andtheelderly.

Blockhaspublishedacogentcriticismoftheorthodoxviewthatonlydouble-blind,placebo-controlledtrialscansupplytheanswertothisquestion[16].Listingaseriesoffallaciesinthisapproach,shesaysthesetrialsusually:

selectpersonsathighriskforadisease;

rarelytestmorethanoneortwosubstancesandusuallyatasingledose;

testonlytheefficacyofanagentgivenforalimitedtime,usuallylateinlife;

telluslittleaboutpreventionoflong-termchronicdiseases;

tellusnothingaboutwhethertheagentathighdosemightreducetheriskofchronicdiseasesiftakenthroughoutalifetime;

tellusnothingaboutthecombinationofantioxidants,whichwehaveseentobesoimportant;

donothingtoresolvethequestionsthatinterestus,whichinvolve

personswithnounusualriskofdisease,alifetimeexposuretonoxiousandprotectiveagentsinvolvinganenormouslycomplexinteractionamongnutrients,andtheeffectsofthesenutrientsonhundredsofdiseases,manyuncommon.

Clinicaltrials,shesays,simplycannotanswerthesequestions.Whatweneedisasolidexaminationofthelaboratoryandepidemiologicalevidence.

Myadditionalcommentsarethatmanypresent-dayrecommendationsapplyonlytopeoplenotunderoxidativestress,thattheydonotaddress

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thequestionofteamworkbetweenantioxidants,andthattheydonotconsiderthepossiblepreventionofanumberofchronicdiseasesasopposedtoonlyone.Furthermore,iftheintakeofvitaminEisraisedto400-800mgperday,thenmorevitaminsCandB3(nicotinamide)willbeneededasavitaminEhelpers.

DraperandBettgersaythatthequestionofwhetherRDAsshouldberaisedisapharmacologicalmatterandnotonefornutritioniststodiscuss[45].Florenetal.placetheresponsibilityontheindividualphysician,whoshouldrelyonhisorherclinicaljudgmentastowhethertoprescribevitaminsupplements[56].Thetroubleisthatmanycliniciansdonothaveaccesstoreliableinformationonwhichtobasetheirclinicaljudgment-thatgapbeingoneofthisbook'sintentionstofill.

A1997surveybasedinNewOrleanswasmadebyaquestionnairethataskedcardiologistsiftheytookantioxidantsupplements[139].Forty-fourpercentofthosewhorespondedtothequestionnairesaidthattheydid(inthedailyrangeof400mgofvitaminE,500mgofvitaminC,and20mgofbeta-carotene).Ironically,only37percentofthemsaidthattheyrecommendedthesesupplementsfortheirpatients.

Anewapproachisnowbeingexplored:howtoenrichourfoodwithantioxidantandprotectiveagents.Thesimplerapproachistoaddantioxidantvitaminstobasicfoods.Studiesaddressthegeneticengineeringoffoodtopreventheartdiseaseandcancer[105],andsuchmeasuresasgrowinggarlicwithseleniumfertilization[95].Theauthorsofthesestudiesstatethat"inviewoftheimpossibletaskofpersuadingthepublictoeatonlythosefoodsthatarepresumablygoodfortheirhealth...thetimehascometoenrichourfoodswithknowncancerpreventiveagentssothattheirbenefitcanberealizedfullyoverthelifespanoftheindividual"[95].Theirgloomyestimationofthepotentialtopersuadethepublictoimproveitsdietis

supportedbyastudyofanintensive,two-yeareducationalandexhortationcampaigninwhichinvestigatorsoperatedfromaselectedsupermarket.Theyhadonly"modest"resultsingettingthesubjectsoftheexperimenttobuymorehealthyfoods.Themainimprovementlayinincreasingthepurchaseoffruitsandvegetables.Measurementofanyfurtherchangesinnutritionalknowledgeandattitudesshowedonly"mostmodest"improvements[179].

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conclusionsInspiteofthemanydisagreementsintheliteratureoverdetails,thetotalevidencefromallsourcesseemstoindicatethatantioxidantscanplayaroleinthepreventionandtreatmentofmanydiseases.Moststudiesreportpositiveeffectsinsomeareaseveniftheydonotagreeonthedetails.Thereareveryfewreportsofactualharmfulresultsofgivingantioxidants-infactasopposedtotheory.Inthosethatdo,thecauseoftheharmfulresultisusuallyclearandcanbeavoided.

However,themainproblemremains,whetherweshouldrelyondiet,orsupplements,oracombinationthereof.Obviously,inthebestofallpossibleworldsthebestsolutionwouldbediet,withtheprovisothatvitaminEsupplementsshouldbetakensothatapersoncanavoidconsumingtoomuchfatfromvitaminE-richfoods.ThisinturnrequirestakingenoughvitaminEhelpers,suchasvitaminsB3andCandselenium.IdonotseehowanyonewhohasstudiedthedataonvitaminEinthepreventionofheartdisease(giveninpart2)couldfailtorecommendthattheRDAforthisantioxidantvitaminberaisedtoatleast400mgperday.Thewell-conductedinvestigationswithpositiveresultsshowingtheprotectiveroleofvitaminEcannotsimplybeignored.AgoodreviewofthistopichasbeengivenbyWeberetal.[228].Furthermore,adiethighinfruitsandvegetablesdoesmorethanprovideantioxidants.AsWisemanandHalliwellsayintheirreview,"itwouldbenaiveintheextremetoassumethattheprotectiveeffectsoffruitsandvegetablesarerelatedonlytotheirantioxidantcontent"[234].Otherimportantfactorsincludeantiangiogenesisfactors,inducersofenzymesthatcombatcarcinogens,fiberandphytates,aswellasareductionoftheintakeoffatandiron.Ontheotherhand,someantioxidantsmayinfactexertsomeoftheirbenefitsbymeansotherthantheirantioxidanteffect-forexample,thelikely

actionofvitaminCinmoppingupcarcinogenicnitrosaminesinthestomach.

Furthermore,thesimpleadmonishmenttoeatmorefruitsandvegetablesisnotenough-whichfruitsandvegetables?Again,prudentadvicewouldbeawidevariety,includingsourcesofcarotenes(carrots,apricots,spinach,redandyellowpeppers,andcollardgreensforbeta-carotene;darkgreenleafyvegetablesforluteinandzeaxanthin;tomatoesandpeanuts

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forlycopene);offlavonoidsandpolyphenols(onions,greentea,oliveoil,redwine,peanuts,coffee,chocolate,oranges,licorice,andmanyothers);ofvitaminE(nuts,grains,margarine,mayonnaise,wholewheatgerm,darkgreenleafyvegetables);andvitaminC(potatoes,citrusfruits,andothers),togetherwitholiveoilwheneverpossible,garlicandshallots(forallicins),andthespicesandherbslistedearlierthatcontainarichvarietyofantioxidants(seetheappendixformoredetails).NotethatpotatoesdonotcontainsignificantamountsofantioxidantsotherthanvitaminC.

Healthauthoritiesneedtomountamuchmorevigorouscampaigntoinformthepublicoftheenormousimportanceofamassivenationwidechangeineatinghabits,inparticularwithregardtofruitsandvegetables.ItissomewhatdepressingthatPattersonetal.madepreciselythissamepointin1990[162].TwoyearslaterBlackburnpointedoutthatthefruitandvegetableindustryhadshowedlackofleadershipbyfailingtopromotetheirwares(exceptforavocados,prunes,raisins,andbananasnoneofwhichcomeatthetopofourlistofhealth-promoters)[15].Healsocalledforanationalcampaign(whichhasfailedtomaterialize).Heestimatedthepotentialsavingofsome$150billionayeariftheU.S.dietcouldbeimprovedsimplytoconformtopresentofficialrecommendations.TheNationalCancerInstitutehasstartedaprojectinconjunctionwiththeagriculturalindustrywiththeaimofincreasingpeople'sfruitandvegetableintake.

ApaperfromSouthAfricaentitled"PublicNutrition:WhoIsListening,Responding,andActing?"makesevenmoredepressingreading[226].Init,Walkermakesthefollowingpointsbasedonasurveyofthecurrentliterature:

Themajority(90percent)ofthepublicintheUnitedStates(andmanyotherindustrializedcountries)donotfollowofficialnutritionalguidelines.

Therehasbeennoreductionintheintakeofcalories,totalfat,andsaturatedfat.

Theconsumptionoffruitsandvegetableshasnotincreased.

Poorpeoplecannotaffordenoughfruitsandvegetables.

InmanydevelopingcountriespreviouslyhealthydietsarebeingreplacedbytheinjuriousWesterndiet.

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OfsevensurveysinvariouscountriesofthehealtheffectsofthedietduringtheWorldWarIIperiod,allshowedareductioninobesity,diabetes,coronaryheartdisease,anddentalcaries.Duringthatperiodtherewasaprofounddecreaseintheconsumptionofanimalfats,sugar,andmeat.Consumptionofmanybasicvegetablesrose.Obesityanddiabetesarecurrentlyontheincreaseamongmanysegmentsoftheworld'spopulation.

Currenttelevisionadvertisingbythefoodindustryconcentratesontryingtosellfoodhighinfat,sugar,andsaltandisparticularlyaimedatchildren.

Parentsneedtoredoubletheireffortstogettheirchildrentoeatfruitsandvegetables,which,forsomeunfathomablereason,manyofthemseemtodetest.Furthermore,howmanydoctors,whotreatcommonchronicdiseases,activelyencouragetheirpatientsandtheirpatients'familiestofollowthissoundnutritionaladvice?AstudyinMassachusettsofprimarycarephysiciansfoundthattheamountofdietaryadvicetheygiveisactuallydeclining[227].Theresearcherssaidthatthiswasprobablyowingtothelackofvalidandconsistentdatapresentedtosupportmanyofficialdietaryrecommendations.OtherstudiesofprimarycarephysiciansinAustraliaandHollandhaveshownthattheirdifficultiesaroseforseveralreasons.Thesephysiciansfeltuncertainastowhethertheywereentitledtointerfereintheirpatient's"lifestyles"unlessaskedtodoso.Theyreflectedtheemphasisinmodernmedicineoncureratherthanpreventionandconfessedtoalackofknowledgeofthefield,lackofconfidenceintheirexpertiseonnutritionalissues,andlackoftimetodiscussthesemattersduringabusyclinicalpractice.

Onepotentreasonwhythepublicdoesnottaketheadvicetoeatmorefruitsandvegetablesseriously,Isuggest,isthefailureoftheauthorities(suchastheFoodandNutritionBoardoftheNational

AcademyofSciences)toraisetheRDAsofantioxidantvitaminsandrelatedsubstances.AdvicetothepublicmustbebackedupbystatementsfromtheNationalResearchCouncil,theNationalAcademyofSciences,theFDA,theSurgeonGeneral,andothersimilarbodiesexplainingthatpeopleshouldtakemoreantioxidantvitaminsthanjusttheminimumamountneededtopreventvitamindeficiencydiseasesinviewofthenowoverwhelming

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evidencethatantioxidantvitamins,andantioxidantsingeneral,domuchmorethanthat.Healthofficialsmustalsothenurgepeopletoobtaintheirvitaminsandantioxidants,asfarasispossible,byimprovingtheirdiets.Onegroupofferinghealth-relatedpronouncements,theAllianceforAgingResearch,hasinfacturgedthattheRDAsberaisedimmediately.

Concedingthatmanypeoplewillstillnotfollowgoodadviceaboutdiet,weneedtoadvisethenextbestthing,whichistotake,undermedicalsupervision,abalancedsupplementregimencontainingaswideavarietyofsynergisticantioxidantsascanbeobtained.Medicalsupervisionisadvisableforthesereasons:Apersonmayhaveaconditionsuchasironoverload,orbeakidneystoneformer,withoutknowingit.Antioxidantscouldinterferewiththewaythebodyusesreactiveoxygenspeciesinfightingacutebacterialinfections.Also,someanticancerdrugsdependonreactiveoxygenspeciesfortheireffectiveness.Thus,duringthecourseofanacutebacterialinfectionorduringcancerchemotherapy,antioxidantsshouldbetakenonlyuponmedicaladvice.Finally,apersoniswell-advisedtotakeasupplementprogramdesignedforhisorherownparticularneeds;andonlyadoctorcandeterminewhattheseparticularneedsare.TheAllianceforAgingResearchrecommendationsfordailyintakelevelsarevitaminC,250-1,000mg;vitaminE,100-400mg;andbeta-carotene,10-30mg.Theyalsorecommendthataphysicianalwaysbeconsultedtosupervisethisprogram.

Ithasbeenclaimedthatbenefitsfromaddingtracemineralstotheregimenarelikelytobeminimalasthesewillsimplynotbeabsorbed,exceptincaseswherethepatient'sdietissopoorastobeshortofessentialminerals.However,aswehaveseen,calciumandmagnesiumformveryinsolublesaltswithundesirablefattyacidsintheintestinesandtherebyhelppreventtheirabsorption,thusremovingoneoftheriskfactorsforcolorectalcancer.Peopleatriskfor

osteoporosishaveaspecialneedforanadequateintakeofcalcium.

Thefailureofthegeneralpopulationtofollowgoodnutritionaladviceisparalleledbytheinabilityorunwillingnessofthebulkofthepopulationtotakeenoughexercise,asmanysurveysshow,andbythefactthatmanypeoplestillsmoketobacco,thesinglebiggestprobleminpreventativemedicine.

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Mostparticipantsinthisdebateassesstheneedtogiveornottogiveantioxidantsupplementsfromtheviewpointofjustonedisease,whetherheartdisease,cancer,cataract,diabetes,andsoon.However,raisingantioxidantintakemayprotectagainstawiderangeofdiseases,whichincreasesthebenefitsideoftherisk-benefitratio.

Theoxidativedamagethateventuallyleadstochronicdiseaseshasacumulativeeffectovermanyyears.Itwouldbeinefficienttotrytocorrectthisbymeansofantioxidantinterventionatalatestageintheprocess.Theantioxidantsshouldbegivenbeforethedamageisdone,aswesawclearlyinthecaseoftypeIdiabetesandParkinson'sdisease.Thetroubleisthatitisdifficulttopredictwhoisgoingtogetaparticulardisease.Incertaindiseases,suchasatherosclerosisandtypeIdiabetes,therearehighriskfactorswecanmeasure.Butwhataboutthosediseases,suchasParkinson'sdisease,nosuchmeasuresyetexist?IfeveryoneovertheageoffortyweretochangetoaMediterranean-stylediet,orpartakeofanadequateantioxidantprogramaswellasthebestdiettheycouldmanage,itseemsverylikelythattheincidenceofmanychronicdiseaseswouldfall.Ofcourse,thiscannotbeabsolutelyguaranteed,butmedicinewouldbeinasorrystateifonlymathematicaldegreesofcertaintyweretobeaccepted.WilliamRaspberry,inacolumnintheWashingtonPost,haspredictedthat,inviewofthecurrentseriousfinancialcrisisfacedbyMedicare,itwillsoonbefiscallyessentialforpeopletoadoptabetterdietandhealthierlifestyle.

Differentlevelsofantioxidantsupplementationmaybeneededfordifferentpurposes.Forexample,PryorshowedthatlevelsofvitaminEwellbelowtheRDAlevelareenoughtoprotectagainstmyopathy(muscledamage)[167].Preventionofredbloodcellhemolysis(rupture)requirestheRDAlevel.InthesetwocasesgivingmorethantheRDAconveysnofurtherbenefit.Buttoimprovethefunctionoftheimmunesystem,muchhigherlevelsthantheRDAarerequiredfor

maximumbenefit.AsPryorconcludes,"wehavepassedawatershedwithregardtoourattitudetowardtheuseofmicronutrientsandtheantioxidantvitamins."Last,andmostimportant,thereareconsiderabledifferencesamongpeopleastotheirantioxidantstatusandrequirements.Therefore,suggestingonelevelofsupplementationforeverybodyisaninefficientwaytoproceed.RemembertheadvicegivenbyTengerdythat,forvitaminE,

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theoptimumdosedependsonmanyfactorsandmustbedeterminedforeachindividual[213].Thisappliestootherantioxidantsaswell.IagreewithSnodderly'ssuggestionthatonerationalthingtodoistoobtainacomprehensiveblood-levelsurveyofthemostimportantantioxidants[204].AgoodmethodofdoingthisiscalledaPantoxprofile,whichincludesalipidandiron-balanceprofile.Thistestdetermineswhichantioxidantsapersonistakingenoughoftomeethisorherneeds,andofwhichmoreorlessisneeded.

Itseemslikelythatwithinafewyearsaphysicianwillnosoonerneglecttocarryoutaplasmaantioxidantprofileinhispatientsasfailtodoabloodglucoseorbloodpressuremeasurement.IsuggestthatallpatientswithanyofthediseasesIhavelisted,inwhichoxidativestressplaysanimportantrole,askthatsuchaprofilebeperformedasanessentialpartoftheinvestigativeworkupoftheirillness.Apparentlyhealthypeople,too,needaregularmonitoringoftheirantioxidantprofileasameasurethatmaycontributetopreventingthedevelopmentofsuchdiseaseslaterinlife.Physicianstodayexpendanenormousamountoftimeandenergyinhelpingpatientsfightoffattacksbydeadlybacteriaandviruses.Itisnowtimetofocusmoreattentiononhelpingpeoplefightofftheattacksontheirbodiesbyreactiveoxygenspecies,whichhavethepotentialtobeequallydeadly.

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appendixThefollowingisalistoffruitsandvegetablesandotherfoodsthataregoodsourcesofantioxidants.Aplussigndenotesanespeciallygoodsource.

CAROTENES

BETA- apricots,beetgreens,cantaloupe,carrots,chicory,collard

BETA-CAROTENE

apricots,beetgreens,cantaloupe,carrots,chicory,collardgreens,fennel,kale,mustardgreens,parsley,peaches,pumpkin,redpepper,romainelettuce,spinach,sweetpotatoes,Swisschard,watercress,wintersquash

LUTEINAND kale(+),broccoli,spinach,wintersquash,Brussels

ZEAXANTHINsprouts,celery,dill,leaflettuce,leeks,mustardgreens,parsley,peas,scallions,summersquash

LYCOPENE tomatoes(+),apricots,guava,pinkgrapefruit,mango,oranges,peaches,papaya,watermelon

VITAMINC broccoli,Brusselssprouts,cauliflower,citrusfruits,greenpepper,kiwi,kohlrabi,papaya,peaches,redcabbage,redpepper,strawberries,potatoes,alfalfa,lettuce

VITAMINE wheatgerm,seeds,nuts,margarine,darkgreenleafyvegetables,avocado,peanuts,sweetpotatoes

LIPOICACID darkgreenleafyvegetables,especiallyspinachandbroccoli

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FLAVONOIDS apples,citrusfruits,flaxseed,licorice,lentils,onions,peanuts,rice,soybeans,manyherbs,blueberries,cranberries(+),blackandredcurrants,loganberries(butlowinstrawberriesandraspberries);chamomiletea,oliveoil,redwine,tea

POLYPHENOLS chocolate,coffee,grapes,nuts,oranges,strawberries,tea,turmeric,whitewine

OTHERANTIOXIDANTS

chives,garlic,shallots,Brusselssprouts,rosemary,yeast

Suggesteddailyamountsforeffectivesupplementsofantioxidantsandantioxidanthelpers:

CAROTENES

BETA-CAROTENE 10mg

LUTEINE 10mg

LYCOPENE 10mg

ZEAXANTHIN 10mg

VITAMINB3 (NICOTINAMIDE) 100mg

VITAMINC 500mg

VITAMINE(ALPHA-TOCOPHEROL) 400-800mg

GAMM A-TOCOPH EROL 1OOmg

VITAMINQ 300m

GLUTAMINE(GLUTATHIONEPRECURSOR) 500mg

MIXEDISOPRENOIDS 20mg

SELENIUM 50mg

SELENIUM 50mg

ZINC 25mg

Totheabove,itwouldbeprudenttoaddvitaminB6(200mg),B12(1mg),andfolicacid(2mg),asmoderndietsareoftenlowintheseparticularvitamins.

However,itmightbewisertohaveanantioxidantprofilemeasuredbydoctorand,followinghisorheradvice,toadjustantioxidantintakeinaccordancewiththeprofile.

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abbreviationsALS amytrophiclateralsclerosis

CARET Beta-CaroteneandRetinolEfficiencyTrial

CAT catalase,anantioxidantenzyme

CHAOS CambridgeHeartAntioxidantStudy

DNA deoxyribonucleicacid,thecarrierofgeneticinformation

G gram

GSHpx glutathioneperoxidase,anantioxidantenzyme

HDL high-densitylipoprotein

L liter

LDL low-densitylipoprotein

L-DOPA levo-dihydroxyphenylalanine

MDA malonyldialdehyde,amarkerforfatoxidation

mg milligram

NAC n-acetylcysteine,anantioxidantNF-kB atranscriptionfactor,proteinthatswitchescertaingeneson

andoff

NHANES-I

FirstNationalHealthandNutritionExaminationSurvey

PGH prostaglandinH

PH Physician'sHealth

RDA recommendeddailyallowance

RDA recommendeddailyallowance

RNA ribonucleicacid

SOD superoxidedismutase,anantioxidantenzyme

TGFa ameasureofinflammation

Page113

references1.AbramsB,DuncanD,andHertz-PicciottoI.(1991)AprospectivestudyofdietaryintakeandacquiredimmunedeficiencysyndromeinHIV-seropositivehomosexualmen.JournalofAcquiredImmuneDeficiencySyndrome,6,949-958.

2.AilletF,Gougerot-PocidaloM-A,VirelizierJ-Letal.(1994)AppraisalofpotentialtherapeuticindexofantioxidantsonthebasisoftheirinvitroeffectsonHIVreplicationinmonocytesandinterleukin2-includedlymphocyteproliferation.AIDSResearchandHumanRetroviruses,10,405-411.

3.AlbanesD,HeinonenOP,HuttunenJKetal.(1995)Effectsofalpha-tocopherolandbeta-carotenesupplementsoncancerincidenceintheAlpha-TocopherolandBeta-CaroteneCancerPreventionStudy.AmericanJournalofClinicalNutrition,62(suppl.),1427S-143430S.

4.AmbrosoneCB,GrahamS,MarshallJR,etal.(1994)Dietaryantioxidantsandbreastcancerrisk:effectmodificationbyfamilyhistory.AdvancesinExperimentalBiologyandMedicine,366,439-440.

5.TheAlpha-Tocopherol,Beta-CaroteneCancerPreventionStudyGroup.(1994)TheeffectofvitaminEandbeta-caroteneontheincidenceoflungcancerandothercancersinmalesmokers.NewEnglandJournalofMedicine,330,1029-1035.

6.ArmstrongAM,ChestnuttJE,GormleyMJetal.(1996)Theeffectofdietarytreatmentonlipidperoxidationandantioxidantstatusinnewlydiagnosednoninsulindependentdiabetes.FreeRadicalBiologyandMedicine,21,719-726.

7.AzharS,CaoL.,andReavenE.(1995)Alterationoftheadrenal

antioxidantdefensesystemduringaginginrats.JournalofClinicalInvestigation,96,1414-1424.

8.Bao-KhanhQ,DoBS,GarewalHS,ClemensNCJr.etal.(1996)Exhaledethaneandantioxidantvitaminsupplementsinactivesmokers.Chest,110,159-164.

9.BarberDAandHarrisSR.(1994)Oxygenfreeradicalsandantioxidants:areview.AmericanPharmacist,NS34,26-35.

Page114

10.BartonJCandBertoliLF(1996)Hemachromatosis:thegeneticdisorderofthe21stcentury.Nature(Medicine),2,394-395.

11.BendichA.(1996)Antioxidantvitaminsandhumanimmuneresponses.VitaminsandHormones,52,35-62.

12.BendichAandLangsethL.(1995)ThehealtheffectsofvitaminCsupplementation:areview.JournaloftheAmericanCollegeofNutrition,14,124-136.

13.BernardGR,WheelerAP,AronsMMetal.(1997)AtrialofantioxidantsN-acetylcysteineandprocysteineinARDS.Chest,112,164-172.

14.BettgerWJ.(1993)Zincandselenium,site-specificversusgeneralantioxidation.CanadianJournalofPhysiologyandPharmacology,71,721-724.

15.BlackburnGL.(1992)ImprovingtheAmericandiet.AmericanJournalofPublicHealth,82,465-466.

16.BlockG.(1995)Areclinicaltrialsreallytheanswer?AmericanJournalofClinicalNutrition,62(suppl.),1517S-1520S.

17.BlockG,PattersonB,andSubarA.(1992)Fruit,vegetables,andcancerprevention:areviewoftheepidemiologicalevidence.NutritionandCancer,18,I-29.

18.BlotWJ,LiJ-Y,TaylorPRetal.(1993)NutritioninterventiontrialsinLinxian,China:supplementationwithspecificvitamin/mineralcombinations,cancerincidence,anddisease-specificmortalityinthegeneralpopulation.JournaloftheNationalCancerInstitute,85,1483-1492.

19.BlumbergJ.(994)Areantioxidantsatanawkwardage?JournaloftheAmericanCollegeofNutrition,13,218-219.

20.BöhmF,EdgeR,LandEJetal.(1997)CarotenoidsenhancevitaminEantioxidantefficiency.JournaloftheAmericanChemicalSociety,119,621-627.

21.Bonithon-KoppC,CoudrayC,BerrCetal.(1997)Combinedeffectsoflipidperoxidationandantioxidantstatusoncarotidatherosclerosisinapopulationaged59-71years:theEVAStudy.AmericanJournalofClinicalNutrition,65,121-127.

22.BrownKM,MorricePC,ArthurJRetal.(1996)EffectsofvitaminEsupplementationonerythrocyteantioxidantdefencemechanismsinsmokingandnonsmokingmen.ClinicalScience,91,107-111.

23.BrowneSE,BowlingAC,MacGarveyWetal.(1997)OxidativedamageandmetabolicdysfunctioninHuntington'sdisease:selectivevulnerabilityofthebasalganglia.AnnalsofNeurology,41,646-653.

24.BukinYVandDraudin-KrylenkoVA.(1997)Theroleofß-caroteneandvitaminEinthetreatmentofgastricpremalignantlesions:biochemicalandclinicalaspects.Abstracts.VIthWorldCongressofNutrition,29.

25.BusseyHJR,DeCosseJJ,DeschnerEEetal.(1982)Arandomizedtrialofascorbicacidinpolyposiscoli.Cancer,50,1434-1439.

26.ByersTandBowmanB.(1993)VitaminEsupplementsandcoronaryheartdisease.NutritionReviews,51,333-336.

27.CalsMJ,SuccariM,MeneguzzerEetal.(1997)Markersofoxidativestressinfit,health-consciouselderlypeoplelivingintheParisarea.Nutrition,13,319-326.

28.CarotenoidResearchInteractiveGroup.(1996)Beta-caroteneandthecarotenoids:beyondtheinterventiontrials.NutritionReviews,54(6),185-187.

29.Ceballos-PicotI,Witko-SarsatV,Merad-BoudiaMetal.(1996)Glutathioneantioxidantsystemasamarkerofoxidativestressinchronicrenalfailure.FreeRadicalBiologyandMedicine,21,845-853.

30.ChalmersAH,CowleyDM,andBrownJM.(1986)Apossibleetiologicalroleforascorbateincalculiformation.ClinicalChemistry,32,333-336.

Page115

31.ChamiecT,Herbaczynska-CedroK,andCeremuzynskiL.(1996)EffectsofantioxidantvitaminsCandEonsignal-averagedelectrocardiograminacutemyocardialinfarction.AmericanJournalofCardiology,77,237-241.

32.ChandrasekarB,ColstonJT,andFreemanGL.(1997)Inductionofproinflammatorycytokineandantioxidantenzymegeneexpressionfollowingbriefmyocardialischemia.ClinicalandExperimentalImmunology,108,346-351.

33.ChaseHP,Butler-SimonN,GargSetal.(1990)Atrialofnicotinamideinnewlydiagnosedpatientswithtype1(insulin-dependent)diabetesmellitus.Diabetologia,33,444-446.

34.ChristenWGJr.(1994)Antioxidiantsandeyedisease.AmericanJournalofMedicine,97(Suppl.3A),14S-17S.

35.ComstockGW,HelzlsouerKJ,andBushTL.(1991)PrediagnosticserumlevelsofcarotenoidsandvitaminEasrelatedtosubsequentcancerinWashingtonCounty,Maryland.AmericanJournalofClinicalNutrition,53(suppl.),260S-264S.

36.CookNCandSammanS.(1996)Flavonoids-chemistry,metabolism,cardioprotectiveeffects,anddietarysources.NutritionalBiochemistry,7,66-76.

37.DailyJWandZemelMB.(1995)Antioxidants:researchvsrhetoric.AmericanJournalofClinicalNutrition,6,866-868.

38.DarrD,CombsS,andPinnell,S.(1993)Ascorbicacidandcollagensynthesis:rethinkingaroleforlipidperoxidation.ArchivesofBiochemistryandBiophysics,307,331-335.

39.DasD,BandyopadhyayD,BhattacherjeeMetal.(1997)Hydroxylradicalisthemajorcausativefactorinstress-inducedgastriculceration.FreeRadicalBiologyandMedicine,23,8-18.

40.DelafuenteJC,PrendergastJM,andModighA(1986)ImmunologicalmodulationbyvitaminCintheelderly.InternationalJournalofImmunopharmacology,8,205-221.

41.deRijkMC,BretelerMBB,denBreeijenJHetal.(1997)DietaryantioxidantsandParkinsonsdisease:theRotterdamstudy.ArchivesofNeurology,54,762-765.

42.deRijkeYB,DemackerPNM,AssenNAetal.(1995)Redwineconsumptiondoesnotaffectoxidizabilityoflow-densitylipoproteinsinvolunteers.AmericanJournalofClinicalNutrition,63,329-334.

43.DiplockAT.(1994)Antioxidantsanddiseaseprevention.MolecularAspectsofMedicine,15,293-376.

44.DiplockAT.(1995)Safetyofantioxidantvitaminsandß-carotene.AmericanJournalofClinicalNutrition,62(suppl.),1510S-1516S.

45.DraperHHandBettgerWJ.(1994)Roleofnutrientsinthecauseandpreventionofoxygenradicalpathology.AdvancesinExperimentalMedicineandBiology,366,269-289.

46.DrögeW,GrossA,HackVetal.(1997)RoleofcysteineandglutathioneinHIVinfectionandcancercachexia:therapeuticinterventionwithN-acetylcysteine.AdvancesinPharmacology,38,581-600.

47.DrögeW,HolmE.(1997)RoleofcysteineandglutationeinHIVinfectionandotherdiseasesassociatedwithmusclewastingandimmunologicaldysfunction.FASEBJournal,11,1077-1089.

48.DrukarchB,LangeveldCH,andStoofJC.(1997)GlutathionehomeostasisislinkedtothevesicularstorageofdopamineinratPC12phechromocytomacells.ExperimentalNeurology,145(suppl.),S39.

49.EdwardsCQandKushnerJP.(1993)Screeningfor

hemochromatosis.NewEnglandJournalofMedicine,328,1616-1620.

Page116

50.EfendyJL,SimmonsDL,andCampbellGRetal.(1997)Theeffectoftheagedgarlicextract,''Kyolic,"onthedevelopmentofexperimentalatherosclerosis.Atherosclerosis,132,37-42.

51.EnstromJE,KanimLE,andKleinMA.(1992)7VitaminCintakeandmortalityamongstasampleoftheUnitedStatespopulation.Epidemiology,3,194-202.

52.EnstromJE.(1993)Counterviewpoint:vitaminCandmortality.NutritionToday,28(3),39-42.

53.EvansPH.(1993)Freeradicalsinbrainmetabolismandpathology.BritishMedicalBulletin,49,577-587.

54.EverallIP,HudsonL,andKerwinRW.(1997)Decreasedabsolutelevelsofascorbicacidandunalteredvasoactiveintestinalpolypeptidereceptorbindinginthefrontalcortexinacquiredimmunodeficiencysyndrome.NeuroscienceLetters,224,119-122.

55.FlaggEW,CoatesRJ,andGreenbergRS.(1995)Epidemiologicstudiesofantioxidantsandcancerinhumans.JournaloftheAmericanCollegeofNutrition,14,419-427.

56.FlorenLC,ZangwillAC,andSchroederDJ.(1994)Antioxidantsmayretardcataractformation.AnnalsofPharmacotherapy,28,1040-1042.

57.FrankeAA,HarwoodPJ,ShimamotoTetal.(1994)Effectsofmicronutrientsandantioxidantsonlipidperoxidationinhumanplasmaandincellculture.CancerLetters,79,17-26.

58.FreudenheimJL,MarshallJR,VenaJEetal.(1996)Premenopausalbreastcancerriskandintakeofvegetables,fruitsandrelatednutrients.JournaloftheNationalCancerInstitute,88,340-348.

59.FuhrmanB,LavyA,andAviramM.(1995)Consumptionofredwinewithmealsreducesthesusceptibilityofhumanplasmaandlow-densitylipoproteintolipidperoxidation.AmericanJournalofClinicalNutrition,6,549-554.

60.FujikiH,SuganumaM,OkabeSetal.(1996)Japanesegreenteaasacancerpreventiveinman.NutritionReviews,54(suppl.),S67-S70.

61.GalleyHF,ThorntonJ,HowdlePDetal.(1997)Combinationoralantioxidantsupplementationreducesbloodpressure.ClinicalScience,92,361-365.

62.GarewalHSandDiplockAT.(1995)How"safe"areantioxidantvitamins?DrugSafety,13,8-14.

63.GershoffSN.(1993)VitaminC(ascorbicacid):newroles,newrequirements?NutritionReviews,51,313-326.

64.GeyKF(1993)Prospectsforthepreventionoffreeradicaldisease,regardingcancerandcardiovasculardisease.BritishMedicalBulletin,49,679-699.

65.GeyKF(1994)Optimumplasmalevelsofantioxidantmicronutrients.Tenyearsofantioxidanthypothesisonarteriosclerosis.BibliotecaNutritioetDieta,51,84-99.

66.GeyKF,SthelinHB,andEichholzerM.(1993)PoorplasmastatusofcaroteneandvitaminCisassociatedwithhighermortalityfromischaemicheartdiseaseandstroke:BaselProspectiveStudy.ClinicalInvestigator,71,3-6.

67.GiavannuchiE,AscherioA,RimmEBetal.(1995)Intakeofcarotenoidsandretinolinrelationtoriskofprostatecancer.JournaloftheNationalCancerInstitute,87,1767-1776.

68.GillissenA,JaworskaM,SchrlingBetal.(1997)Beta-2-agonistshaveantioxidantfunctionsinvitro.Respiration,64,16-22.

69.GoldbergDM.(1995)Editorial:doeswinework?ClinicalChemistry,41,14-16.

70.GoldbergDM.(1996)Moreonantioxidantactivityofreversatolinredwine.ClinicalChemistry,42,113-114.

71.GoldbohmRA,VerhoevenDTH,VoorripsLEetal.(1997)Consumptionoffruitandvegetablesandriskoflungcancerinaprospectivestudy.AmericanJournalofEpidemiology,145,S7.1

Page117

72.GoldfarbS.(1994)Dietandnephrolithiasis.AnnualReviewofMedicine,45,235-243.

73.GoodPF,WernerP,HsuAetal.(1996)EvidenceforneuronaloxidativedamageinAlzheimer'sdisease.AmericanJournalofPathology,149,21-28.

74.GreenbergERandSpornMB.(1996)Editorial:antioxidantvitamins,cancerandcardiovasculardisease.NewEnglandJournalofMedicine,334,1189-1190

75.GridleyG,McLaughlinJK,BlockGetal.(1992)Vitaminsupplementuseandreducedriskoforalandpharyngealcancer.AmericanJournalofEpidemiology,135,1083-1092.

76.HaberB.(1997)TheMediterraneandiet:aviewfromhistory.AmericanJournalofClinicalNutrition,665(suppl.),1053S-1057S.

77.HankinsonSE,StampferMJ,SeddonJMetal.(1992)Nutrientintakeandcataractextractioninwomen:aprospectivestudy.BritishMedicalJournal,305,335-339.

78.HannonMP,HughesC,O'KaneMJetal.(1997)OxidativestressandDNAdamageinplateletsinpatientswithinsulin-dependentdiabetesmellitus.Abstracts.VlthWorldCongressofClinicalNutrition,35.

79.HatchGE.(1995)Asthma,inhaledoxidants,anddietaryantioxidants.AmericanJournalofClinicalNutrition,61(suppl.),625S-630S.

80.HathcockJN.(1997)Vitaminsandminerals:efficacyandsafety.AmericanJournalofClinicalNutrition,66,427-437.

81.HemilHandHermanZS.(1996)VitaminCandthecommoncold:aretrospectivestudyofChalmers'review.AmericanJournalof

ClinicalNutrition,14,116-123.

82.HennekensCH,BuringJE,MansonJEetal.(1996)Lackofeffectoflong-termsupplementationwithbetacaroteneontheincidenceofmalignantneoplasmsandcardiovasculardisease.NewEnglandJournalofMedicine,334,1145-1149.

83.HerbertV.(1993)Viewpoint.Doesmega-Cdomoregoodthanharm,ormoreharmthangood?NutritionToday,28,28-32.

84.HerbertV.(1994)Theantioxidantsupplementmyth.AmericanJournalofClinicalNutrition,60,157-158.

85.HerbertV.(1995)Editorial.VitaminCsupplementsanddisease-counterpoint.JournaloftheAmericanCollegeofNutrition,14,112-113.

86.HertogMGL,FeskensEJM,HolmanPCHetal.(1993)Dietaryantioxidantflavonoidsandriskofcoronaryheartdisease:theZutphenElderlyStudy.Lancet,342,1007-1011.

87.HertogMGL,SweetmanPM,FehilyAMetal.(1997)AntioxidantflavonolsandischemicheartdiseaseinaWelshpopulationofmen:theCaerphillystudy.AmericanJournalofClinicalNutrition,65,1489-1494.

88.HodisHN,MackWJandLaBreeL.(1995)Serialcoronaryangiographicevidencethatantioxidantvitaminintakereducesprogressionofcoronaryarteryatherosclerosis.JournaloftheAmericanMedicalAssociation,273,1845-1854.

89.HofferA,OsmondH,andSmythiesJ.(1954)Schizophrenia.Anewapproach.PartII.JournalofMentalScience,1oo,29-37.

90.HoffmanRMandGarewalHS.(1995)Antioxidantsandthepreventionofcoronaryheartdisease.ArchivesofInternalMedicine,155,241-246.

91.HollmanPCH,HertogMGL,andKatanMB.(1996)Roleofdietaryflavonoidsinprotectionagainstcancerandcoronaryheartdisease.BiochemicalSocietyTransactions,24,785-789·

92.HuG,CassanoP,andChenJ.(1997)DietaryvitaminCintakeandlungfunctioninruralChina.AmericanJournalofEpidemiology,145(suppl.),S80.

93.HubelCA,KaganVE,KisinERetal.(1997)Increasedascorbateradicalformationandascorbatedepletioninplasmafromwomenwithpreeclampsia:implicationsforoxidativestress.FreeRadicalBiologyandMedicine,23,597-609.

Page118

94.IllingworthDR.(1993)Thepotentialroleofantioxidantsinthepreventionofatherosclerosis.JournalofNutritionalScienceandVitaminology,39(suppl.),S43-S47.

95.IpC,LiskDJ,andScimecaJA.(1994)Potentialoffoodmodificationincancerprevention.CancerResearch,54(suppl.),S957-S1959.

96.JacquesPF,HalpnerAD,andBlumbergJB.(1995)Influenceofcombinedantioxidantnutrientintakesontheirplasmaconcentrationsinanelderlypopulation.AmericanJournalofClinicalNutrition,62,1228-1233.

97.JacquesPF,TaylorA,HankinsonSEetal.(1997)Long-termvitaminCsupplementuseandprevalenceofearlyage-relatedlensopacities.AmericanJournalofClinicalNutrition,66,911-916.

98.JohnsonLE.(1994)Theemergingroleofvitaminsasantioxidants.ArchivesofFamilyMedicine,3,809-820.

99.KampmanE,VerhoevenD,SlootsLetal.(1995)VegetableandanimalproductsasdeterminantsofcoloncancerriskinDutchmenandwomen.CancerCausesandControl,6,225-234.

100.KanofskyJDandSandykR.(1992)Antioxidantsinthetreatmentofschizophrenia.InternationalJournalofNeuroscience,62,97-100.

101.KaugarsGE,SilvermanSJr.,LovasJGLetal.(1993)Areviewoftheuseofantioxidantsupplementsinthetreatmentofhumanoralleukoplakia.JournalofCellularBiochemistry,7F(suppl.),292-298.

102.KeimowitzRM.(1997)Dementiaimprovementwithcytotoxicchemotherapy:acaseofAlzheimer'sdiseaseandmultiplemyeloma.ArchivesofNeurology,54,485-488.

103.KennesB,DumontI,BroheeDetal.(1983)EffectofvitaminC

supplementsoncellmediatedimmunityinoldpeople.Gerontology,29,305-310

104.KimmickGG,BellRA,andBostickRM.(1997)VitaminEandbreastcancer:areview.NutritionandCancer,27,109-117.

105.KnaufVCandFacciottiD.(1995)Geneticengineeringoffoodstoreducetheriskofheartdiseaseandcancer.AdvancesinExperimentalBiologyandMedicine,369,221-228.

106.KnektP,HeliovaaraM,RissanenAetal.(1992)Serumantioxidantvitaminsandriskofcataract.BritishMedicalJournal,305,1392-1394.

107.KnektP,JrvinenR,ReunanenAetal.(1996)FlavonoidintakeandcoronarymortalityinFinland:acohortstudy.BritishMedicalJournal,312,478-481.

108.KnektP,JrvinenR,SeppnenRetal.(1997)Dietaryflavonoidsandtheriskoflungcancerandothermalignantneoplasms.AmericanJournalofEpidemiology,146,223-230.

109.KoedelWandPfisterH-W.(1997)ProtectiveeffectoftheantioxidantN-acetyl-L-cysteineinpneumococcalmeningitisintherat.NeuroscienceLetters,225,33-36.

110.KohlmeierL,KarkD,Gomez-GarciaEetal.(1997)LycopeneandmyocardialinfarctionriskintheEURAMICStudy.AmericanJournalofEpidemiology,146,618-626.

111.KristensonM,ZiedénB,KucinskienëZetal.(1997)AntioxidantstateandmortalityfromcoronaryheartdiseaseinLithuanianandSwedishmen:concomitantcrosssectionalstudyofmenaged50.BritishMedicalJournal,314,629-633.

112.KritchevskySB,SchwartzGG,andMorrisDL.(1995)Beta-carotenesupplementation,vitaminD,andcancerrisk:ahypothesis.Epidemiology,6,89.

113.KuklinskiB,WeissenbacherE,andFhnrichA.(1994)CoenzymeQ10andantioxidantsinacutemyocardialinfarction.MolecularAspectsofMedicine,15(suppl.),S143-S147.

114.KushiLH,FolsomAR,PrineasRJetal.(1996)Dietaryantioxidantvitaminsanddeathfromcoronaryheartdiseaseinpostmenopausalwomen.NewEnglandJournalofMedicine,334,1156-1162.

Page119

15.LandrumJT,BoneRA,andKilburnMD.(1997)Themacularpigment:possibleroleinprotectionfromagerelatedmaculardegeneration.AdvancesinPharmacology,38,537-556.

116.LangsjoenH,LangsjoenP,LangsjoenPetal.(1994a)UsefulnessofcoenzymeQ10inclinicalcardiology:alongtermstudy.MolecularAspectsofMedicine,15(suppl.),S165-S175.

17.LangsjoenP,LangsjoenP,WillisRetal.(994b)TreatmentofessentialhypertensionwithcoenzymeQ10.MolecularAspectsofMedicine,15(suppl.),S265-S272.

118.LeeuwenburghC,FiebigR,ChandwaneyRetal.(1995)Agingandexercisetraininginskeletalmuscle:responsesofglutathioneandantioxidantenzymesystems.AmericanJournalofPhysiology,267,R439-R445.

119.LehrH-AandMessmerK.(1996)Rationalefortheuseofantioxidantvitaminsinclinicalorgantransplantation.Transplantation,62,1197-1199.

120.Lehr,H-A,FreiB,andArforsK-E.(1994)VitaminCpreventscigarettesmoke-inducedleukocyteaggregationandadhesiontoendotheliuminvivo.ProceedingsoftheNationalAcademyofSciences.USA,91,7688-7692.

121.LeskeMC,ChylackLTJr,andWuSY.(1991)TheLensOpacitiesCase-ControlStudy.Riskfactorsforcataract.ArchivesofOphthalmology,109,244-251.

122.LevineM,DhariwalKR,WelchRWetal.(1995)DeterminationofoptimalvitaminCrequirementsinhumans.AmericanJournalofClinicalNutrition,62(suppl.),S1347-SI356.

123.LevineM,Conry-CantilenaC,WangYetal.(1996)VitaminCpharmacokineticsinhealthyvolunteers:evidenceforarecommended

dailyallowance.ProceedingsoftheNationalAcademyofSciences.USA,93,3704-3709.

124.Lih-BrodyL,PowellSR,CollierKPetal.(1996)Increasedoxidativestressanddecreasedantioxidantdefensesinmucosaofinflammatoryboweldisease.DigestiveDiseasesandSciences,41,2078-2086.

125.LiuJandMoriA.(1993)Monoaminemetabolismprovidesanantioxidantdefenseinthebrainagainstoxidant-andfreeradical-induceddamage.ArchivesofBiochemistryandBiophysics,302,118-127.

126.LivreaMA,TesoriereL,PintaudiAMetal.(1996)Oxidativestressandantioxidantstatusinß-thalassemiamajor:ironoverloadanddepletionoflipidsolubleantioxidants.Blood,88,3608-3614.

127.LockwoodK,MoesgaardS,HaniokaTetal.(1994)Apparentpartialremissionofbreastcancerin"highrisk"patientssupplementedwithnutritionalantioxidants,essentialfattyacidsandcoenzymeQ10.MolecularAspectsofMedicine,15,S231-S240.

128.LosonczyKG,HarrisTB,andHavlikRJ.(1996)VitaminEandvitaminCsupplementuseandriskofall-causeandcoronaryheartdiseasemortalityinolderpersons:theEstablishedPopulationsforEpidemiologicalStudiesoftheElderly.AmericanJournalofClinicalNutrition,64,190-196.

129.LuomaPV,NyhS,SikkilaKetal.(1995)Highserumalpha-tocopherol,albumin,seleniumandcholesterol,andlowmortalityfromcoronaryheartdiseaseinnorthernFinland.JournalofInternalMedicine,237,49-54.

130.LykkesfeldtJ,LoftS,NielsenJBetal.(1997)Ascorbicacidanddehydroascorbicacidasbiomarkersofoxidativestresscausedbysmoking.AmericanJournalofClinicalNutrition,65,959-963.

131.Mares-PerlmanJA,BradyWE,KleinRetal.(1995)Serumantioxidantsandagerelatedmaculardegenerationinapopulation-basedcase-controlstudy.ArchivesofOphthalmology,113,1518-1523.

Page120

132.MaxwellSRJ.(1995)Prospectsfortheuseofantioxidanttherapies.Drugs,49,345-361.

133.MaxwellSRJ,ThomasonH,SandlerDetal.(1997)Antioxidantstatusinpatientswithuncomplicatedinsulin-dependentandnon-insulin-dependentdiabetesmellitus.EuropeanJournalofClinicalInvestigation,27,484-490.

134.McGeerPLandMcGeerEG.(1995)Theinflammatoryresponsesystemofbrain:implicationsfortherapyofAlzheimer'sandotherneurodegenerativediseases.BrainResearchReviews,21,195-218.

135.McGeerPL,SchulzerM,andMcGeerEG.(1996).Arthritisandanti-inflammatoryagentsaspossibleprotectivefactorsforAlzheimer'sdisease:areviewof17epidemiologicalstudies.Neurology,47,425-432.

136.McKeown-EyssenG,HollowayC,JazmajiVetal.(1988)ArandomizedtrialofvitaminsCandEinthepreventionofrecurrenceofcolorectalpolyps.CancerResearch,48,4701-4705.

137.MedinaJH,ViolaH,WolfmanCetal.(1997)Overview-flavonoids:anewfamilyofbenzodizepinereceptorligands.NeurochemistryResearch,22,419-425.

138.MehraMR,LavieCJ,VenturaHOetal.(1995)Preventionofatherosclerosis.Thepotentialroleofantioxidants.PostgraduateMedicine,98,175-184.

139.MehtaJ.(1997)IntakeofantioxidantsamongAmericancardiologists.AmericanJournalofCardiology,79,1558-1560.

140.MenaMA,PardoB,PainoCLetal.(1993)Levodopatoxicityinfoetalratmidbrainneuronesinculture:modulationbyascorbicacid.NeuroReport,4,438-440.

141.MeydaniSN,BarklundMP,LiuSetal.(1990)VitaminEsupplementationenhancescell-mediatedimmunityinhealthyelderlysubjects.AmericanJournalofClinicalNutrition,52,557-563.

142.MeyersDGandMaloleyPA.(1993)Theantioxidantvitamins:impactonatherosclerosis.Pharmacotherapy,13,574-582.

143.MeyersDG,MaloleyPA,andWeeksD.(1996)Safetyofantioxidantvitamins.ArchivesofInternalMedicine,156,925-935.

144.MillerNJ,JohnstonJD,CollisCSetal.(1997)Serumtotalantioxidantactivityaftermyocardialinfarction.AnnalsofClinicalBiochemistry,34,85-90.

145.MoertelCG,FlemingTR,CreaganETetal.(1985)High-dosevitaminCversusplacebointhetreatmentofpatientswithadvancedcancerwhohavehadnopriorchemotherapy.Arandomizeddouble-blindcomparison.NewEnglandJournalofMedicine,312,137-141.

146.MorrisDL,KritchevskySB,andDavisCE.(1994)Serumcarotenoidsandcoronaryheartdisease.JournaloftheAmericanMedicalAssociation,272,1439-1441.

147.MukhopadhyayCKandChatterjeeB.(1994)NADPH-initiatedcytochromeP450mediatedfreemetalion-dependentoxidativedamageofmicrosomalproteins:exclusivepreventionbyascorbicacid.JournalofBiologicalChemistry,269,13,390-13,397.

148.NathR,PandavS,ParasharSetal.(1997)Roleofoxygenfreeradicalsinetiopathogenesisofagerelatedmaculardegeneration(AMD).Abstracts.VIthWorldCongressofClinicalNutrition,43.

149.NyyssönenK,ParviainenM,SalonenRetal.(1997)VitaminCdeficiencyandriskofmyocardialinfarction:prospectivepopulationstudyofmenfromeasternFinland.BritishMedicalJournal,314,634-638.

150.OberleyTDandOberleyLW.(1997)Antioxidantenzymelevels

incancer.HistologyandHistopathology,12,525-535.

151.OliverME(1995)Antioxidantnutrients,atherosclerosis,andcoronaryheartdisease.BritishHeartJournal,73,299-301.

Page121

152.OmayeST,BurriBJ,SwendseidMEetal.(1996)Bloodantioxidantschangeinyoungwomenfollowingß-carotenedepletionandrepletion.JournaloftheAmericanCollegeofNutrition,15,469-474.

153.OmennGS.(1995)Editorial.Whataccountsfortheassociationofvegetablesandfruitwithlowerincidenceofcancersandcoronaryheartdisease?AnnalsofEpidemiology,5,333-335.

154.OmennGS,GoodmanGE,ThornquistMDetal.(1996)EffectsofacombinationofbetacaroteneandvitaminAonlungcancerandcardiovasculardisease.NewEnglandJournalofMedicine,334,1150-1155.

155.PackerLandDiplockA.HandbookofAntioxidants.NewYork,Dekker,1996.

156.PackerL,WittEH,andTritschlerHJ.(1995)Alpha-lipoicacidasabiologicalantioxidant.FreeRadicalBiologyandMedicine,19,227-250.

157.PallerMSandEatonJW.(1995)Hazardsofantioxidantcombinationscontainingsuperoxidedismutase.FreeRadicalBiologyandMedicine,18,883-890.

158.PandeyDK,ShekelleR,SelwynBJetal.(1996)DietaryvitaminCandbetacaroteneandriskofdeathinmiddle-agedmen:theWesternElectricstudy.AmericanJournalofEpidemiology,142,1269-1278.

159.PanettaJA,ShadleJK,PhillipsMLetal.(1993)4-thiazolidinones,potentantioxidantsasanti-inflammatoryagents.AnnalsoftheNewYorkAcademyofSciences,696,415-416.

160.PaolissoG,BalbiV,VolpeCetal.(1995)MetabolicbenefitsderivingfromchronicvitaminCsupplementationinagednon-insulin-dependentdiabetics.JournaloftheAmericanCollegeofNutrition,14,

387-392.

161.ParfittVJ,RubbaP,BoltonCetal.(1994)AcomparisonofantioxidantstatusandfreeradicalperoxidationofplasmalipoproteinsinhealthyyoungpersonsfromNaplesandBristol.EuropeanHeartJournal,15,871-876.

162.PattersonBH,BlockG,RosenbergerWFetal.(1990)FruitsandvegetablesintheAmericandiet:datafromtheNHANESIIsurvey.AmericanJournalofPublicHealth,80,1443-1449.

163.PetersonPL.(1995)Thetreatmentofmitochondrialmyopathiesandencephalomyopathies.BiochimicaetBiophysicaActa,1271,275-280.

164.PorananAK,EkbladU,UotilaPetal.(1997)Lipidperoxidationandantioxidantsinnormalandpre-eclampticpregnancies.Placenta,17,401-405.

165.PrasadKNandKumarR.(1996)Effectofindividualandmultipleantioxidantvitaminsongrowthandmorphologyofhumannontumorigenicandtumorigenicparotidacinarcellsinculture.NutritionandCancer,26,11-19.

166.PrieméH,LoftS,NyyssönenKetal.(1997)NoeffectofsupplementationwithvitaminE,ascorbicacidorcoenzymeQ10onoxidativeNDAdamageestimatedby8-oxo-7,8-dihydro-2'-deoxyguanosineexcretioninsmokers.AmericanJournalofClinicalNutrition,65,503-507.

167.PryorWA.(1991)Theantioxidantnutrientsanddiseaseprevention-whatdoweknowandwhatdoweneedtofindout?AmericanJournalofClinicalNutrition,53(suppl.),S391-S393.

168.RachmilewitzEA,ShifterA,andKahane1.(1979)VitaminEdeficiencyinß-thalassemiamajor:changesinhematologicalandbiochemicalparametersafteratherapeutictrialwithalpha-tocopherol.

AmericanJournalofClinicalNutrition,32,1850-1858.

169.RamseyBW,FarrellPMandPencharzP.(1992)Nutritionalassessmentandmanagementincysticfibrosis:aconsensusreport.AmericanJournalofClinicalNutrition,55,108-116.

Page122

170.RapolaJM,VirtamoJ,RipattiSetal.(1997)Randomizedtrialofalphatocopherolandbeta-carotenesupplementsonincidenceofmajorcoronaryeventsinmenwithpreviousmyocardialinfarction.Lancet,349,1715-1720.

171.RautalahtiMandHuttunenJ.(1994)Antioxidantsandcarcinogenesis.AnnalsofMedicine,26,435-441.

172.ReeceEAandWuY-K.(1997)Preventionofdiabeticembryopathyinoffspringofdiabeticratswithuseofacocktailofdeficientsubstancesandanantioxidant.AmericanJournalofObstetricsandGynecology,176,790-797.

173.ReiderCRandPaulsonGW.(1997)LouGehrigandamyotrophiclateralsclerosis.ArchivesofNeurology,54,527-528.

174.RiemersmaRA.(1994)Epidemiologyandtheroleofantioxidantsinpreventingcoronaryheartdisease:abriefoverview.ProceedingsoftheNutritionSociety,53,59-65.

175.RiemersmaRA,OliverM,EltonRAetal.(1990)Plasmaantioxidantsandcoronaryheartdisease:vitaminsCandE,andselenium.EuropeanJournalofClinicalNutrition,44,143-150.

176.RimmEB,StampferMJ,AscherioAetal.(1993)VitaminEconsumptionandtheriskofcoronarydiseaseinmen.NewEnglandJournalofMedicine,328,1450-1456.

177.RiversJM.(1987)Safetyofhigh-levelvitaminCingestion.AnnalsoftheNewYorkAcademyofSciences,498,445-454.

178.RobertsonJM,DonnerAP,andTrevithickJR.(1989)VitaminEintakeandriskofcataractsinhumans.AnnalsoftheNewYorkAcademyofSciences,570,372-382.

179.RodgersAB,KesslerLG,PortnoyLBetal.(1994)"Eatfor

Health":asupermarketinterventionfornutritionandcancerriskreduction.AmericanJournalofPublicHealth,84,72-76.

180.RojasC,CadenasS,Lopéz-TorresMetal.(1996)IncreaseinheartglutathioneredoxratioandtotalantioxidantcapacityanddecreaseinlipidperoxidationaftervitaminEdietarysupplementationinguinea-pigs.FreeRadicalBiologyandMedicine,21,907-915.

181.RondanelliM,Melzid'ErilGV,AnesiAetal.(1997)Alteredoxidativestressinhealthyoldsubjects.Aging.ClinicalandExperimentalResearch,9,221-223.

182.RuckerRBandStitesT.(1994)Newperspectivesonfunctionofvitamins.Nutrition,10,507-513.

183.SanoM,ErnestoC,ThomasRGetal.(1997)Acontrolledstudyofselegiline,alphatocopherol,orbothastreatmentforAlzheimer'sdisease.NewEnglandJournalofMedicine,336,1216-1222.

184.SantiniSA,MarraG,GiardinaBetal.(1997)DefectiveplasmaantioxidantdefensesandenhancedsusceptibilitytolipidperoxidationinuncomplicatedIDDM.Diabetes,46,1853-1858.

185.SathiyarajD,MuthuR,andMohamedAJ.(1997)Antioxidantstatus,proinflammatorycytokinesandacute-phaseproteinresponseinsmokersaftermyocardialinfarction.JournalofClinicalandBiochemicalNutrition,22,131-137.

186.SawyerMAJ,MikeJJ,ChavinKetal.(1989)AntioxidanttherapyandsurvivalinARDS.CriticalCareMedicine,17,S153.

187.SchalchWandWeberP.(1994)Vitaminsandcarotenoids-apromisingapproachtoreducingtheriskofcoronaryheartdisease,cancerandeyediseases.AdvancesinExperimentalMedicineandBiology,366,335-350.

188.ScheiderWL,HersheyLA,VenaJEetal.(1997)DietaryantioxidantsandotherdietaryfactorsintheetiologyofParkinson's

disease.MovementDisorders,12,190-196.

189.SchmidtK-H,HagmaierV,HornigDHetal.(1981)Urinaryoxalateexcretionafterlargeintakesofascorbicacidinman.AmericanJournalofClinicalNutrition,34,305-311.

Page123

190.SchünemannHJ,FreudenheimJL,MutiPetal.(1997)Cross-sectionalstudyofvitaminCandamarkerforlipidperoxidation.AmericanJournalofEpidemiology,145(suppl.),S71.

191.SchwartzJCandShklarG.(1997)Retinoidandcarotenoidangiogenesis:apossibleexplanationforenhancedoralcarcinogenesis.NutritionandCancer,27,192-199.

192.SeddonJM,AjaniUA,SperdutoRDetal.(1994)Dietarycarotenoids,vitaminsA,C,andE,andadvancedage-relatedmaculardegeneration.JournaloftheAmericanMedicalAssociation,272,1413-1420.

193.SenCK.(1995)Oxidantsandantioxidantsinexercise.JournalofAppliedPhysiology,79,675-686.

194.ShklarG,SchwartzJ,TricklerDetal.(1993)Theeffectivenessofamixtureofbetacarotene,alpha-tocopherol,glutathione,andascorbicacidforcancerprevention.NutritionandCancer,20,145-151.

195.SimonianNAandCoyleJT.(1996)Oxidativestressinneurodegenerativediseases.AnnualReviewofPharmacologyandToxicology,36,83-106.

196.SinghRB,NiazMA,BishnoiIetal.(1994a)Diet,antioxidantvitamins,oxidativestressandriskofcoronaryarterydisease:thePeerzadaProspectiveStudy.ActaCardiologica,49,453-467.

197.SinghRB,NiazMA,SharmaJPetal.(1994b)Plasmalevelsofantioxidantvitaminsandoxidativestressinpatientswithacutemyocardialinfarction.ActaCardiologica,49,441-452.

198.SinghRB,NiazMA,RastosiSSetal.(1996)Usefulnessofantioxidantvitaminsinsuspectedacutemyocardialinfarction(TheIndianExperimentinInfarctSurvival-3).AmericanJournalof

Cardiology,77,232-236.

199.SistoT,PaajanenH,Mets-KetelTetal.(1995)Pretreatmentwithantioxidantsandallopurinoldiminishescardiaconseteventsincoronarybypassgrafting.AnnalsofThoracicSurgery,59,1519-1523.

200.SivamGP,LampeJW,UlnessBetal.(1997)Helicobacterpylori-invitrosusceptibilitytogarlic(Alliumsativum)extract.NutritionandCancer,27,118-121.

201.SmythiesJR.(1997a)Thebiochemicalbasisofsynapticplasticityandneurocomputation:anewtheory.ProceedingsoftheRoyalSocietyofLondon.B,264,575-579.

202.SmythiesJR.(1997b)Oxidativereactionsandschizophrenia:areview.SchizophreniaResearch,24,357-364.

203.SmythiesJRandTolbertL.(1981)"Neuropharmacologicalrolesformethionine,nicotinamideandascorbicacid."InNutritionandBehavior(SAMiller,ed.).Philadelphia:TheFranklinInstitutePress,263-267.

204.SnodderlyDM.(1995)Evidenceforprotectionagainstage-relatedmaculardegenerationbycarotenoidsandantioxidantvitamins.AmericanJournalofClinicalNutrition,62(suppl.),1448S-1461S.

205.SthelinHB,GeyKF,EicholzerMetal.(1991)betacaroteneandcancerprevention:theBaselstudy.AmericanJournalofClinicalNutrition,53(suppl.),S265-S269.

206.StampferMJ,HennekensCH,MansonJEetal.(1993)VitaminEconsumptionandtheriskofcoronarydiseaseinwomen.NewEnglandJournalofMedicine,328,1444-1449.

207.StampferMJandRimmEB.(1995)EpidemiologicalevidenceforvitaminEinpreventionofcardiovasculardisease.AmericanJournalofClinicalNutrition,62(suppl.),S1365-S1369.

208.SteinerM,GlantzM,andLekosA.(1995)VitaminEplusaspirincomparedwithaspirinaloneinpatientswithtransientischemicattacks.AmericanJournalofClinicalNutrition,62(suppl.),S1381-S1384.

Page124

209.StephensN.(1997)Editorial.Antioxidanttherapyforischaemicheartdisease:wheredowestand?Lancet,349,1710-1711.

210.StephensNG,ParsonsA,SchofieldPMetal.(1996)RandomizedcontroltrialofvitaminEinpatientswithcoronarydisease:CambridgeHeartAntioxidantStudy(CHAOS).Lancet,347,781-786.

211.SuboticanecK,Folnegovic-SmalcV,KorbarMetal.(1990)VitaminCstatusinchronicschizophrenia.BiologicalPsychiatry,28,959-966.

212.TangAM,GrahamNMH,andSaahAJ.(1996)EffectsofmicronutritionalintakeonsurvivalofhumanimmunodeficiencyvirustypeIinfection.AmericanJournalofEpidemiology,143,1244-1256.

213.TavaniAandLaVecchiaC.(1995)FruitandvegetableconsumptionandcancerriskinaMediterraneanpopulation.AmericanJournalofClinicalNutrition,61(suppl.),1374S-1377S.

214.TaylorA.(1992)Roleofnutrientsindelayingcataracts.AnnalsoftheNewYorkAcademyofSciences,669,111-123.

215.TengerdyRP.(1990)TheroleofvitaminEinimmuneresponseanddiseaseresistance.AnnalsoftheNewYorkAcademyofSciences,587,24-33.

216.ToddS,WoodwardM,Bolton-SmithCetal.(1995)Aninvestigationoftherelationshipbetweenantioxidantvitaminintakeandcoronaryheartdiseaseinmenandwomenusingdiscriminantanalysis.JournalofClinicalEpidemiology,48,297-305.

217.TooheyL,HarrisMA,AllenKGDetal.(1995)PlasmaascorbicacidconcentrationsarerelatedtocardiovascularriskfactorsinAfrican-Americans.JournalofNutrition,126,121-128.

218.TrichopoulouA.(1995)Editorial.Oliveoilandbreastcancer.CancerCausesandControl,6,475-476.

219.TúriS,NémethI,TorkosAetal.(1997)Oxidativestressandantioxidantdefencemechanisminglomerulardiseases.FreeRadicalBiologyandMedicine,22,161-168.

220.UrivetskyM,KessarisD,andSmithAD.(1992)Ascorbicacidoverdosing:ariskfactorforcalciumoxalatenephrolithiasis.JournalofUrology,147,1215-1218.

221.VanderHagenAM,YoltonDP,KaminskiMSetal.(1993)Freeradicalsandantioxidantsupplementation:areviewoftheirrolesinage-relatedmaculardegeneration.JournaloftheAmericanOptometricAssociation,64,871-878.

222.VanderVlietA,EiserichJP,MarelichGPetal.(1997)Oxidativestressincysticfibrosis:doesitoccuranddoesitmatter?AdvancesinPharmacology,38,491-513.

223.VelussiM,CernigoiAM,DeMonteAetal.(1997)Long-term(12months)treatmentwithanantioxidantdrug(silymarin)iseffectiveonhyperinsulinemia,exogenousinsulinneedandmalondialdehydelevelsincirrhoticdiabeticpatients.JournalofHepatology,26,871-879.

224.VoelkerR.(1994)Recommendationsforantioxidants:howmuchevidenceisenough?JournaloftheAmericanMedicalAssociation,271,1148-1149.

225.VoelkerR.(1997)Antioxidantsandasthma.JournaloftheAmericanMedicalAssociation,277,1926.

226.WalkerARP.(1997)"Publicnutrition":whoislistening,responding,andacting.NutritionResearch,17,759-773.

227.WatanabeH,KakihanaM,OhtsukaSetal.(1997)Randomized,double-blind,placebo-controlledstudyofsupplementalvitaminEon

attenuationofthedevelopmentofnitritetolerance.Circulation,96,2545-2550.

228.WeberP,BendichA,andMachlinLJ.(1997)VitaminEandhumanhealth:rationalefordeterminingrecommendedintakelevels.Nutrition,13,450-460.

Page125

229.WechslerH,LevineS,IdelsonRKetal.(1996)Thephysician'sroleinhealthpromotionsrevisited-asurveyofprimarycarepractitioners.NewEnglandJournalofMedicine,334,996-998.

230.WeisburgerJH.(1991)Nutritionalapproachtocancerpreventionwithemphasisonvitamins,antioxidants,andcarotenoids.AmericanJournalofClinicalNutrition,53(suppl.),S226-S237.

231.WeisburgerJH.(1995)Editorial.VitaminCanddiseaseprevention.JournaloftheAmericanCollegeofNutrition,14,109-111.

232.Winklhofer-RoobBM,EllemunterH,FrühwirthMetal.(1997)PlasmavitaminCconcentrationsinpatientswithcysticfibrosis:evidenceofassociationswithinflammation.AmericanJournalofClinicalNutrition,65,1858-1866.

233.WinyardPGandBlakeDR.(1997)Antioxidants,redox-regulatedtranscriptionfactors,andinflammation.AdvancesinPharmacology,38,403-421.

234.WisemanHandHalliwellB.(1996)DamagetoDNAbyreactiveoxygenandnitrogenspecies:roleininflammatorydiseaseandprogressiontocancer.BiochemicalJournal,313,17-29.

235.WisemanH,PlitzanopoulouP,andO'ReillyJ.(1996)Antioxidantpropertiesofethanolicandaqueousextractsofgreenteacomparedtoblacktea.BiochemicalSocietyTransactions,24(suppl.),390S.

236.WorkStudyGrouponDiet,Nutrition,andCanceroftheAmericanCancerSociety.(1991)Ca-aCancerJournalforPhysicians,41,334-338.

237.YokoyamaH,LingleDM,CrestanelloJAetal.(1996)CoenzymeQ10protectscoronaryendothelialfunctionfromischemia

reperfusioninjuryviaanantioxidanteffect.Surgery,120,189-196.

238.YongL-C,BrownCC,SchatzkinAetal.(1997)IntakeofvitaminsE,C,andAandriskoflungcancer:theNHANESIEpidemiologicalfollow-upstudy.AmericanJournalofEpidemiology,146,231-243.

239.ZhangH-M,WakisakaN,MaedaOetal.(1997)VitaminCinhibitsthegrowthofabacterialriskfactorforgastriccarcinoma:HelicobacterPylori.Cancer,80,1897-1903.

240.ZhengW,DoyleTJ,KushiLHetal.(1996)Teaconsumptionandcancerincidenceinaprospectivecohortstudyofpostmenopausalwomen.AmericanJournalofEpidemiology,144,175-182.

241.ZieglerDandGriesFA.(1997)¬-lipoicacidinthetreatmentofdiabeticperipheralandcardiacautonomicneuropathy.Diabetes,46(suppl.),S62-S66.

242.ZieglerD,SchatzH,ConradFetal.(1997)Effectsoftreatmentwiththeantioxidantalpha-lipoicacidoncardiacautonomicneuropathyinNIDDMpatients.DiabetesCare,20,369-373.

243.ZieglerRG.(1991)Vegetables,fruits,andcarotenoidsandtheriskofcancer.AmericanJournalofClinicalNutrition,53(suppl.),S251-S2599.

244.ZieglerRG,MayneST,andSwansonCA.(1996a)Nutritionandlungcancer.CancerCausesandControl,7,157-177.

245.ZieglerRG,ColavitoEA,HartgePetal.(1996b)Importanceofalpha-carotene,betacarotene,andotherphytochemicalsintheetiologyoflungcancer.JournaloftheNationalCancerSociety,88,612-615.

246.ZieglerR,NomuraA,CraftNetal.(1997)Individualcarotenoidsintheetiologyoflungandupperaerodigestivetractcancers.AmericanJournalofEpidemiology,145(suppl.),S79.

Page127

index

A

N-acetylcysteine(NAC),10

inacuteinfection,80

forAIDSpatients,74,75

andARDS,70,71

andEKGchanges,34

inneonate,83

inpancreatitis,83

insepticshockpatients,76

acuterespiratorydistresssyndrome(ARDS),antioxidantsfor,70-71,96

adrenalgland,andaging,73

adrenochrome,62

AfricanAmericans,heartdiseasein,30

aging,dietand,72-73

AIDS

antioxidantsfor,96

andoxidativestress,74

Aillet,F.,74

albumin,10,11

alcohol,andoralcancer,51

AllianceforAgingResearch,106

allicin,14,88

andcancerresearch,87

sourcesof,104

alliin,14

alliumvegetables,87

aloe-emodin(aloe),13

alpha-carotene,andlungcancer,45,49

alpha-limonene,15

alphalipoicacid,forAIDSpatients,74

alpha-tocopherol,1o.SeealsovitaminE

alpha-tocopherol-beta-carotene(ATBC)study,33,42,44,90,97,98

alternativemedicine,4

Alzheimer'sdisease,8

andantioxidants,54-55,96

causesof,53-54

preventionof,54-55

AmericanCancerSociety,39

AmericanJournalofClinicalNutrition,92

AmericanJournalofEpidemiology,49

aminoacids,ingarlic,14

amytrophiclateralsclerosis(ALS),57-58,96

anemia,beta-thalassemia,80

ANICAprotocol,andbreastcancer,48

Page128

anserine,13

anticancercompounds

curcumin,15

isoprenoids,15-16

insoybeans,13

intea,14

anti-inflammatoryagents,and

Alzheimer'sdisease,54

antioxidants.Seealsospecificantioxidantsandacuteinfections,79-80

balancedformulafor,42,43-44,49

andcancerdevelopment,46

deficiencyof,9

effectonarteriesof,35-36

essential,10

functionsof,3,9

helper,38

large-moleculeprotein,11

misleadinginformationon,96

needfor,96,105

plantsourcesof,12-15

potentialdangerof,80

preventativenatureof,20

propertiesof,9

protectiveeffectof,31

RDAsfor,96

reactiveoxygenspeciesand,17

safetyof,89-95

scienceof,2

sideeffectsof,1-2

small-molecule,10-11

synergismbetween,12,102

synthetic,66

antioxidantsupplements

andagingprocess,73

balancedregimenof,106

incancerprevention,39

andcarcinogenesis,51

fordiabetics,66

reasonsfor,107

antioxidanttherapy

complexitiesof,98

inprediabeticstage,65

antitumorcompounds,inrosemary,13.Seealsoanticancercompounds

apigenin,13,15

apples,36

protectiveeffectof,50

andquercetin,13

arachidonicacid,indiabetes,66

L-arginine,65

arthritis,prostaglandinsand,7

ascorbicacid(ascorbate),1o.SeealsovitaminC

aspirin

andPGHsynthase,8

andvitaminEtherapy,32

asthma,8,69-70,96

atheromatousplaque,23

atherosclerosis,8,72,87

antioxidantsupplementsfor,97

indialysispatients,84

earlyinterventionfor,107

preventionof,99

autoimmunediseases

diabetes,63-66

rheumatoidarthritis,84-85

ayurvedicmedicine,15

B

bacteria,andantioxidants,78

Barber,D.A.,100

Barton,J.C.,92

Bendich,A.,93

benzothiazines,61

beri-beri,2

berries,13

Bertoli,L.F,92

beta-amyloid,53

beta-blockers,andasthma,70

beta-carotene,1.Seealsocarotenes,2

andaging,73

inAIDSpatients,75

inAlzheimer'sdisease,53

inbeta-thalassemia,80

bloodlevelsof,22

andbreastcancer,47,48

andcancerrisk,40,41,42,43,98

andcataractformation,67

incigarettesmoking,71

incysticfibrosis,78

andfatoxidation,35

andheartattacks,34

andheartdisease,26,27,28,29

andhighbloodpressure,38

inHIVpatients,75

lowlevelsof,32

andlungcancer,45

ODCactivityreducedby,47

andoralcancer,51

Page129

inpancreatitis,83

protectiveeffectof,31,32,45,46

recommendationsfor,99,100,106

andriskforrheumatoidarthritis,85

roleof,11

safetyof,90

andsmokers,44

sourcesof,103,109

suggestedamountsfor,110

toxiclevelsof,100

beta-cells,indiabetes,64,65

beta-cryptoxanthin

andbreastcancer,48

andlungcancer,45

beta-thalassemia,80

beta-tyrosol,inoliveoil,14

Bettger,W.J.,102

BHT(butylatedhydroxytoluene),indiabetes,66

bilirubin

asantioxidant,11

andexposuretosmog,72

Blackburn,G.L.,104

blacktea,14

bladder,cancerof,40,41

Block,G.,40,92,101

bloodpressure,effectofantioxidantson,29,37-38

Blot,William,98

Blumberg,J.,98

boldine,15

boweldisease,inflammatory,82

Bowman,B.,99

brain

aging,73

inAlzheimer'spatients,53

cerebralvasospasm,77

andoxidativestress,52

braindamage,andantioxidants,52

breastcancer,41

andantioxidants,47-48,51

andsoy,85-86

Brown,K.M.,71

brusselssprouts,11o

Bukin,Y.V.,46

burns,prostaglandinsand,7

Bussey,H.J.R.,93

butter,antioxidantsfor,7

Byers,T.,99

C

caffeicacid,inoliveoil,14

calcium

andfattyacids,96

needfor,106

calories

reductionin,104

restrictionof,72

Cals,M.J.,73

Cameron,92

cancer

andantioxidants,39,40,98

breast,47-48,51,85-86

clinicalstudies,40-46

colorectal,50

lung,48-50,51

oral,51

prostate,51

roleofdietin,40

stomach,46-47,51

uterine,50-51

andvitaminC,92,93-94

canthaxanthin,90

cardiologists,antioxidantsupplementstakenby,102

CARETstudy(beta-caroteneandRetinolEfficacyTrial),41,44,90

carnosine,andglutamatesynapse,60

carotenes,10.Seealsospecificcarotenes

andbreastcancer,47-48

andcataractformation,68

andlungcancer,49

occurrenceof,11

protectiveeffectof,46

sourcesof,103,109

CarotenoidResearchInteractiveGroup,44

carotenoids

inAIDSpatients,74

andbeta-caroteneintake,90

andcancerrisk,98

andheartdisease,28

andlungcancer,49

andoralcancer,51

protectiveeffectof,31,32

andvitaminE,12

carotidarteries,andvitamintherapy,35

carrots,andcataracts,67

carvacuol,13

Page130

carvone,15

catalase(CAT),11,52,53

andaging,73

incancercells,39

incigarettesmoking,71

duringheartattack,25

inoxidativestress,22

inrenaldialysis,84

cataracts

andantioxidants,66-68

typesof,68

andvitaminC,93

catechins

inredwine,36

intea,13,14

cauliflower,andcancerrisk,49

Cecil'sTextBookofMedicine,98

cells

chemicalreactionsin,5

compositionof,6

energyproductionof,7

membraneof,6-7

cerebralvasospasm,77

cerebrospinalfluid,vitaminCin,84

cervix,cancerof,41,51

Chalmers,A.H.,90

Chamiec,T.,34

chamomiletea,13

Chandrasekar,B.,24

CHAOS(CambridgeHeartAntioxidantStudy),32,33

Chase,H.P.,64

chemotherapy,antioxidantsduring,1o6

China

folkmedicineof,82

Linxiantrialin,97

chives,11o

chlorpromazine,63

chocolate,13

cholesterol,LDL,23-24

andalcoholconsumption,86

andexercise,81

chorea,ofHuntington'sdisease,58

Christen,W.G.Jr,68

chronicobstructivepulmonarydisease(COPD),72

chrysin,15

citrusoils,15

claudication,intermittent,77

clinicaltrials,3-4,101.Seealsostudies

clotformation,24

clozapine,58

coffee,13

cold,common,79

collardgreens,andmaculardegeneration,68

coloncancer

anddiet,40

andsoy,85-86

colorectalcancer,50

Comstock,G.W.,45

ConsumerReports,2

copper

indiabetes,64

andvitaminC,100

coronaryarterydisease

causeof,23-24

studiesof,25-38

CoronaryPrimaryPreventionTrial,ofLipidResearchClinics,28

Coyle,J.T,8

Crohn'sdisease,82

cryptoxanthin,13

curcumin,15

5-cysteinyldopamine,61

cysticfibrosis

antioxidantsfor,96

causeof,77-78

cytokines,13

inAIDSpatients,74

duringheartattack,24

D

Daily,J.W.,92

deficiencydiseases,2,3,10

dementia,ofHuntington'sdisease,58

deRijk,M.C.,57

DeRijka,Y.B.,86

developingcountries,dietsin,104

diabetes

andantioxidants,64,96

causeof,63

earlyinterventionfor,107

increasein,105

treatmentof,56

type1,63-64

andvitaminC,93

dialysis,renal

andantioxidantintake,35

oxidativestressduring,84

Page131

dienes,conjugated,22

dieseloilfumes,8

diet

andcarcinogenesis,51

Mediterranean,29

needforbetter,4,104,107

protectiveeffectof,43

recommendationforprudent,100

ofU.S.population,95

vegetarian,50

Western,104

duringWorldWarII,105

dietaryfiber,incolorectalcancer,51

digestivetract,cancerof,41

Diplock,A.T.,41,44,5,68,9,98

disease,effectsofantioxidantsin,18-21

DNA

damageto,7,8

inHuntington'sdisease,58

oxidativeattackon,22

dopamine,55,56

andglutamatesynapse,60-61

quinonesderivedfrom,62

dopaminochrome,55,6

dose/responserelationship,40

double-blindstudies,19-20.Seealsostudies

Down'ssyndrome,53

Draper,H.H.,102

Dröge,W.,75

drugindustry,syntheticantioxidantsproducedby,12

E

eatinghabits,public'sneedtochange,104

Eaton,J.W.,77

Ebselen,76

EKGchanges,andvitamintherapy,34

electrons,transferof,5

emphysema,pulmonary,72

endive,andcancerrisk,49

enrichment,possibilitiesfor,102

Enstrom,J.E.,30

enzymes

antioxidant,9,22,39,52,53,57

essential,11

inrenaldialysis,84

epidemiologicalstudies,18,87,98

ofAlzheimer'sdisease,54

andbreastcancer,48

ofcataracts,66-68

ofeffectofsoy,85-86

NHANES1,49

ofteaconsumption,87

epigallocatechingallate,14

epinephrine,62

esophagus,cancerof,40

EstablishedPopulationforEpidemiologicalStudiesintheElderly,33

estrogens,anduterinecancer,50

EUK-8,70

Everall,I.P.,75

exerciseandantioxidants,81failureto,1o6

experiments,scientific,3-4.Seealsostudies

eyedisease,andantioxidants,66-69,100

F

fatintake

andantioxidantstatus,66

reductionin,104

fatoxidation

inAIDSpatients,74

inAlzheimer'sdisease,54

andbeta-carotene,44

indiabetics,64

anddiseaseprocess,7,8

effectofoliveoilon,14

effectofteaon,14

inheartdisease,23-24

inhyperthyroidism,81

measuringlevelsof,31

insepticshockpatients,76

andvitaminC,92

ferulicacid,inherbs,13

fiber,andbreastcancer,48

Finland

flavonoidstudyin,36

heartdiseasestudiesin,28-29,30

Finns.SeealsoLapps

cancerriskin,49-50

incancerriskstudy,42-43

vitaminCdeficiencyin,31

fisetin,13

Flagg,E.W.,40

flavins,intea,14

Page132

flavonoids,1

actionof,12-13

antioxidant,13

clinicaldataon,85-88

aspainrelievers,15

andParkinson'sdisease,57

protectiveeffectof,36,50

sourcesof,104,110

asvitaminEhelpers,13

Floren,L.C.,102

''foamycells,"24

folkmedicine,14

Chilean,15

Chinese,82

ofIndia,15

FoodandDrugAdministration(FDA),105

FoodandNutritionBoard,ofNAS,105

Franke,A.A.,51

freeradicals,6

"Frenchparadox,"36-37

Freudenheim.J.L.,47

fruits,12,13,102

anticancereffectsof,16,41

andbreastcancer,48

andcancerrisk,40,98

andcarcinogenesis,51

indiet,39,95

andlungcancer,48-49

protectiveeffectsof,43,103

G

Galley,H.F,38

gallicacid,innutgall,13

gamma-lineolicacid,andbreastcancer,48

gamma-tocopherol,10

andheartdisease,29,30

lowlevelsof,32

suggestedamountsfor,110

Garewal,H.S.,51,97

garlic,12,104,110asantioxidant,14clinicaldataon,87-88

gastriccancer,andvitaminE,45

Gehrig,Lou,58

gender,andeffectofantioxidants,31

Geniforte,15

genistin,13,85

geraniol,15

Gershoff,S.N.,68

Gey,K.F.,28,99,1oo

glucose-6-phosphatedehydrogenasedeficiency,93

glutamate,59

glutamine

forAIDSpatients,74

suggestedamountsfor,110

glutathione,56

inAIDSpatients,74

andasthma,69

incigarettesmoking,71

indiabetes,64,66

andgastriccarcinoma,45

inneonate,83

occurrenceof,10

potentialtoxicityof,77

inschizophrenia,62

andstrenuousexercise,81

inyeast,15

glutathioneperoxidase(GSHpx),111,52,53

inAIDSpatients,74

andasthma,69

incancercells,39

indiabetes,64

duringheartattack,25

inmaculardegeneration,69

inoxidativestress,22

inpreeclampsia,84

inrenaldialysis,84

inschizophrenia,62

Goldberg,D.M.,86

Goldfarb,S.,91

gossypol,13,15

grains,protectiveeffectof,43

grapefruit,13

greentea,13,14

Gridley,G.,51

H

H290/51,76

Halliwell,B.,46,103

haloperidol,63

Hankinson,S.E.,67

Harris,S.R.,1oo

Hathcock,J.N.,100

Hawking,Stephen,57

health-foodstores,1

healthinsuranceindustry,4

healthy-lifestylehypothesis,97

Page133

heartattack,90.Seealsomyocardialinfarction

andantioxidants,34

andfatoxidation,76-77

oxidativestressof,24

preventionof,25

andteaconsumption,87

heartdisease

andantioxidants,97,98

andoxidativestress,23-38

Helicobacterpylori,87

Hemil,H.,79

hemorrhagicstroke,55

Herbert,V.,30,92

herbs,12,13

Herman,Z.S.,79

Hertog,M.G.L.,36

hesperetin,inoranges,13

HIVinfection,8

andantioxidants,74-75

monocyteblockadein,75

Hodis,H.N.,35

Hoffer,Abram,4,61,62,63

Hoffman,R.M.,97

Hollman,P.C.H.,36

Huntington'sdisease,58

Huttunen,J.,97

hydrogenperoxide(H2O2),6

andasthma,70

andcancercells,39

inDown'ssyndrome,53

andglutamatesynapse,60

inParkinson'sdisease,56

inschizophrenia,59

hydroxylradical(OH)

asoxidatingagent,6

inpsychologicalstress,63

hydroxytyrosol,inoliveoil,13,14

hyperthyroidism,81

I

Illingworth,D.R.,97

immuneresponse

andaging,73

andvitaminC,79

andvitaminE,10,99-100

infections

andantioxidants,79-80

prostaglandinsand,7

inflammation

effectofflavonoidson,13

effectofoliveoilon,14

prostaglandinsand,7

andredwine,13

IowaHealthStudy,86

iron,free

incysticfibrosis,78

indiabetes,64

inrheumatoidarthritis,84

andvitaminC,91-92

ironoverload,andvitaminC,92-93

ischemia

antioxidantsfor,96

andoxidativestress,76

insystemicsclerosis,85

isoniazid,85

isoprenoids

indirectantioxidantpropertiesof,16

sourcesof,15-16

suggestedamountsfor,110

Italy,heartdiseasestudiesin,28

J

Jacques,P.F,67,94

Japanese,lungcancerratesin,87

JapaneseHawaiians,cancerriskin,45

Johnson,L.E.,100

JournaloftheAmericanCollegeofNutrition,98

K

kaempferol,14

kale,andmaculardegeneration,68

kidneystones,andvitaminC,9o-91

Kimmick,G.C.,47

Knekt,P.,45,49

kojo-kon,14

Krikker,M.,92

Kristensen,M.,29

Kuklinski,B,35

Kumar,R.,94

L

laboratorytests,effectofvitaminCon,93

Landrum,J.T.,69

Langseth,L.,93

Lapps,dietof,33

laryngealcancer

anddiet,40

roleofcarotenoidsin,5

LDLcholesterol,12

L-DOPA,56

learning,andantioxidants,60

Page134

Leewenburgh,C.,73

Lehr,H.-A.,72,76

lettuce,andcancerrisk,49

Levine,M.,100

licorice,13

Lih-Brody,L.,82

Linxiantrial,97

lipidperoxides,22

LipidResearchClinics,28

lipoicacid,10,11indiabeticpatients,65sourcesof,109

Lithuanians,heartdiseasein,29-30

Liu,Jiankang,60

liver,cirrhosisof

andantioxidants,80-81

indiabetes,65

Livrea,M.A.,80

Lockwood,K.,48

LouGehrig'sdisease,57-58,96

lungcancer

andantioxidants,41,48-50,51

anddiet,40

lutein,11

andbeta-caroteneintake,90

andbreastcancer,47-48

andlungcancer,49

andmaculardegeneration,68-69

sourcesof,103,109

suggestedamountsfor,110

lycopene,1,11,29

inbeta-thalassemia,80

andbreastcancer,48

andheartdisease,29

lowlevelsof,32

andlungcancer,45

inmaculardegeneration,69

andprostatecancer,41

protectiveeffectof,37,45

sourcesof,104,109

suggestedamountsfor,110

Lykkesfeldt,J.,71

lymphaticsystem,cancersof,40

M

macrophages,24

maculardegeneration

andantioxidants,68-69

andbeta-caroteneintake,90

magnesium

andfattyacids,96

needfor,106

malaria,82

Maloley,P.A.,97

MarioNegriInstitute,40

Marmite,15

Mason,Joel,98

massmedia,confusingreportsin,1-2

Matricariarecutitis,15

Maxwell,S.R.J.,97

MayoClinicgroup,92

McGeer,P.L.,54

McKeowen-Eyssen,G.,93

MDA(malonyldialdehyde),22

medicalcare,costsof,4

Medicare,4,107

Mediterraneandiet,29

megavitamins

vs.RDAs,2

suspicionof,17

Mehra,M.R.,99

melanoma,97

melatonin,1,11

Mena,M.A.,56

menopause,andheartdisease,27

menthol,15

Messmer,K.,76

Meyers,D.G.,97

micronutrients,107

mifepristone,12

minerals,96

mineralsupplements,18

mitochondrialdiseases,83

Moertel,C.G.,92

MONICA,28

monocytes,inHIVinfection,74

monosodiumglutamate,59

Mori,Akitane,60

morin,13

motorneurondisease,57-58

mouth,cancerof,40

multiplemyeloma,54

mutations,7

myocardialinfarction.Seealsoheartattack

antioxidantsfor,96

andvitaminQ10,35

andvitamintherapy,34

myo-inositol,indiabetes,66

myotonicdystrophy,83

myrecetin,14

N

NAC.SeeN-acetylcysteinenaringenin,ingrapefruit,13

Page135

nasopharyngealcancer,andteaconsumption,86

NationalAcademyofSciences(NAS)FoodandNutritionBoardof,105RDAspublishedby,2

NationalCancerInstitute,44,48,104

NationalHealthandNutritionExaminationSurveyI(NHANES-I),30,49

NationalResearchCouncil,105

nervoussystem,diseasesof,52-63

NetherlandsCohortStudyonDietandCancer,36,49

neuraltubedefects,indiabetes,66

neuroblastoma,vitaminCin,93

neuromelanin

inParkinson'sdisease,55

inschizophrenia,61

neurotransmitters,52

epinephrine,62

inschizophrenia,59

NewEnglandJournalofMedicine,41,43,54

NF-kBmolecule,8,22

nicotinamide(vitaminB3),12.SeealsovitaminB3

indiabetes,64-65

efficacyincombinationof,28

nitricoxide,61

andglutamatesynapse,60

andhighbloodpressure,38

nitricoxidesynthase,60

nitrogendioxide(NO2),72

nitrogenspecies,reactive,61

nitroglycerine,toleranceto,37

nitrosamines,effectofvitaminCon,46

NMDAreceptor,59,60

norepinephrine,62

Nurse'sHealthStudy,26

nutgall,13

nutrition

centersfor,1

guidelinesfor,104

physicians'attitudestoward,105

nuts,13

Nyyssönen,K.,30

O

obesity

andantioxidants,29

increasein,105

ODC(ornithinedecarboxylase),47

8-OH¬G,22,71

oleuropein,14

oliveoil,12,13,29

asantioxidant,14-15

protectiveeffectof,88

Oliver,M.F,97

Omage,S.T.,44

Omenn,G.S.,44,98

onions

flavonoidsin,36

protectiveeffectof,50,87

oralcancer

preventionof,51

andteaconsumption,86

oranges,13

organmeats,vitaminQ10in,11

Osmond,Humphry,4,61,62,63

osteoporosis,calciumfor,106

ovary,cancerof,41

oxalicacid,90-91

oxidants,3

oxidation,5

oxidativestress,3,5

inAIDSpatients,74

inAlzheimer'sdisease,53,55

andbloodflowinterruption,76

causesof,8-9

andcellularmetabolism,22

incigarettesmoking,71,72

indiabetes,64

indisease,22-23

andheartdisease,23-38

inhyperthyroidism,81

andincreasedfoodconsumption,72

inlungs,69

inmalaria,82

measurementof,21-22

neonatal,83

Pantoxprofilefor,108

andParkinson'sdisease,56

inpreeclampsia,84

reperfusion,76-77

inshockpatients,76

andstroke,52

oxidizingagents,6

oxygenspecies,reactive,6,17,46

inAlzheimer'sdisease,54

body'sdefensesagainst,95

andbraincells,8

andcaloricrestriction,73

cancer-producing,39

Page136

oxygenspecies,reactive(cont'd)

incigarettesmoking,71

indiabetes,64

fighting,108

duringheartattack,25

inHuntington'sdisease,58

productionof,9

proteinattackedby,7

inschizophrenia,59

andWBCs,7

P

Packer,L.,44,65

painrelievers,flavonoidsas,15

Paller,M.S.,77

pancreas

cancerof,40,41

failureof,78

pancreatitis,83

Panetta,J.A.,85

Pantoxprofile,108

Paolisso,G.,93

parasiticfoci,inschizophrenia,59

Parkinson'sdisease,20-21

antioxidantsfor,56-57,96

causesof,55-56

earlyinterventionfor,107

symptomsof,56

treatmentof,56

passifloracoerulea,15

Patterson,B.H.,104

Pauling,Linus,2-3,79,90,92

Paulson,G.W.,57

peanuts

lycopenein,103

reservatolin,13

pellagra,2,10

pentane,22

peptides,antioxidant,13

peroxynitrite,61

PGHsynthase,7

pharyngealcancer,andteaconsumption,86

phenols

antioxidant,13

andflavonoids,12

physicians

andantioxidanttherapy,108

dietaryadviceof,105

Physician'sHealthStudy,27,42

phytochemicals,12

placebo

inantioxidantstudies,19-20

indouble-blindstudies,32-34

plants,antioxidantsfoundin,12-15

plasmaantioxidantprofile,108

platelets

effectofflavonoidson,13

effectofoliveoilon,14

effectofvitaminEon,24

andredwine,13

pneumococcalmeningitis,80

polygonumcuspidatum,14

polyphenols,50

antioxidant,13

sourcesof,104,110

portwine,14

potatoes,vitaminCin,97

Prasad,K.N.,94

preeclampsia,84

probucol,64

procysteine,andARDSpatients,71

progesterone,11

pro-oxidants,6

propaganda,4

prospectivestudies,98

prostaglandinHsynthase(PGHsynthase)

inAlzheimer'sdisease,53

ininflammationprocess,7

inschizophrenia,59

prostaglandins

effectofflavonoidson,13

effectofredwineon,13

duringinflammation,7

prostatecancer

andantioxidants,41,51

andsoy,85-86

proteins

andreactiveoxygenspecies,7

roleof,7

sacrificial,10

proteins,blood,andsmogexposure,72

Pryor,W.A.,107

pseudomonasaeruginosa,78

PSstudy,44

psychologicalstress,63

Q

qinghaosu,82

quercetin,14,15

inapples,13

Page137

protectiveeffectof,50

inredwine,36

quinones,61

derivedfromdopamine,62

inschizophrenia,61

R

Rachmilewitz,E.A.,81

Ramsey,B.W.,78

Raspberry,William,107

Rautalahti,M.,97

Raynaud'ssyndrome,81

recommendeddailyallowances(RDAs),2

ofantioxidantvitamins,105

raising,106

replacementof,99

rectum,cancerof,40

redwineclinicaldataon,86flavonoidsin,13protectiveeffectof,36-37

Reider,C.R.,57

reinforcement,positive,andantioxidants,60

reperfusion

antioxidantsfor,96

andoxidativestress,76

insystemicsclerosis,85

reservatol,11

actionof,13-14

inredwine,36

respiratorydiseases,andantioxidants,69-72

respiratorytract,cancerof,41

rhein,inrhubarb,13

rheumatoidarthritis,8,84-85

rhubarb,13

riboflavin,andcataracts,67

rice,13

Riemersma,R.A.,28

Rimm,E.B.,26

rosemary,13,110

Rucker,R.B.,17

rutin,inredwine,13,36

S

Santini,S.A.,64

Scheider,W.L.,57

schizophrenia

antioxidantdefensesin,62

antioxidantsin,61,96

causesof,59-61

norepinephrinepathwayin,62

oxidativestressin,4

typesof,58-59

Schmidt,K.-H.,91

scleroderma,85

Scotland,heartdiseasestudiesin,28

ScottishHeartHealthStudy,27

scurvy,2,10

seeds,13

selegiline,andAlzheimer'sdisease,54-55

selenium,96

inAIDSpatients,74

andARDS,70

andasthma,69-70

andbreastcancer,48

indiabeticpatients,65

andfatoxidation,35

inHIVpatients,75

recommendationsfor,100

andriskforrheumatoidarthritis,85

insepticshockpatients,76

suggestedamountsfor,110

toxiclevelsof,100

asvitaminEhelper,103

self-medication,97

Sen,C.K.,81

SeventhDayAdventists,heartdiseasein,30

shallots,104,1

shock

andantioxidantdefenses,75-76

antioxidantsfor,96

silymarin,indiabeticpatients,60

Simonian,N.A.,8

Singh,R.B.,29,34

smog,exposureto,72

smoking,90,106

andantioxidants,37,71-72

andbeta-carotene,26,42,44

andcarotenoids,28

andlungcancer,49

Snodderly,D.M.,1o8

soy

anticancercompoundsin,13

clinicaldataon,85-86

spinach

andcataracts,67

andmaculardegeneration,68

Page138

Sthelin,H.B.,45

Stampfer,M.J.,26

Stephens,N.G.,32,33

steroids,12

Stites,T,17

stomachcancer

andantioxidants,41,46-47,51

anddiet,40

stress

vs.oxidativestress,23

psychological,63

stroke,andantioxidants,52

studies.Seealsoepidemiologicalstudies;specificstudies

coronaryarterydisease,25-38

double-blind,placebo-controlled,18,19-20,32-34,41,43,47,55,65,70,75,98,99,101

limitationsof,20-21

randomized,double-blindIcontrolled,34

sunflowerseedoil,36

superoxidedismutase(SOD),11,53,57,58

duringheartattack,25

inmaculardegeneration,69

inoxidativestress,22

potentialtoxicityof,77

inrenaldialysis,84

superoxideion(0-),6

supplementation,suspicionof,17

SurgeonGeneral,105

Swedishmen,heartdiseasein,29-30

synapsedeletion,inschizophrenia,59

syntheticmolecules,12

systemicsclerosis,85

T

Tavani,A.,40

Taylor,A.,68

tea,12,13,36

asantioxidant,14

clinicaldataon,86-87

television,advertisingon,105

Tengerdy,R.P.,99,107

4-thiazolidinone,85

thrombolytictreatment,antioxidantsin,77

thromboxanes,effectofoliveoilon,14

thyme,13

thymol,13

Timemagazine,1-2

tobacco,andoralcancer,51

tobaccosmoke,8

Tolbert,Leland,3

tomatoes,29,103

andmaculardegeneration,69

protectiveeffectof,37

Toohey,L.,30

traceminerals,1o6

transmethylation,61

transmethylationhypothesis,4

transplantsurgery,oxidativestressof,76

Trichopoulou,A.,88

tuberculosis,andantioxidantdefenses,85

tumeric,15

turniptops,andmaculardegeneration,68

U

ulcerativecolitis,82

ulcers

antioxidantsfor,63

andgarlicconsumption,87-88

"uncontrolledvariable"problem,19

urate,andgastriccarcinoma,45

uricacid,11,14indiabetes,64inpreeclampsia,84

Urivetsky,M.,91

uterinecancer,andantioxidants,50-51

V

Valium,15

VanderHagen,A.M.,1oo

VanderVliet,A.,78

vanillicacid,inoliveoil,14

LaVecchia,C.,40

vegetables,12,102

allium,87

anticancerpropertiesof,16,41

andbreastcancer,48

andcancerrisk,40,98

andcarcinogenesis,51-52

indiet,39,95

andlungcancer,48-49

protectiveeffectsof,43,103

vegetariandiet,50

vitaminA,1,10

inAIDSpatients,75

inbeta-thalassemia,80

andcancerrisk,41

indiabetes,64

Page139

vitaminB3.Seealsonicotinamide

suggestedamountsfor,110

asvitaminEhelper,102,103

vitaminB6

inAIDSpatients,75

suggestedamountsfor,110

vitaminB12

inAIDSpatients,75

suggestedamountsfor,110

vitaminC,1,2

allegedtoxicityof,93

andcommoncold,79

antinitrosamineactionof,51

andARDS,70

andasthma,69,70

inbeta-thalassemia,80

bloodlevelsof,22

inbrain,52,56

andbreastcancer,47,48

afterbypasssurgery,35

cancerand,40

andcancerrisk,98

andcataracts,66,67-68

incigarettesmoking,71,72

incombinationdoses,94

incysticfibrosis,78

indiabetes,64,66

effectonnitrosaminesof,46

efficacyincombination,28

fat-solublederivativesof,12,21

andgastriccarcinoma,45

andglutamatesynapse,60

andheartdisease,26-27,28,29,30

andhighbloodpressure,38

inHIVpatients,75

andlipoicacid,11

lowlevelsof,32

andlungcancer,49

andnitrosamines,103

occurrenceof,10

andoralcancer,51

inpancreatitis,83

andParkinson'sdisease,57

pro-oxidanteffectof,93

protectiveeffect1f,31,32

RDAfor,2,100-101

recommendationsfor,97,99,100,106

safetyof,90-94

inschizophrenia,62

insepticshockpatients,76

andsmogexposure,72

sourcesof,104,109

andstrenuousexercise,81

suggestedamountsfor,110

insystemicsclerosis,85

toxiclevelsof,100

andvitaminE,12,32,102,103

vitaminCdeficiency,30-31,32

vitaminCsupplements,duringL-DOPAtherapy,56

vitaminD

anticancereffectof,42

forsmokers,42

vitaminE,1,2

inAIDSpatients,74,75

andALS,57-58

andAlzheimer'sdisease,54-55

andARDS,70

andasthma,69

inbeta-thalassemia,80

bloodlevelsof,22

andbreastcancer,47,48

afterbypasssurgery,35

andbypasssurgery,77

andcancerrisk,40,42,43,45,98

andcataracts,66,67,68

incigarettesmoking,71,72

incysticfibrosis,78

indiabetes,64,65,66

effectonplateletsof,24

efficacyincombinationof,28

andfatoxidation,35

andgastriccarcinoma,45

andheartattacks,33,34

andheartdisease,26-27,29

helpervitaminsfor,102

andhighbloodpressure,38

inhyperthyroidism,81

andimmuneresponse,73

andlipoicacid,11

lowlevelsof,32

andlungcancer,49

moppingupoperationof,94

andnitroglycerinetherapy,37

ODCactivityreducedby,47

optimumdosefor,107-108

andoralcancer,51

inpancreatitis,83

andParkinson'sdisease,57

protectiveeffectof,31,32,38,46

RDAfor,2,38

Page140

vitaminE(cont'd)

recommendationsfor,97,99,100,106

andriskforrheumatoidarthritis,85

roleof,10

safetyof,94-95

insepticshockpatients,76

andsmogexposure,7

sourcesof,104,109

andstrenuousexercise,81

suggestedamountsfor,110

insystemicsclerosis,85

toxiclevelsof,100

vitaminEsupplements,103

vitaminK,55

vitaminQ10,10

andbreastcancer,48

andhighbloodpressure,38

protectiveeffectof,35-36

andsmogexposure,72

suggestedamountsfor,110

inyeast,15

vitamins

industryfor,1

typesof,10-11

vitaminsupplements,18

andcataracts,67-68

self-medicationwith,97

Voelker,R.,18

W

Wales,coronaryheartdiseasestudyin,87

Walker,A.R.P.,104

water(H20),6

Weber,P.,103

Weinsier,Roland,98

Weisburger,J.H.,99,100

whitebloodcells,7

whitewine,13.Seealsoredwine,36

wholegraincereals,13

Winklhofer-Roob,B.M.,78

Wiseman,H.,103

Wiseman,Helen,46

WorkStudyGrouponDiet,NutritionandCancer,ofACS,39

WorldHealthOrganization,MONICAprojectof,28

Y

yeast,15,110

Yong,L.-C.,49

Z

Z-103,76

zeaxanthin,1,11

andbeta-caroteneintake,90

andbreastcancer,48

andlungcancer,49

andmaculardegeneration,68-69

sourcesof,103,109

suggestedamountsfor,110

Zemel,M.B.,92

Ziegler,R.G.,45,48

zinc,100

inAIDSpatients,74

andhighbloodpressure,38

suggestedamountsfor,110