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Vitamin E Society For Free Radical Biologyand Medicine

1

Tocopherol (Vitamin E) in Health

and disease

What is Veris? VERIS = Vitamin E Research and Information Service

The worldwide VERIS Research Information Service disseminatesnutritional information, emphasizing the potential health-enhancing

benefits of antioidants and botanicals! VERIS began in "#$% as one ofthe first science-based resources for information on natural ingredientsfound in dietar& supplements and foods, and continues to serve in thisrole as a credible communications resource!

The Virtal Free Radical School

!y

RIS

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Tocopherol (Vitamin E) in Health

and disease#$er$ie%& Vitamin E is an essential fat-soluble vitamin!

Recentl&, the 'ational (cadem& of Sciences defined vitamin E

as the )R stereoisomers of alpha-tocopherol! *owever, past

classifications of vitamin E included a group of eight compounds+ alpha-, beta-, gamma- and delta-tocopherols and tocotrienols!

The naturall& occurring d-alpha-tocopherol has the highest

biological activit&! This presentation %ill re$ie% 'nctions

a!sorption and transport intae and re*irements 'orms

de'iciency states and sa'ety o' $itamin E+This presentation

will also provide an overview of the current research status of

vitamin Es role in preventing or minimizing oidative damage

associated with the development of cancer, coronar& heart

disease, cataracts and (lzheimers disease!

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,

Fnctions o' Vitamin E

.hain-brea/ing antioidant

0rotects cell membranes

Enhances immune response

Regulates platelet aggregation

Regulates protein /inase . activation

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.otes to Fnctions

Vitamin E is the ma1or chain-brea/ing antioidant in bod&

tissues and is the first line of defense against lipid

peroidation, protecting cell membranes from free radical

attac/ through its free radical 2uenching activit&!

Vitamin E protects pol&unsaturated fats in cell membranesthat are important for membrane structure and function!

Increased inta/e of vitamin E enhances immune response!

Vitamin E regulates platelet aggregation b& inhibiting platelet

c&cloo&genase activit& and thus decreases prostaglandin

production! It also has a role in regulation of protein /inase. activation!

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/

Vitamin E as an antioidant

O

R3

R2

HO

R1

Chromane Head

Phythyl Tail

R1 R2 R3

CH3 CH3 CH3

CH3 H CH3

H CH3 CH3

H H CH3

.

OCH3

CH 3

CH 3

O

CH3

(CH2)3CH(CH2)3CH(CH2)3CH(CH3)2

CH3 CH3

R 0 T#H

RH 0 T#

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2!sorption and Transport

3ependent on abilit& to absorb fat

(bsorbed into l&mphatic s&stem

.omponent of ch&lomicrons (lpha-tocopherol is ma1or tocopherol in

plasma

0ositive association between serum lipid and

tocopherol levels

'ormal range is 4!%-"!5 mg6dl

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3

.otes to 2!sorption and Transport

The abilit& of an individual to a!sor! $itamin E is dependent

on the a!ility to a!sor! 'at+

Vitamin E is absorbed into the l&mphatic s&stem from the

intestines and enters the blood as a component of the

ch&lomicrons! The ma4ority o' $itamin E in plasma is in the

lo%5density lipoproteins+ (lpha-tocopherol is the ma1or

tocopherol in adult plasma and accounts for approimatel& $78

of the total tocopherol concentration!

There is a positive association between serum lipid levels and

tocopherol levels! Vitamin concentrations in !ody tisses

$ary considera!ly+(dipose tissue and adrenal glands have the

highest levels! Vitamin E levels in plasma range from 4!%-"!5

mg6dl in normal populations! In general, a "4-fold increase in

vitamin E inta/e will double plasma concentrations!

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6

7linical 8e'iciency States

Susceptible groups+ 0atients with malabsorption s&ndromes

+ 0remature infants

+ 0atients on T0'

.haracterized b& progressive neurological s&ndrome

+ 9ait disturbances

+(bsent or altered reflees

+ :imb wea/ness

+ Sensor& loss in arms and legs

Improved neurological function with vitamin E therap&

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9

.otes to 7linical Vitamin E de'iciency

7linical $itamin E de'iciency that is alleviated b& vitamin E

administration is seen in individuals with chronic malabsorption

s&ndrome, premature infants and patients on total parenteral

nutrition ;T0'

.onditions that interfere with normal digestion, absorption or

transport of fat have been associated with low serum levels of

vitamin E! Serum vitamin E concentrations can be less than )48 of

normal in individuals with mala!sorption syndromes such as

celiac disease, c&stic fibrosis and biliar& atresia!

0atients with abetalipoproteinemia ;an inherited disorder mar/edb& absence of lipoproteins in the blood and low levels of

ch&lomicrons< fre2uentl& have ver& low serum vitamin E

concentrations, below measurable levels!

2+ Mala!sorption Syndrome

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1:


( progressive nerological syndromecan develop due to long

term, severe vitamin E deficienc& and is characterized b& gait

disturbances, absent or altered reflees, limb wea/ness andsensor& loss in the arms and legs! S&mptoms of neurological

d&sfunction develop within "$-) months in children with

vitamin E deficienc& but s&mptoms in vitamin E-deficient adults

usuall& re2uire "4-)4 &ears of fat and vitamin E malabsorption!

.erological 'nction has !een sho%n to impro$e %ith

appropriate $itamin E therapyand progressive neurological

damage ma& be prevented b& initiation of vitamin E therap& at

an earl& age in children with chronic cholestatic disease!

B+ .erological Syndrome

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.e%!orn in'ants, especiall& those that are premature, are

susceptible to vitamin E deficienc& due to inade2uate bod&

stores, impaired absorption and reduced transport capacit& in

the blood due to low :3: levels at birth!

0lasma vitamin E levels are fre2uentl& low in patients on total

parenteral nutrition as the ma1or source of vitamin E in the

parenteral solution is the fat emulsion, which provides primaril&

- and -tocopherols that are much less biologicall& active forms

of tocopherol!

Ths alpha5tocopherol spplementation is re*ired 'or

patients on total parenteral ntrition+

7+ ;rematre

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1"

Sorces !!S! stud& ofpatients who had a colorectal tumor removed before entering the stud&!

In a multi-center >!S! trial that evaluated vitamin E treatment in patients

with precancerous lesions in the oral cavit&, almost one-half had clinical

responses ;at least %48 disappearance of lesions< and another one-

fourth had histologic responses ;improvement in the degree ofabnormal tissue

and mortalit& rate of prostate cancer but not lung cancer in a primar&

prevention trial in Binland!

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7oronary Heart 8isease

Increased vitamin E inta/es associated with

decreased ris/ of coronar& heart disease in

epidemiologic studies 3ose-dependent resistance of :3: to oidation

with vitamin E supplementation

In ) of @ secondar& prevention trials, vitamin E

showed protective effects

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.otes to 7oronary Heart 8isease

Results of animal studies suggest that vitamin E and other antioidants

alter cancer incidence and growth b& acting as (nimal studies and

epidemiologic data sggest that redced antio=idant protection

may increase the ris o' coronary heart disease and increased

intae o' $itamin E and other antio=idants may ha$e a role in

pre$ention o' the disease+The ma1orit& of epidemiologic studies have

shown that increased vitamin E inta/es or blood levels are associated

with a decreased ris/ of coronar& heart disease! In two large *arvard-

based epidemiologic studies, sub1ects who too/ dail& vitamin E

supplements of "44 I!>! or more for at least two &ears had a

significantl& reduced ris/ of coronar& heart disease compared tosub1ects who did not supplement with vitamin E!

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Spplemental $itamin E intaes ha$e !een sho%n to

decrease the sscepti!ility o' lo%5density lipoprotein

(>8>) to o=idati$e damage+?idative modification of :3:

is implicated in the initiation of coronar& heart disease!

Resistance of :3: to oidation increased in a dose-

dependent manner during vitamin E supplementation! The

maimum effect of vitamin E in decreasing susceptibilit& of

:3: to oidation was observed at dail& inta/es of at least

44 I!>!

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( limited number of intervention trials have also evaluated the e''ects

o' spplementation %ith $itamin E alone or in com!ination %ith

other antio=idants on ris or progression o' coronary heart

diseasein various groups, with mied results!

In three secondar& prevention trials of vitamin E supplementation, in

which patients had diagnosed coronar& heart disease or were at highris/ for the disease, a >!C! stud& showed protective effects against

subse2uent heart attac/s, a stud& in Ital& showed some benefits and

the third conducted in a number of countries showed no significant

benefits!

Dased on a review of all available research evidence, $itamin E mayha$e a role in pre$ention o' coronary heart disease, the leading

cause of death in developed countries!

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7ataracts

Vitamin E dela&ed or minimized cataract

development in animal models

Epidemiologic data suggest a relationshipbetween blood vitamin E levels and cataract

ris/

3ecreased cataract ris/ associated with

vitamin E supplementation

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"3

.otes to 7ataracts

?idative damage is considered to be an earl&, significant event in thedevelopment of most cases of senile cataract, which affects the elderl&

and is the most common t&pe of cataract! Results of animal stdies

ha$e sho%n that $itamin E is a!le to arrest and re$erse cataract

de$elopment to some e=tent+ In isolated animal lenses and in a

number of animal models, vitamin E dela&ed or minimized cataract

development induced b& eperimental oidative stress!Epidemiologic data sggest an in$erse relationship !et%een

!lood le$els o' $itamin E and other antio=idants and cataract ris+

Two studies showed a significant decrease in cataract ris/ in sub1ects

who regularl& too/ vitamin E supplements compared to those who did

not! :eading investigators who have studied the relationship between

nutrition and cataracts have suggested that although moderatesupplementation with $itamin E %ill not pre$ent cataracts it may

delay the onset and slo% the progression o' cataract

de$elopment!

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"6

2lheimer@s 8isease

Increased vitamin E inta/es or blood levelsassociated with reduced ris/ of (lzheimersdisease

Vitamin E or selegiline slowed diseaseprogression in multicenter trial

.urrent practice guidelines recommend vitaminE or selegiline for patients with moderate

disease Vitamin E ma& be preferred from a safet&

standpoint

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"9

.otes to 2lheimer@s 8isease

?idative damage is also implicated in brain aging and in

development of certain degenerative conditions affecting the

brain, such as (lzheimers disease! Stdies ha$e sho%n that

increased intaes or !lood le$els o' $itamin E %ere

associated %ith redced ris o' 2lheimer@s disease+

( multicenter two-&ear trial evaluated the effects of vitamin E or

the drug selegiline on disease progression in patients with

moderatel& severe (lzheimers disease! Stud& results showed

that either vitamin E or selegiline slowed the progression of the

disease compared to the placebo group! The researchers

concluded that cost and convenience ma& be involved in

treatment decisions since both vitamin E and selegiline were

effective!

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,:

.otes to 2lheimer@s 8isease

The (lzheimers 3isease .ooperative Stud& has initiated a three-

&ear multicenter trial in patients with mild cognitive impairment to

evaluate whether vitamin E can prevent or dela& the clinical

diagnosis of (lzheimers disease!

.urrent clinical practice guidelines from the (merican 0s&chiatric(ssociation recommend that vitamin E or selegiline be considered

for patients with moderate (lzheimers disease to dela& the

mental deterioration and that vitamin E ma& be preferred from a

safet& standpoint!

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,1

Sa'ety

Bew side effects in double-blind, controlled

human studies

.ould affect blood clotting in patients on

blood thinners

'o other specific side effects

>: set at ",444 mg per da& for adults

Vitamin E is safe and well tolerated over widerange of inta/es and time periods

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,"

.otes to Sa'ety

Since vitamin E inta/es considerabl& above those needed to

prevent deficienc& are ta/en b& man& individuals over long

periods of time to help prevent free radical-mediated

conditions and diseases and to maintain health, safet& is an

important consideration! In double-blind, placebo-controlledhuman studies, ver& few observed side effects were seen

with oral dail& inta/es of 544-@)44 I!>! for three wee/s to si

months! Side e''ects associated %ith $itamin E %ere also

ncommon in other hman stdies+

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,,

.otes to Sa'ety

(lthough high vitamin E inta/es have not been demonstrated to cause

abnormalities in blood clotting in normal adults, the& ma& intensif& aneisting blood coagulation defect produced b& vitamin C deficienc& due

to malabsorption or blood thinners! In two clinical trials of patients on

blood thinning drugs, vitamin E inta/es of "44 or 44 I!>! in one stud&

and $44 or ",)44 I!>! in the other stud& did not significantl& affect blood

clotting in these groups! Dased on potential effects of vitamin E on

blood clotting, the Tolera!le Apper e$el (A>)set b& the'ational (cadem& of Sciences in )444 for all forms of alpha-tocopherol

is 1::: mg per day 'or adlts! Since vitamin E supplementation

could potentiall& affect blood clotting in patients on blood thinners, high

vitamin E dosages ma& be contraindicated for these patients or should

be used onl& under medical supervision!

Ecept for a vitamin C interaction in patients on blood thinners, there

are no specific side effects associated with vitamin E inta/e! Thus,

based on a review of both animal and human data, oral vitamin E is

safe and well tolerated over a wide range of inta/es and over long

periods of time!

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,-

Smmary

Increasing research evidence implicates oidative damage in developmentof various degenerative diseases and conditions!

(s the ma1or fat-soluble antioidant, vitamin E is protective againstoidative damage!

The ma1orit& of epidemiologic evidence suggests that increased inta/es orblood levels of vitamin E are associated with decreased ris/ of certain

t&pes of cancer, coronar& heart disease, cataracts and (lzheimersdisease!

( limited number of intervention trials have shown mied but fre2uentl&beneficial effects of vitamin E supplements at inta/es considerabl& abovelevels re2uired to prevent deficienc& s&mptoms!

Research results suggest that the bioavailabilit& of natural-source vitaminE is approimatel& twice that of s&nthetic vitamin E!

( review of safet& data has shown that oral vitamin E is safe and welltolerated over a wide range of dail& inta/e levels!

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Vitamin E Society For Free Radical Biology ,/

eneral Re'erences

"! D1orneboe, (!, D1orneboe, 9! and 3revon, .! (bsorption, Transport and 3istribution of Vitamin E! ! 'utr!")4F)@@-)), "##4!

)!

Durton, 9!G!, Traber, A!9!, (cuff, R!V!, Galters, 3!'!, Ca&den, *!, *ughes, :! and Ingold, C!>! *uman 0lasma

and Tissue (lpha-Tocopherol .oncentrations in Response to Supplementation with 3euterated 'aturaland S&nthetic Vitamin E! (m! ! .lin! 'utr! 57F55#-5$, "##$!

@!

3evara1, S! and ialal, I! (ntioidants and Vitamins to Reduce .ardiovascular 3isease! .urrent (therosclerosisRep! )F@)-@%", )444!

! 3reher, 3! and unod, (!B! Role of ?&gen Bree Radicals in .ancer 3evelopment! Eur! ! .ancer @)(F@4-@$,"##5!

%! Bord, E!S! and Sowell, (! Serum (lpha-Tocopherol Status in the >nited States 0opulationF Bindings from theThird 'ational *ealth and 'utrition Eamination Surve&! (m! ! Epidemiol! "%4F)#4-@44, "###!

5!

9rundman, A! Vitamin E and (lzheimer 3iseaseF The Dasis for (dditional .linical Trials! (m! ! .lin! 'utr!

7"F5@4S-5@5S, )444!

7!

Cappus, *! and 3iploc/, (!T! Tolerance and Safet& of Vitamin EF ( Toicological 0osition Report! Bree Rad! Diol!Aed! "@F%%-7, "##)!

$!

Aorrise&, 0!(! and Sheeh&, 0!!(! ?ptimal 'utritionF Vitamin E! 0roc! 'utr! Soc! %$F%#-5$, "###!

#! 'ational (cadem& of Sciences! 3ietar& Reference Inta/es for Vitamin ., Vitamin E, Selenium and.arotenoids! 'ational (cadem& 0ress, pp! "$5-)$@, )444!

"4! 0ractice 9uidelines .over Aanagement of (lzheimers 3isease! (m! ! *ealth S&st! 0harm! %F"$"-"$%,"##7!

""!

0r&or, G!(! Vitamin E and *eart 3iseaseF Dasic Science to .linical Intervention Trials! Bree Rad! Diol! Aed!)$F""-"5, )444!

")!

So/ol, R!! Vitamin E 3eficienc& and 'eurologic 3isease! (nn! Rev! 'utr! $F@%"-@7@, "#$$!

"@!

Ta&lor, (! and *obbs, A! )44" (ssessment of 'utritional Influences on Ris/ for .ataract! 'utrition "7F$%-$%7,)44"!

"! Geber, 0!, Dendich, (! and Aachlin, :!! Vitamin E and *uman *ealthF Rationale for 3eterminingRecommended Inta/e :evels! 'utrition "@F%4-54, "##7!

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