DSM Nutritional Products

Vitamin BasicsThe Facts about Vitamins in Nutrition

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Disclaimer

Copyright by [DSM Nutritional Products AG] 2007

All rights reserved. No part of this publication may be reproduced, distri-buted or translated in any form or by any means, or stored in a database orretrieval system, without the prior written permission of the publisher. Themention of specific companies and trademarks does not imply that they areendorsed by DSM Nutritional Products AG (DSM). While making reaso-nable efforts to ensure that all information in this book is accurate and upto date, DSM makes no representation or warranty of the accuracy, reliabili-ty, or completeness of the information. The information provided herein is for informational purposes only. All medical information presented should be discussed with your healthcareprofessional. Remember, the failure to seek timely medical advice can haveserious ramifications. We strongly urge you to discuss any current healthrelated problems you are experiencing with a healthcare professional imme-diately. This publication does not constitute or provide scientific or medicaladvice, diagnosis, or treatment and is distributed without warranty of anykind, either express or implied. In no event shall DSM be liable for anydamages arising from the reader's reliance upon, or use of, these materials.The reader shall be solely responsible for any interpretation or use of thematerial contained herein.

Edited byDr. Volker Spitzer, Global Science Manager, DSM Nutritional Products Ltd.

With a foreword byProf. Dr. Florian Schweigert, President of the German Society for AppliedVitamin Research, Potsdam.

3rd edition 2007

(C) 1994, 1997, 2007 DSM Nutritional Products Ltd.

Designed by graphic art studio, Grenzach-Wyhlen, Germany

Printed in Germany Burger Druck, Waldkirch, Germany

2007 REI 50970 (1/0997.6.5)

DSM Nutritional Products is theworlds largest supplier of nutritionalingredients, such as vitamins,carotenoids (antioxidants and pig-ments), other biochemicals and finechemicals, and premixes. The com-pany covers an unmatched breadthof applications in the area of ingre-dients, addressing the animal andhuman nutrition and health as wellas personal care industries.Starting in 1935 with the chemicalsynthesis of vitamin C, Roche grad-ually added other synthesized vita-mins to its range. In 2003, DSMacquired Roche's Vitamins and FineChemicals Division and today DSMNutritional Products sells the fullrange of fat-soluble and water-solu-ble vitamins, carotenoids, long chainpolyunsaturated fatty acids,enzymes, citric acid and nutraceuti-cals.

DSM OverviewHeadquartered in the Netherlands, DSM is active worldwide and develops,produces and sells innovative products and services that help improve thequality of life. DSMs products are used in a wide range of end-markets andapplications, such as human and animal nutrition and health, personalcare, pharmaceuticals, automotive and transport, coatings, housing andelectrics & electronics. The group has annual sales of over 8 billion andemploys some 22,000 people. DSM ranks among the global leaders in manyof its fields.

Global operations:DSM Nutritional Products has 11 large production sites in 7 countries. Thecompany also runs 35 premix plants for Animal Nutrition and Health and 11premix plants for Human Nutrition and Health, where product combinationsare custom made to serve specific customer needs. DSM NutritionalProducts has some 40 sales offices that are active in over 100 countries. Itemploys approximately 6,200 people.

Research & Development: Building on its long tradition of industry leadership, DSM NutritionalProducts is committed to continuously providing outstanding products andservices for human and animal well-being. Most of these products arenature-identical, which means that their chemical structures and propertiescannot be distinguished from those found in plants or animals. R&D facili-ties are concentrated in the region of Basel, Switzerland, and are stronglyintegrated in an innovation network with other nutrition-related DSM R&Dcampuses in the Netherlands. Additionally, R&D satellites are managed inFrance and in China. In the area of process improvement, DSM makes everyeffort to keep the businesss main products competitive. The R&D strategyis based on the introduction of new chemical processes and the develop-ment of new biotechnology-based approaches. The latter efforts are sup-ported by advanced biotechnological techniques such as genomics andproteomics. DSM Nutritional Products supports its activities in vitamins andfine chemicals by conducting research that focuses primarily on processimprovement and the development of new products. Apart from developingnew products, DSM Nutritional Products is also working on improvedformulations and new combinations of existing products.

A pioneer in innovation:DSM Nutritional Products fosters innovation to the benefit of both the con-sumers future and that of the company. Lateral thinking and innovativeattitudes are valuable tools with which to secure that future. These lead todiscoveries that DSM then links to customers needs, extending the rangeof offering and creating new business opportunities.

DSM NUTRITIONAL PRODUCTS

Quality management:In 1991, DSM Nutritional Products introduced qualitymanagement based on Good Manufacturing Principles(GMP) and all the relevant International StandardsOrganization ISO (9000) quality standards. Since 1January 2002, the company has had a uniform andgroup-wide certification based on the new internationalstandard ISO 9001:2000. This means that all productionunits, premix plants, distribution centers and the entireglobal marketing organization are covered by the certifi-cate. All processes are designed to anticipate customerrequirements and market trends.

You can find more information on www.dsmnutritionalproducts.com

Products and servicesDSM Nutritional Products is the leading supplier ofvitamins, carotenoids and fine chemicals to the foodand pharmaceutical industries with a very strong globalmarketing and sales base. The company provides thefollowing products:

Carotenoidsb-CaroteneCaroCare (b-Carotene Natural Source)ApocarotenalApocarotenoic EsterCanthaxanthinLuteinredivivo (Lycopene)OPTISHARP (Zeaxanthin)

Fat soluble VitaminsVitamin A Liquid and DryVitamin D3 Liquid and DryVitamin E, Synthetic Liquid and DryVitamin E, Natural SourceVitamin K1

Water soluble VitaminsVitamin B1 ThiamineVitamin B2 RiboflavinVitamin B3 Niacin/NiacinamideVitamin B5 PantothenatesPro-Vitamin B5 PanthenolVitamin B6 PyridoxineVitamin B12 CyanocobalaminFolic AcidBiotinVitamin C

Long chain polyunsaturated fatty acidsROPUFA (Omega-3 LC PUFA Polyunsaturated FattyAcids)ROPUFA (Omega-6 LC PUFA Polyunsaturated FattyAcids)

NutraceuticalsALL-Q (Coenzyme Q10)TEAVIGO (EGCG)BONISTEIN (Genistein)LAFTI (Probiotics)HIDROX (Olive Polyphenols)

Other ingredientsCitric AcidDextromethorphan Hydrobromide (DMH)Tretinoin

Micronutrient blends

Contents

Foreword 4

Introduction 5

Vitamin A 11

Beta-carotene 17

Vitamin D 23

Vitamin E 29

Vitamin K 35

Vitamin C 40

Vitamin B1 47

Vitamin B2 53

Vitamin B6 59

Vitamin B12 65

Niacin 71

Vitamin B5 76

Folic Acid 81

Biotin 87

References 93

Index 94

2Foreword

While plants and micro organism have the capability toproduce the vitamins necessary for the metabolismthemselves, humans and animals have unfortunatelylost this ability during evolution. Because of the lack ofspecific enzymes for synthesis, vitamins became essen-tial nutrients for them. It was recognized more than3500 years ago that vitamins are essential food ingre-dients for maintaining health and well-being. The firstrecords related to the use of specific food items, as weknow today contain information on specific vitamins,such as vitamin A in liver, to prevent specific diseasessuch as night blindness. Only 3000 years later specificconditions of deficiency were recorded that could beattributed to the deficiency of selected nutrients. Wellknown examples are scurvy (vitamin C deficiency),beriberi (vitamin B1) and rickets (vitamin D). It tookanother 400 years until we ware able to attribute thesedisease conditions to specific active substances in ourdiet named then vitamins. Although we now know thatvitamins are not a uniform group of chemical sub-stances like proteins, carbohydrates and lipids, we stilluse the term to describe the whole group.

Since the beginning of the last century our knowledgeon the biological function of vitamins on the molecularand cellular level has increased significantly. Thisresearch is reflected by 20 Noble Prize winners between1928 and 1967. Despite intensive research efforts noadditional vitamins have been added to the list of 13vitamins accumulated between 1897 and 1941.

While in the past, scientist have basically been concern-ed with the role of vitamins in preventing vitamin relateddisease and their biochemical functions, today it isrecognized that vitamins have an important role inhealth and well-being beyond the mere prevention ofdeficiency. This aspect of vitamins is based on theobservation that vitamins are not only coenzymes inmetabolic processes but also act as potent antioxidantsand have hormone-like functions. The later is clearly

visible in the history of vitamin D research. In the late1970s, research established vitamin D as a hormoneessential in bone metabolism. Based on such findings,vitamins are no longer classified into groups definedsimply by their physical-chemical properties such aswater-soluble and fat-soluble vitamins. More appro-priately, vitamins are now classified according to theirbiological function in the body; vitamins with coenzymefunctions, vitamins with hormone-like properties andvitamins with antioxidants properties. But as expectedthe borderlines between these groups can not clearly bedefined and needs readjustment with the rapid progressin research.

In developing countries chronic, diet-related diseasesare still an important public health problem but in theaffluent societies, the prevention of degenerativediseases and also acute vitamin deficiencies might be ofconcern. Regarding the continuing debate of optimalvitamin levels and tolerable upper intake levels (UL) avalid knowledge-base of the daily expanding scientificevidence is necessary. This includes for example thedefinition of populations at risk, the problem of appro-priate biomarkers that not only reflect the dietary intakebut also the local status in specific tissues at risk ofdeficiency as well as environmental factors that influ-ence status and need for certain vitamins.

The following chapters of this book will contribute to thebetter understanding of the important role of vitaminsnot only in preventing specific deficiencies but alsomaintaining and improving human health and well-beingby summarizing the actual knowledge-base for the in-dividual vitamins.

Prof. Dr. Florian J. SchweigertPresident of the German Society for Applied VitaminResearch (GVF)Professor for Nutrition, University of PotsdamPotsdam, Germany

3Introduction

Vitamins are essential organic nutrients required in very small amounts fornormal metabolism, growth and physical well-being. Most vitamins are notmade in the body, or only in insufficient amounts, and are mainly obtainedthrough food. When their intake is inadequate, vitamin deficiency disordersare the consequence. Vitamins are present in food in minute quantitiescompared to the macronutrients protein, carbohydrates and fat. The aver-age adult in industrialised countries eats about 600g of food per day on a -dry-weight basis, of which less than 1 gram consists of vitamins.

No single food contains all of the vitamins and, therefore, a balanced andvaried diet is necessary for an adequate intake. Each of the 13 vitaminsknown today has specific functions in the body, which makes every one ofthem unique and irreplaceable. Vitamins are essential for life!

Of the 13 vitamins, 4 are fat-soluble, namely vitamins A, D, E and K. Theother vitamins are water-soluble: vitamin C and the B-complex, consistingof vitamins B1, B2, B6, B12, folic acid, biotin, pantothenic acid and niacin.

The history of vitamins can be divided into five periods.

4Vitamin Discovery Isolation Structure Synthesis

Vitamin A 1909 1931 1931 1947

Provitamin A (Beta-carotene) 1831 1930 1950

Vitamin D 1918 1932 1936 1959

Vitamin E 1922 1936 1938 1938

Vitamin K 1929 1939 1939 1939

Vitamin B1 1897 1926 1936 1936

Vitamin B2 1920 1933 1935 1935

Niacin 1936 1935 1937 1894

Vitamin B6 1934 1938 1938 1939

Vitamin B12 1926 1948 1956 1972

Folic Acid 1941 1941 1946 1946

Pantothenic Acid 1931 1938 1940 1940

Biotin 1931 1935 1942 1943

Vitamin C 1912 1928 1933 1933

Table 1: The History of Vitamins

1. The empirical healing of di-seases, now associated with vit-amin deficiency, through con-sumption of particular foods. Anexample is the use of liver to treatnight blindness (vitamin A defi-ciency) by the Egyptians (PapyrusEbers 1550-1570 BC), Assyrians,Chinese, Japanese, Greeks,Romans, Persians and Arabs.

2. The second phase was charac-terised by the ability to induce adeficiency disease in animals,which started with the classicalstudies of Lunin and Eijkmanaround 1890. The ability to pro-duce deficiency diseases, such asberiberi in animals, led toHopkins concept that smallamounts of accessory growthfactors are necessary for growthand life, and the coining of theterm vitamine in 1912 by thePolish-American scientist, Funk.

3. The third phase consisted inseven decades of excitingresearch involving the discovery,isolation, structure elucidationand synthesis of all the vitamins,and culminating in the synthesisof vitamin B12 in 1972. Most sci-entists think that the discovery of

any new vitamin is quite unlikely,although efforts are stil lcontinuing in that quest. Many ofthe researchers involved in thisgolden age of the vitaminsreceived a Nobel prize in reco-gnition of their great achie-vements (Table 2).

4. During the era of discovery, afourth period began which wasconcerned with the biochemicalfunctions, establishment ofdietary requirements andcommercial production. In theearly 1930s it was realised thatriboflavin (vitamin B2) was part ofthe yellow enzyme, which intime led to the elucidation of therole of the B-vitamins as coen-zymes. The subsequent identifi-cation of most of the B-vitaminsas coenzymes remained a centraltheme, defining their function formany decades. The first com-mercial synthesis of vitamin C byReichstein in 1933 was the startof a successful industrial effortthat led to the availabi l i ty ofrelatively inexpensive vitamins forresearch and use in animalfeedstuffs, for the fortification offood products, and for supple-ments.

5. The accumulation of reports of health benefits beyondpreventing deficiencies and excit-ing new biochemical functions ofvitamins ushered in a fifth period,starting with the report in 1955 ofthe cholesterol-lowering effect ofniacin (1). This is now a wellaccepted effect of the vitamin,which has nothing at all to do withits classical coenzyme role, and isa clear health effect beyond pre-venting the deficiency diseasepellagra.

Finally, work on the biochemicalfunction of vitamins in the last threedecades has considerably expandedour concept of how vitamins func-tion in the body and has helped pro-vide a chemical basis for the in vivoobservation of their health effects(Table 3).

Year Name Field Comments

1928 Adolf Windaus Chemistry for his research into the constitution of the steroids

and their connection with vitamins

1929 Christiaan Eijkman Medicine & for his discovery of the antineuritic vitamins

Physiology

Sir Frederick G. Hopkins Medicine & for his discovery of the growth stimulating vitamin

Physiology

1934 George R. Minot Medicine & for their discoveries concerning liver therapy of

William P. Murphy Physiology anaemias

George H. Whipple

1937 Sir Walter N. Haworth Chemistry for his research into the constitution of

carbohydrates and vitamin C

Paul Karrer Chemistry for his research into the constitution of carotenoids,

flavins and vitamins A and B2Albert Szent-Gyrgyi Medicine & for his discoveries in connection with the biological

Physiology combustion processes, with particular reference to

vitamin C and the catalysis of fumaric acid

1938 Richard Kuhn Chemistry for his work on carotenoids and vitamins

1943 Carl Peter Henrik Dam Medicine & for his discovery of vitamin K

Physiology

Edward A. Doisy Medicine & for his discovery of the chemical nature of vitamin K

Physiology

1953 Fritz A. Lipmann Medicine & for his discovery of Coenzyme A and its importance

Physiology for intermediary metabolism

1955 Axel H.T. Theorell Medicine & for his discoveries concerning the nature and mode

Physiology of action of oxidation enzymes

1964 Konrad E. Bloch Medicine & for his discoveries concerning the mechanism and

Physiology regulation of cholesterol and fatty acid metabolism

Feodor Lynen Medicine & as above

Physiology

Dorothy C. Hodgkin Chemistry for her structural determination of vitamin B121967 Ragnar A. Granit Medicine & for his research, which illuminated the electrical

Physiology properties of vision by studying wavelength

discrimination in the eye

Halden K. Hartline Medicine & for his research on the mechanisms of sight

Physiology

George Wald Medicine & for his research on the chemical processes that

Physiology allow pigments in the retina of the eye to convert

light into vision

5

Table 2: Vitamin-Related Nobel Prize Winners

6Vitamin Classical Role More Recent Role

Vitamin C Hydroxylation Reaction In Vivo Antioxidant

Beta-carotene Provitamin A Antioxidant, Immune Function

Vitamin K Clotting Factors Calcium Metabolism

Vitamin D Calcium Absorption, Differentiation and Growth,

Mineralisation of Bone Immune Function

Vitamin B6 Coenzyme Steroid Regulation

Niacin Coenzyme Lipid Lowering

Folic Acid Production and Maintenance Protection Against Neural Tube

of New Cells Birth Defects

Folic Acid, B6 and B12 Energy Metabolism May Lower Risk of Heart Disease and

Stroke*

Antioxidant vitamins Protection against Cancer and Heart

Disease*

Dietary ReferenceIntakes

From 1941 until 1989, RDAs(Recommended Dietary Allowances)were established and used to evalu-ate and plan menus to meet thenutrient requirements of certaingroups. They were also used inother applications such as interpre-ting food consumption records ofpopulations, establishing standardsfor food assistance programs,establishing guidelines for nutritionlabelling, etc.

The primary goal of RDAs was toprevent diseases caused by nutrientdeficiencies.

In the early 1990s, the Food andNutrition Board (FNB), the Instituteof Medicine, the National Academyof Sciences (USA), with the involve-ment of Health Canada, undertookthe task of revising the RDAs, and anew family of nutrient reference val-ues was born the DietaryReference Intakes (DRIs).

The primary goal of having thesenew dietary reference values wasnot only to prevent nutrient deficien-cies, but also to reduce the risk ofchronic diseases such as osteo-porosis, cancer, and cardiovasculardisease.

The first report, Dietary ReferenceIntakes for Calcium, Phosphorus,Magnesium, Vitamin D and Fluoride,was published in 1997. Since then,three additional vitamin relatedreports have been released,addressing folate and other B vit-amins, dietary antioxidants (vitaminsC, E, selenium and the carotenoids),and the micronutrients (vitamins A,K, and trace elements such as iron,iodine, etc). The DRIs are a compre-hensive scientific source primarily fornutrition scientists (see References).They are used by health authoritiesin many countries as a basis fordecisions regarding nutritional infor-mation on micronutrients.There are four types of DRI referencevalues: the Estimated AverageRequirement (EAR), the Recom-mended Dietary Allowance (RDA), theAdequate Intake (AI) and the TolerableUpper Intake Level (UL).

Estimated Average Requirement(EAR) the amount of a nutrientthat is estimated to meet therequirement of half of all healthyindividuals in a given age andgender group. This value is basedon a thorough review of the scien-tific literature.

Recommended Dietary Allowance(RDA) the average daily dietaryintake of a nutrient that is sufficientto meet the requirement of nearlyall (97-98%) healthy persons. Thisis the number to be used as a goalfor individuals. It is calculated fromthe EAR.

Adequate Intake (AI) only estab-lished when an EAR (and thus anRDA) cannot be determinedbecause the data are not clear-cutenough; a nutrient has either anRDA or an AI. The AI is based onexperimental data or determinedby estimating the amount of anutrient eaten by a group ofhealthy people and assuming thatthe amount they consume is ade-quate to promote health.

Table 3: Biochemical Function of Vitamins

*Research ongoing

7 Tolerable Upper Intake Level (UL) the highest continuing dailyintake of a nutrient that is likely topose no risks of adverse healtheffects for almost all individuals. Asintake increases above the UL, therisk of adverse effects increases.Consistently consuming a nutrientat the upper level should not causeadverse effects. Intake levels at theUL can be interpreted as a war-ning flag, not as reason for alarm.

Certain groups atrisk of vitamindeficienciesWith the advent of vitamin fortifica-tion in the manufacturing of flour,cereals and other foods, specificvitamin deficiency diseases such asscurvy, beriberi, rickets and pellagrahave become rare in most industri-alised countries. However, in manyAfrican, Asian and Latin Americancountries, chronic, diet-related di-seases continue to be a major healthproblem. In these countries there isa need to eliminate frank vitamin A,C and B-complex deficiencies, aswell as other micronutrient deficien-cies (iodine, iron, selenium, zinc andcalcium).

However, even in highly industri-alised countries, numerous largegovernment nutrition surveys of thepopulation indicate that marginalvitamin deficiencies with unspecificsymptoms, like fatigue and frequentheadaches, are probably not rare.They are difficult for the individual todetect and are largely ignored.Marginal vitamin deficiency is astate of gradual vitamin depletion inwhich there is evidence of personallack of well-being associated withimpairment of certain biochemicalreactions. Studies have found thatmany people have nutritional defi-ciencies which do not show up in aroutine physical examination. It has

also been suggested that marginaldeficiencies are linked to behaviour-al and physiological changes.Extensive surveys have revealed thatmore than 60% of the elderly havedeficient dietary intake of vitamin D,E and folate. Other vitamins criticalnot just for the elderly includethiamin (B1), panthothenic acid, andbiotin.

Many individuals have healthproblems, habits, or living situationsin which chronic or periodic intake of vitamins should exceed theordinary requirement. High-risk-groups include:

the elderly adolescents young or pregnant and lactating

women alcoholics cigarette smokers vegetarians people fasting or on dietary

intervention laxative abusers users of contraceptives and

analgesics and other medicationsfor chronic disease

people with specific disorders ofthe gastrointestinal tract.

However, marginal deficiencies arenot only limited to those groupslisted. The gradual change in theway we live has influenced our dietsand has altered our habitual intakeof vitamins and minerals. Hecticlifestyles, reduced physical activityand an increase in fast and conve-nience food have all played a signifi-cant role. As a result, a significantproportion of the population fails toreach recommended intake levels.

AntioxidantVitamins

Vitamin C, vitamin E and caro-tenoids, such as beta-carotene, aremicronutrients with antioxidantproperties. Antioxidants are sub-stances that prevent oxidation orchemical reactions involving oxygen.

As the atmosphere changed frombeing anaerobic to aerobic, oxygenbecame available in energy pro-duction for living organisms, but italso carried a price. When energy isproduced, unstable oxygen speciesknown as free radicals are formed.Free radicals are also produced atother sites in the metabolism (e.g.,by activated phagocytes as part ofthe immune defence), and throughexogenous sources such as expo-sure to cigarette smoke, environ-mental pollutants and ultravioletlight. Free radicals are atoms or mo-lecules that have an unpaired elec-tron which makes them very reac-tive. They have the potential to dam-age DNA, proteins, carbohydrates,lipids and cell membranes. In addi-tion to free radicals, there is anotherhighly reactive compound that is apotent generator of free radicals: it iscalled singlet oxygen. This moleculeis unique in that it contains a pair ofelectrons but exists in an unstableconfiguration and is very reactive.

The body has an elaborate antioxi-dant defence system that works toneutralise free radicals and otherhighly reactive species. The majorbiological antioxidants are enzymes(superoxide dismutase, catalase andglutathione peroxidase) as well asnon-enzymatic scavengers (such asuric acid, CoQ10, glutathione, thiolsin proteins) and the antioxidantvitamins (beta-carotene, vitamin Cand E).

Each of the antioxidant nutrients hasspecific characteristics, and theyoften work synergistically to

8strengthen the overall antioxidantcapability of the body.

Vitamin E is the principal fat-solubleantioxidant in the body and isresponsible for protecting thepolyunsaturated fatty acids in cellmembranes from oxidation by freeradicals. Vitamin E exhibits a sparingeffect on beta-carotene by pro-tecting the conjugated double bondsfrom being oxidised. Exposure toincreased oxygen levels, such asreperfusion, results in free radical-mediated tissue damage. However,due to the capability of vitamin E towork at higher oxygen pressures,free radicals are scavenged andtissue injury is minimised.

Beta-carotene also has antioxidantproperties and is one of the mostpowerful quenchers of singlet oxy-gen. It can dissipate the energy ofsinglet oxygen, thus preventing thisactive molecule from generating freeradicals.

Vitamin C, a water-soluble antioxi-dant, interacts with free radicals inthe aqueous compartment of cells.Additionally, vitamin C is consideredthe most important antioxidant inextra-cellular fluids. Vitamin C hasthe ability to regenerate vitamin Eafter it has neutralised free radicalsand terminated chain reactions.

The balance of free radical produc-tion and the level of antioxidantdefences have important diseaseand health implications. If there aretoo many free radicals produced,and too few antioxidants, to a condi-tion of oxidative stress developswhich can lead to chronic injury.

It has therefore been suggested thatoxidative stress might play a role inthe development of a number ofdiseases:

cancer atherosclerosis cardiovascular diseases cataracts age-related macular degeneration Alzheimers disease immune dysfunction rheumatoid arthritis

Oxidative stress also plays a rolein the aging process.

The scientific literature containsmany research articles on thepotential roles of the antioxidant

nutrients in disease prevention.Many studies are just beginning

while others continue to show thepositive effects of the antioxidant

nutrients. It therefore seemsprudent to ensure an ade-

quate intake of beta-carotene, vitamin C

and vitamin E in thediet or throughsupplementation.

Vitamins continueto fascinate, and

have become thefocus of renewed

attention on the part of researchers,health/nutrition professionals, andgovernment policymakers, as well asthe general public.

References

http://riley.nal.usda.gov/nal_display/index.php?inf

o_center=4&tax_level=3&tax_subject=256&topic_

id=1342&level3_id=5141

Dietary Reference Intakes for Calcium, Phos-

phorus, Magnesium, Vitamin D, and Fluoride

(1997) National Academy of Sciences. Institute of

Medicine. Food and Nutrition Board.

Dietary Reference Intakes for Thiamin, Riboflavin,

Niacin, Vitamin B6, Folate, Vitamin B12,

Pantothenic Acid, Biotin, and Choline (1998)

National Academy of Sciences. Institute of

Medicine. Food and Nutrition Board.

Dietary Reference Intakes for Vitamin C, Vitamin E,

Selenium, and Carotenoids (2000) National

Academy of Sciences. Institute of Medicine. Food

and Nutrition Board.

Dietary Reference Intakes for Vitamin A, Vitamin K,

Arsenic, Boron, Chromium, Copper, Iodine, Iron,

Manganese, Molybdenum, Nickel, Silicon,

Vanadium, and Zinc (2001) National Academy of

Sciences. Institute of Medicine. Food and Nutrition

Board.

9Vitamin A

SynonymsRetinol, axerophthol

ChemistryRetinol and its related compounds consist of four isoprenoid units joinedhead to tail and contain five conjugated double bonds. They naturally occuras alcohol (retinol), as aldehyde (retinal) or as acid (retinoic acid).

CH3 CH3CH2OH

CH3

CH3CH3

Molecular formula of vitamin A (retinol)

Vitamin A crystals in polarised light

10

Introduction

Vitamin A is a generic term for agroup of lipid soluble compoundsrelated to retinol. Retinol is oftenreferred to as preformed vitamin A. Itis found only in animal sources,mainly as retinyl esters and in foodsupplements. Many cultures haveused ox liver as an excellent sourceof vitamin A to cure night blindness.The liver was first pressed to the eyeand then eaten; the Egyptiansdescribed this cure at least 3,500years ago. Beta-carotene and othercarotenoids that can be convertedto vitamin A by an enzymaticprocess in the body are referred toas provitamin A. They are found onlyin plant sources.

Functions

Retinal, the oxidised metabolite ofretinol, is required for the process ofvision. Retinoic acid, another vitaminA metabolite, is considered to beresponsible for all non-visual func-tions of vitamin A. Retinoic acidcombines with specific nuclearreceptor proteins which bind to DNAand regulate the expression of vari-ous genes, thereby influencingnumerous physiological processes.Retinoic acid is therefore classifiedas a hormone.

VisionReceptor cells in the retina of theeye (rod cells) contain a light-sensi-tive pigment called rhodopsin, whichis a complex of the protein opsinand the vitamin A metabolite retinal.The light-induced disintegration ofthe pigment triggers a cascade ofevents which generate an electricalsignal to the optic nerve. Rhodopsincan only be regenerated from opsinand vitamin A. Rod cells with thispigment can detect very smallamounts of l ight, making themimportant for night vision.

Cellular differentiationThe many different types of cells inthe body perform highly specialisedfunctions. The process wherebycells and tissues become pro-grammed to carry out their specialfunctions is called differentiation.Through the regulation of geneexpression, retinoic acid plays amajor role in cellular differentiation.Vitamin A is necessary for normaldifferentiation of epithelial cells, thecells of all tissues lining the body,such as skin, mucous membranes,blood vessel walls and the cornea.In vitamin A deficiency, cells losetheir ability to differentiate properly.

Growth and developmentRetinoic acid plays an important rolein reproduction and embryonicdevelopment, particularly in thedevelopment of the spinal cord andvertebrae, limbs, heart, eyes andears.

Immune functionVitamin A is required for the normalfunctioning of the immune systemand therefore helps to protectagainst infections in a number ofways. It is essential in maintaining

Food Vitamin A (Retinol) RE

g/100g g/100g

Veal liver 28000 28000

Carrots - 1500

Spinach - 795

Melon (cantaloupe) - 784

Butter 590 653

Cheese (Cheddar) 390 440

Egg 276 272

Broccoli - 146

Salmon 41 41

Milk (whole) 35 35

Vitamin A content of foods

(Souci, Fachmann, Kraut)

11

the integrity and function of the skinand mucosal cells, which function asa mechanical barrier and defend thebody against infection. Vitamin Aalso plays a central role in the devel-opment and differentiation of whiteblood cells, such as lymphocytes,killer cells and phagocytes, whichplay a critical role in the defence ofthe body against pathogens.

Main functions in a nutshell: Vision Reproduction Growth and development Cellular differentiation Immune function

Dietary sources

The richest food source of prefor-med vitamin A is l iver, with considerable amounts also found inegg yolk, whole milk, butter andcheese. Provitamin A carotenoidsare found in carrots, yellow and darkgreen leafy vegetables (e.g. spinach,broccoli), pumpkin, apricots andmelon.Until recently, vitamin A activity infoods was expressed as interna-tional units (IU). This is still themeasurement generally used onfood and supplement labels. In orderto standardise vitamin A measure-ment, it has now been international-ly agreed to state vitamin A activityin terms of a new unit called theretinol equivalent, or RE, whichaccounts for the rate of conversionof carotenoids to retinol.

1 RE = 1 g retinol= 6 g beta-carotene= 12 g other provitamin A

carotenoids= 3.33 IU vitamin A activity

from retinol

Absorption andbody stores

Vitamin A is absorbed in the upperpart of the small intestine. Pro-vitamin A carotenoids can becleaved into retinol via an enzymaticprocess. Preformed vitamin Aoccurs as retinyl esters of fattyacids. They are hydrolysed andretinol is absorbed into intestinalmucosal cells (i.e. enterocytes). Afterre-esterification it is incorporatedinto chylomicrons, excreted intolymphatic channels, delivered to theblood and transported to the liver.Vitamin A is stored in the liver asretinyl esters; stores are enough forone to two years in most adultsliving in industrialised countries.

Measurement

Vitamin A can be measured in theblood and other body tissues by various modern techniques. Forrapid field tests, a method has beendeveloped recently using driedblood spots. Typical serum level is1.1-2.3 mol/L. According to theWHO, plasma levels of #0,35 mol/Lindicate a vitamin A deficiency.

Stability

Vitamin A is sensitive to oxidation by air. Loss of activity is accelerated by heat and exposure to light.Oxidation of fats and oils (e.g. butter, margarine, cooking oils) candestroy fat soluble vitamins includ-ing vitamin A. The presence ofantioxidants such as vitamin E there-fore contributes to the protection ofvitamin A.

InteractionsPositive interactions Vitamin E protects vitamin A from

being oxidised; hence, adequatevitamin E status protects vitamin Astatus.

Negative interactions Disease and infection, especially

measles, compromise vitamin Astatus and conversely, poorvitamin A status decreasesresistance to diseases.

Chronic heavy alcohol intake canimpair liver storage of vitamin A.

Acute protein deficiency interfereswith vitamin A metabolism; simi-larly, too little fat in the diet inter-feres with the absorption of bothvitamin A and carotenoids.

Vitamin A deficiency may result inimpaired iron absorption anddecrease its utilisation for erythro-poiesis, thereby potentially exacer-bating iron deficiency anaemia.

Zinc deficiency may adverselyaffect mobilisation of vitamin Afrom hepatic stores and absorp-tion of vitamin A from the gut.

12

DeficiencyVitamin A deficiency is rare in theWestern world, but in developingcountries it is one of the most wide-spread, yet preventable, causes ofblindness. The earliest symptom ofvitamin A deficiency is impaired darkadaptation, or night blindness.Severe deficiency causes a condi-tion called xerophthalmia, charact-erised by changes in the cells of thecornea that ultimately result incorneal ulcers, scarring and blind-ness. The appearance of skinlesions (follicular hyperkeratosis) isalso an early indicator of inadequatevitamin A status. Growth retardationis a common sign in children.Because vitamin A is required for thenormal functioning of the immunesystem, even children who are onlymildly deficient in vitamin A have ahigher incidence of respiratory dis-ease and diarrhoea, as well as ahigher rate of mortality from infec-tious diseases, than children whoconsume sufficient vitamin A.Some diseases may themselvesinduce vitamin A deficiency, mostnotably liver and gastrointestinal dis-eases, which interfere with theabsorption and utilisation of vitamin A. Vitamin A deficiency during pregnancyleads to malformations during foetaldevelopment.

Disease preventionand therapeuticuse

Studies have shown that vitamin Asupplementation given to childrenaged over 6 months reduces all-cause mortality by between 23%and 30% in low income countries. Thebeneficial effect is assumed to be dueto the prevention of vitamin A deficien-cy. The World Health Organisation(WHO) recommends that supplementsshould be given when children arevaccinated. The currently recom-mended doses are 100,000 IU at age6-11 months and 200,000 IU at age $ 12 months every 3-6 months. Xerophthalmia is treated with highdoses of vitamin A (50,000-200,000IU according to age).In developing countries, wherevitamin A deficiency is one of themost serious health problems,children under the age of 6 yearsand pregnant and lactating womenare the main vulnerable groups.Since vitamin A can be stored in theliver, it is possible to build up a

reserve in children by administrationof high-potency doses. In regularperiodic distribution programmes forthe prevention of vitamin Adeficiency, infants < 6 months of agereceive a dose of 50,000 IU ofvitamin A, and children between sixmonths and one year receive100,000 IU every 4-6 months, whilechildren > 12 months of age receive200,000 IU every 4-6 months. Asingle dose of 200,000 IU given tomothers immediately after delivery oftheir child has been found to in-crease the vitamin A content ofbreast milk. However, caution isnecessary when considering vitaminA therapy for lactating women, oth-erwise a co-existing pregnancy maybe endangered: during pregnancy, adaily dose of 10,000 IU vitamin Ashould not be exceeded.Administration of high doses ofvitamin A to children with measlescomplications, but no overt signs ofvitamin A deficiency, decreasesmortality by over 50% and signifi-cantly lowers morbidity.Natural and synthetic vitamin A ana-logues have been used to treat pso-riasis and severe acne.

Child suffering from corneal scar

Current recommendations in the USA

RDA*

Infants # 6 months 400 g (Adequate Intake, AI)

Infants 712 months 500 g (AI)

Children 13 years 300 g

Children 48 years 400 g

Children 913 years 600 g

Males $ 14 years 900 g

Females $ 14 years 700 g

Pregnancy 14-18 years 750 g

Pregnancy $ 19 years 770 g

Lactation 1418 years 1,200 g

Lactation $ 19 years 1,300 g

*The Dietary Reference Intakes (DRIs) are actually

a set of four reference values: Estimated Average

Requirements (EAR), Recommended Dietary

Allowances (RDA), Adequate Intakes (AI), and

Tolerable Upper Intake Levels, (UL) that have

replaced the 1989 Recommended Dietary

Allowances (RDAs). The RDA was established as

a nutritional norm for planning and assessing

dietary intake, and represents intake levels of

essential nutrients considered to meet adequately

the known needs of practically all healthy people

13

RecommendedDietary Allowance(RDA)

The recommended daily intake ofvitamin A varies according to age,sex, risk group and other criteriaapplied in individual countries (7001000 g RE/day for men, 600800 g RE/day for women. Inthe USA the RDA for adults is 900g (men) and 700 g (women) perday of preformed vitamin A (retinol).During lactation, an additional 500600 g per day are recom-mended. Infants and children, due totheir smaller body size, have a lowerRDA than adults.

Safety

Because vitamin A (as retinyl ester) isstored in the liver, large amounts takenover a period of time can eventuallyexceed the liver's storage capacity,spill into the blood, and produceadverse effects (liver damage, boneabnormalities and joint pain, alopecia,headaches, vomiting, and skindesquamation). Hypervitaminosis Acan occur acutely following very highdoses taken over a period of severaldays, or as a chronic condition fromhigh doses taken over a long period oftime. Thus, there is concern about thesafety of high intakes of preformedvitamin A (retinol), especially forinfants, small children, and women ofchildbearing age.Normal foetal development requiressufficient vitamin A intake, butconsumption of excess retinol duringpregnancy is known to cause malfor-mations in the newborn.Several recent prospective studiessuggest that long-term intakes of pre-formed vitamin A in excess of 1,500g/day are associated with increasedrisk of osteoporotic fracture anddecreased bone mineral density inolder men and women. Only excess

intakes of preformed vitamin A, notbeta-carotene, were associated withadverse effects on bone health.Current levels of vitamin A in fortifiedfoods are based on RDA levels, ensur-ing that there is no realistic possibilityof vitamin A overdosage in the gener-al population. In the vast majority ofcases, signs and symptoms of toxicityare reversible upon cessation of vita-min A intake. Beta-carotene is consid-ered a safe form of vitamin A becauseit is converted by the body only asneeded.

The Food and Nutrition Board of theInstitute of Medicine (2001) and theEC Scientific Committee on Food(2002) have set the tolerable upperintake level (UL) of vitamin A intake foradults at 3000 g RE/day with appro-priately lower levels for children.

Supplements andfood fortification

Vitamin A is available in soft gelatinecapsules, as chewable or efferves-cent tablets, or in ampoules. It isalso included in most multivitamins.Retinyl acetate, retinyl palmitate andretinal are the forms of vitamin Amost commonly used in supple-ments.Margarine and milk are commonlyfortif ied with vitamin A. Beta-carotene is added to margarine andmany other foods (e.g. fruit drinks,salad dressings, cake mixes, icecream) both for its vitamin A activityand as a natural food colourant.

Industrial production

Nowadays vitamin A is rarelyextracted from fish liver oil. Themodern method of industrial synthe-sis of nature-identical vitamin A is ahighly complex, multi-step process.

14

History

Although it has been known since ancient Egyptian times that certain foods,such as liver, would cure night blindness, vitamin A per se was not identi-fied until 1913. Its chemical structure was defined by Paul Karrer in 1931.Professor Karrer received a Nobel Prize for his work because this was thefirst time that a vitamins structure had been determined.

1831 Wackenroder isolates the orange-yellow colourant from carrotsand names it carotene.

1876 Snell successfully demonstrates that night blindness and xeroph-thalmia can be cured by giving the patient cod liver oil.

1880 Lunin discovers that, besides needing carbohydrates, fats andproteins, experimental animals can only survive if given smallquantities of milk powder.

1887 Arnaud describes the widespread presence of carotenes inplants.

1909 Stepp successfully extracts the vital liposoluble substance frommilk.

1915 McCollum differentiates between fat-soluble A and water-soluble B.

1929 The vitamin A activity of beta-carotene is demonstrated in animalexperiments.

1931 Karrer isolates practically pure retinol from the liver oil of aspecies of mackerel. Karrer and Kuhn isolate active carotenoids.

1946 Isler undertakes the first large-scale industrial synthesis of vita-min A.

1984 Sommer demonstrates that vitamin A deficiency is a major causeof infant mortality in Indonesia.

1987 Chombon in Strasbourg and Evans in San Diego, and theirrespective coworkers, simultaneously discover the retinoic acidreceptors in cell nuclei.

1997 UNICEF, the World Health Organisation (WHO), and the govern-ments of countries including Canada, the United States and theUnited Kingdom, as well as national governments in countrieswhere vitamin deficiency is widespread, launch a global cam-paign to distribute high-dose vitamin A capsules to malnourishedchildren.

Paul Karrer

Otto Isler

Elmer V. McCollum

15

Beta-carotene

ChemistryBeta-carotene is a terpene. It is made up of eight isoprene units, which arecyclised at each end. The long chain of conjugated double bonds is respon-sible for the orange colour of beta-carotene.

CH3 CH3

CH3

CH3H3C

CH3 CH3CH3 CH3

H3C

Molecular formula of beta-carotene

Beta-carotene crystals in polarised light

16

IntroductionBeta-carotene is one of more than600 carotenoids known to exist innature. Carotenoids are yellow,orange and red pigments that arewidely distributed in plants. In 1831,beta-carotene was isolated byWackenroder. Its structure was deter-mined by Karrer in 1931, whoreceived a Nobel prize for his work.About 50 of the naturally occurringcarotenoids can potentially yield vita-min A and are thus referred to asprovitamin A carotenoids. Beta-carotene is the most abundant andmost efficient provitamin A in ourfoods.Currently available evidence suggeststhat in addition to being a source ofvitamin A, beta-carotene plays manyimportant biological roles that may beindependent of its provitamin status.

Functions

Beta-carotene is the main safedietary source of vitamin A. Vitamin Ais essential for normal growth anddevelopment, immune system func-tion, and vision.Beta-carotene can quench singletoxygen, a reactive molecule that isgenerated, for instance, in the skin byexposure to ultraviolet light, andwhich can induce precancerouschanges in cells. Singlet oxygen iscapable of triggering free radicalchain reactions.

Beta-carotene has antioxidant prop-erties that help neutralise free radi-cals reactive and highly energisedmolecules which are formed throughcertain normal biochemical reactions(e.g. the immune response,prostaglandin synthesis), or throughexogenous sources such as air pollu-tion or cigarette smoke. Free radicalscan damage lipids in cell membranesas well as the genetic material incells, and the resulting damage maylead to the development of cancer.

Main functions in a nutshell: Provitamin A Antioxidant activity

Dietary sources

The best sources of beta-caroteneare yellow/orange vegetables andfruits and dark green leafy vegeta-bles:

Yellow/orange vegetables car-rots, sweet potatoes, pumpkins,winter squash

Yellow/orange fruits apricots,cantaloupes, papayas, mangoes,carambolas, nectarines, peaches

Dark green leafy vegetables spinach, broccoli, endive, kale,chicory, escarole, watercress andbeet leaves, turnips, mustard,dandelion

Other good vegetable and fruitsources summer squash,asparagus, peas, sour cherries,prune plums.

The beta-carotene content of fruitsand vegetables can vary accordingto the season and degree of ripen-ing.

Absorption andbody stores

Bile salts and fat are needed for theabsorption of beta-carotene in theupper small intestine. Many dietaryfactors, e.g. fat and protein, affectabsorption. Approximately 10-50%of the total beta-carotene consumedis absorbed in the gastrointestinaltract. The proportion of carotenoidsabsorbed decreases as dietaryintake increases. Within the intestin-al wall (mucosa), beta-carotene ispartially converted into vitamin A(retinol) by the enzyme dioxygenase.This mechanism is regulated by theindividual's vitamin A status. If thebody has enough vitamin A, the con-version of beta-carotene decreases.Therefore, beta-carotene is a verysafe source of vitamin A and highintakes will not lead to hypervita-minosis A.Excess beta-carotene is stored inthe fat tissues of the body and theliver. The adult's fat stores are oftenyellow from accumulated carotenewhile the infant's fat stores arewhite.

Bioavailability of beta-caroteneBioavailability refers to the pro-portion of beta-carotene that canbe absorbed, transported andutilised by the body once it hasbeen consumed. It is influencedby a number of factors: Beta-carotene from dietary

supplements is better absorbedthan beta-carotene from foods

Food processing such aschopping, mechanical homo-genisation and cooking en-hances bioavailability of beta-carotene

The presence of fat in the intes-tine affects absorption of beta-carotene. The amount of dietaryfat required to ensure caro-tenoid absorption seems to below (approximately 3-5g permeal)

Food Beta-carotene (mg/100g)

Carrots 7.6

Kale 5.2

Spinach 4.8

Cantaloupes 4.7

Apricots 1.6

Mangoes 1.2

Broccoli 0.9

Pumpkins 0.6

Asparagus 0.5

Peaches 0.1

Beta-carotene content of foods

(Souci, Fachmann, Kraut)

17

MeasurementPlasma carotenoid concentration isdetermined by HPLC. It reflects theintake of carotenoids. Traditionally,vitamin A activity of beta-carotenehas been expressed in InternationalUnits (IU; 1 IU = 0.60 g of all-transbeta-carotene). However, this con-version factor does not take intoaccount the poor bioavailability ofcarotenoids in humans. Thus, theFAO/WHO Expert Committee pro-posed that vitamin A activity beexpressed as retinol equivalents(RE). 6 g beta-carotene provide 1g retinol.For labelling, official national direc-tives should be followed.

1 RE = 1 g retinol = 6 g beta-carotene= 3.33 IU vitamin A activity

from retinol= 10 IU vitamin A activity

from beta-carotene

StabilityCarotenoids can lose some of theiractivity in foods during storage dueto the action of enzymes and expo-sure to light and oxygen. Dehy-dration of vegetables and fruits maygreatly reduce the biological activityof carotenoids. On the other hand,carotenoid stability is retained infrozen foods.

Interactions

Negative interactionsCholestyramine and colestipol (cho-lesterol-lowering agents), mineral oil,orlistat (a weight loss medication)and omeprazole (proton-pumpinhibitor) can reduce absorption ofcarotenoids.

Deficiency

Although consumption of provitaminA carotenoids can prevent vitamin Adeficiency, there are no knownadverse clinical effects of a lowcarotenoid diet, provided vitamin Aintake is adequate.

Disease prevention andtherapeutic use

Immune systemIn a number of animal and humanstudies beta-carotene supplementa-tion was found to enhance certainimmune responses. Early studiesdemonstrated the ability of beta-carotene and other carotenoids toprevent infections. Some clinical tri-als have found that beta-carotenesupplementation improves severalbiomarkers of immune function. Itcan lead to an increase in the num-ber of white blood cells and theactivity of natural killer cells. Both ofthese are important in combatingvarious diseases. It may be the casethat beta-carotene stimulates theimmune system once it has under-gone conversion to vitamin A.Another explanation could be thatthe antioxidant actions of beta-carotene protect cells of the immunesystem from damage by reducingthe toxic effects of reactive oxygenspecies.

SkinRecent evidence points to a role ofbeta-carotene in protecting the skinfrom sun damage. Beta-carotenecan be used as an oral sun protec-tant in combination with sunscreensfor the prevention of sunburn. Itseffectiveness has been proven bothalone and in combination with othercarotenoids or antioxidant vitamins.

Cancer and cardiovascular dis-easesEpidemiological studies consistentlyindicate that as consumption ofbeta-carotene-rich fruits and veg-etables increases, the risk of certaincancers (i.e. lung and stomach can-cer) and cardiovascular diseasesdecreases.Additionally, animal experimentshave shown that beta-carotene actsas a cancer risk reduction agent.

18

This is further supported by studiesof biomarkers for the developmentof certain cancers. There is no evi-dence that beta-carotene supple-mentation reduces the risk of cardio-vascular diseases.

Erythropoietic protoporphyriaIn patients with erythropoietic proto-porphyria a photosensitivity disor-der leading to abnormal skin reac-tions to sunlight beta-carotene indoses of up to 180 mg has beenshown to exert a photoprotectiveeffect.

RecommendedDietary Allowance(RDA)

Until now, dietary intake of beta-carotene has been expressed aspart of the RDA for vitamin A. Thedaily vitamin A requirements foradult men and women are 900 gand 700 g of preformed vitamin A(retinol) respectively (FNB, 2001).Apart from its provitamin A function,data continue to accumulate sup-porting a role for beta-carotene asan important micronutrient in its ownright. Consumption of foods rich inbeta-carotene is being recommend-ed by scientific and governmentorganisations such as the USNational Cancer Institute (NCI) andthe US Department of Agriculture(USDA). If these dietary guidelinesare followed, dietary intake of beta-carotene (about 6 mg) would be sev-eral times the average amountpresently consumed in the US(about 1.5 mg daily).

Safety

Beta-carotene is a safe source ofvitamin A. Due to the regulated con-version of beta-carotene into vitamin

A, overconsumptiondoes not pro-duce hypervita-minosis A.Excessive intakesof beta-carotene maycause carotenodermia,which manifests itself ina yellowish tint of theskin, mainly in the palms of thehands and soles of the feet. The yel-low colour disappears whencarotenoid consumption is reducedor stopped. High doses of beta-carotene (up to180 mg/day) used for the treatmentof erythropoietic protoporphyriahave shown no adverse effects.In two studies investigating theeffect of beta-carotene supplemen-tation on the risk of developing lungcancer, an apparent increase of lungcancer in chronic heavy smokerswith intakes of more than 20 mg/dayover several years has beenobserved.The reasons for these find-ings are not yet clear.The British Expert Committee onVitamins and Minerals (EVM) recom-mends a Safe Upper Level for sup-plementation of 7 mg/day over a life-time period. Other agencies such asthe European DACH Society(German Society of Nutrition,Austrian Society of Nutrition, SwissSociety of Nutrition Research) haveconcluded that a daily intake of upto 10 mg of beta-carotene is safe.

Supplements andfood fortification

Beta-carotene is available in hardand soft gelatine capsules, in multi-vitamin tablets, and in antioxidantvitamin formulas and as food colour.Margarine and fruit drinks are oftenfortified with beta-carotene. In 1941,the US Food and Drug Admini-stration (FDA) established a stand-ard of identity for the addition ofvitamin A to margarine; since

then, however, vitamin A has beenpartly replaced by beta-carotene, which additionally imparts an attrac-tive yellowish colour to this product.Due to its high safety margin, beta-carotene has been recognised asmore suitable for fortification pur-poses than vitamin A.

Industrial production

Isler and coworkers developed amethod to synthesise beta-carotene, and it has been commer-cially available in crystalline formsince 1954.

19

History

1831 Wackenroder isolates the orange-yellow pigment in carrots andcoins the term 'carotene'.

1847 Zeise provides a more detailed description of carotene.

1866 Carotene is classified as a hydrocarbon by Arnaud and co-workers.

1887 Arnaud describes the widespread presence of carotenes inplants.

1907 Willstatter and Mieg establish the molecular formula for carotene,a molecule consisting of 40 carbon and 56 hydrogen atoms.

1914 Palmer and Eckles discover the presence of carotene andxanthophylls in human blood plasma.

1919 Steenbock (University of Wisconsin) suggests a relationshipbetween yellow plant pigments (beta-carotene) and vitamin A.

1929 Moore demonstrates that beta-carotene is converted into thecolourless form of vitamin A in the liver.

1931 Karrer and collaborators (Switzerland) determine the structuresof beta-carotene and vitamin A.

1939 Wagner and coworkers suggest that the conversion of beta-carotene into vitamin A occurs within the intestinal mucosa.

1950 Isler and colleagues develop a method for synthesising beta-carotene.

1966 Beta-carotene is found acceptable for use in foods by the JointFAO/WHO Expert Committee on Food Additives.

1972 Specifications for beta-carotene use in foods is established bythe U.S. Food Chemicals Codex.

1979 Carotene is established as 'GRAS', which means that the ingre-dient is 'Generally Recognised As Safe' and can be used as adietary supplement or in food fortification.

1981-82 Beta-carotene/carotenoids are recognised as important factors(independent of their provitamin A activity) in potentially reducingthe risk of certain cancers. R. Doll and R. Peto: Can DietaryBeta-carotene Materially Reduce Human Cancer Rates? (in:Nature, 1981; 290: 201-208) R. Shekelle et al: Dietary Vitamin Aand Risk of Cancer in the Western Electric Study (in: Lancet,1981: 1185-1190) Diet, Nutrition and Cancer (1982): Review ofthe U.S. National Academy of Sciences showing that intake ofcarotenoid-rich foods is associated with reduced risk of certaincancers.

20

1982 Krinsky and Deneke show the interaction between oxygen andoxyradicals using carotenoids.

1983-84 The US National Cancer Institute (NCI) launches large-scaleclinical intervention trials using beta-carotene supplements aloneand in combination with other nutrients.

1984 Beta-carotene is demonstrated to be an effective antioxidant invitro.

1988 Due to the large number of epidemiological studies that demon-strate the potential reduction of cancer incidence with increasedconsumption of dietary beta-carotene, the US National CancerInstitute (NCI) issues dietary guidelines advising Americans toinclude a variety of vegetables and fruits in their daily diet.

1993-94 Availability of results from several large-scale clinical interventiontrials using beta-carotene alone or in various other combinations.

1997 Evidence indicates that beta-carotene acts synergistically withvitamins C and E.

1999 The Womens Health Study shows no increased risk of lungcancer for woman receiving 50 mg beta-carotene on alternatedays.

2004 Results from the French SU.VI.MAX study indicate that a com-bination of antioxidant vitamins (C, E and beta-carotene) andminerals lowers total cancer incidence and all-cause mortality inmen.

Paul Karrer

Otto Isler

21

Vitamin D

SynonymsCalciferol; antirachitic factor; sunshine vitamin

ChemistryVitamin D is a generic term and indicates a molecule of the general struc-ture shown for rings A, B, C, and D with differing side chain structures. TheA, B, C, and D ring structure is derived from the cyclopentanoperhydro-phenanthrene ring structure for steroids. Technically, vitamin D is classifiedas a seco-steroid. Seco-steroids are those in which one of the rings hasbeen broken; in vitamin D, the 9,10 carbon-carbon bond of ring B is broken.

CH2

CH3

OH

H

H

H3CH

H

CH3

CH3

Molecular formula of vitamin D3 (cholecalciferol)

Vitamin D crystals in polarised light

22

IntroductionVitamin D is the general name givento a group of fat-soluble compoundsthat are essential for maintaining themineral balance in the body. Thechemical structure of vitamin D wasidentified in the 1930s. The mainforms are vitamin D2 (ergocalciferol:found in plants, yeasts and fungi)and vitamin D3 (cholecalciferol: ofanimal origin).

As cholecalciferol is synthesised inthe skin by the action of ultravioletlight on 7-dehydrocholesterol, acholesterol derivative, vitamin Ddoes not fit the classical definition ofa vitamin. Nevertheless, because ofthe numerous factors that influenceits synthesis, such as latitude, sea-son, air pollution, area of skinexposed, pigmentation, age, etc.,vitamin D is recognized as an essen-tial dietary nutrient.

Functions

Following absorption or endogenoussynthesis, the vitamin has to bemetabolised before it can perform itsbiological functions. Calciferol istransformed in the liver to 25-hydroxycholecalciferol (25(OH)D,calcidiol). This is the major circulat-ing form, which is metabolised in thekidney to the active forms asrequired. The most important ofthese is 1,25-dihydroxy-cholecalcif-erol (1,25(OH)2D, calcitriol) becauseit is responsible for most of the bio-logical functions. The formation of1,25(OH)2D, which is considered ahormone, is strictly controlledaccording to the body's calciumneeds. The main controlling factorsare the existing levels of 1,25(OH)2Ditself and the blood level of parathy-roid hormone, calcium and phos-phorus.To perform its biological functions,1,25(OH)2D, like other hormones,binds to a specific nuclear receptor

(vitamin D receptor, VDR). Uponinteraction with this receptor,1,25(OH)2D regulates more than 50genes in a wide variety of tissues.Vitamin D is essential for the controlof normal calcium and phosphateblood levels. It is known to berequired for the absorption of cal-cium and phosphate in the smallintestine, their mobilisation from thebones, and their reabsorption in thekidneys. Through these three func-tions it plays an important role forthe proper functioning of muscles,nerves and blood clotting and fornormal bone formation and minerali-sation.

It has been suggested that vitamin Dalso plays an important role in con-trolling cell proliferation and differen-tiation, immune responses andinsulin secretion.

Main functions in a nutshell: Regulation of calcium and phos-

phate blood levels Bone mineralisation Control of cell proliferation and

differentiation Modulation of immune system

Dietary sources

Vitamin D is found only in a fewfoods. The richest natural sources ofvitamin D are fish liver oils and salt-water fish such as sardines, herring,salmon and mackerel. Eggs, meat,milk and butter also contain smallamounts. Plants are poor sources,with fruit and nuts containing novitamin D at all. The amount of vita-min D in human milk is insufficient tocover infant needs.

Absorption andbody stores

Absorption of dietary vitamin D takesplace in the upper part of the smallintestine with the aid of bile salts. Itis incorporated into the chylomicronfraction and absorbed through thelymphatic system. Vitamin D isstored in adipose tissue. It has to bemetabolised to become active.

Measurement

Vitamin D status is best determinedby the serum 25(OH)D concentrationbecause this reflects dietary sourcesas well as vitamin D production byUV light in the skin. Usual serum25(OH)D values are between 25 and130 nmol/L depending on geograph-ic location.1 g vitamin D is equivalent to 40 IU(international unit).

Stability

Vitamin D is relatively stable infoods. Storage, processing andcooking have little effect on its activ-ity, although in fortified milk up to40% of the vitamin D added may belost as a result of exposure to light.

Food Vitamin D (g/100g)

Herring 25

Salmon 16

Sardines 11

Mackerel 4

Egg 2.9

Butter 1.2

Milk (whole) 0.07

Vitamin D content of foods

(Souci, Fachmann, Kraut)

23

InteractionsPositive interactionsWomen taking oral contraceptiveshave been found to have slightly ele-vated blood levels of 1,25(OH)2D.

Negative interactionsCholestyramine (a resin used to stopreabsorption of bile salts) and laxa-tives based on mineral oil inhibit theabsorption of vitamin D from theintestine. Corticosteroid hormones,anticonvulsant drugs and alcoholcan affect the absorption of cal-cium by reducing the response to vitamin D.Animal studies also suggest thatanticonvulsant drugs stimulateenzymes in the liver, resulting in anincreased breakdown and excretionof the vitamin.

Deficiency

Among the first symptoms of mar-ginal vitamin D deficiency arereduced serum levels of calcium andan increase in parathyroid hormone(PTH) production. Serum alkalinephosphatase is elevated in vitamin Ddeficiency states. This can beaccompanied by muscle weaknessand tetany, as well as an increasedrisk of infection. Children may showunspecific symptoms, such as rest-lessness, irritabil ity, excessivesweating and impaired appetite.Marginal hypovitaminosis D maycontribute to bone brittleness in theelderly. Vitamin D deficiency canalso cause hearing loss.The most widely recognised mani-festations of severe vitamin D defi-ciency are rickets in children andosteomalacia in adults. Both arecharacterised by loss of mineral fromthe bones. This results in skeletaldeformities such as bowed legs inchildren. The ends of the long bonesin both the arms and legs areaffected, and their growth may beretarded. Rickets also results in

inadequate mineralisation of toothenamel and dentin.Osteoporosis, a disorder of olderage in which there is loss of bone,not just demineralisation, has alsobeen associated with less obviousstates of deficiency.

Groups at risk of deficiency: Infants who are exclusively breast

fed are at high risk of vitamin Ddeficiency, because human milk isa poor source of vitamin D. Inaddition, in premature and low-birth-weight infants, liver and kid-ney function may be inadequatefor optimal vitamin D metabolism.

The elderly have a reduced capac-ity to synthesise vitamin D in theskin by exposure to sunlight.

People with diseases affecting theliver, kidneys, the thyroid gland orfat absorption, as well as vegetari-ans, alcoholics and epileptics onlong-term anticonvulsant therapyhave a greater risk of deficiency,as do people who are house-bound.

Dark-skinned people produce lessvitamin D from sunlight and are atrisk of deficiency when living farfrom the equator.

Populations living at latitudes ofaround 40 degrees north or southare exposed to insufficient levelsof sunlight to cover vitamin Drequirements through endogenousproduction, especially during win-ter months.

Hereditary vitamin D-dependentrickets (type I and II):These rare forms of rickets occurin spite of an adequate supply ofvitamin D. These are inheritedforms in which the formation orutil isation of 1,25(OH)2D isimpaired.

Diseaseprevention andtherapeutic use

In the treatment of rickets, a dailydose of 40 g (1,600 IU) vitamin Dusually results in normal plasmaconcentrations of calcium and phos-phorus within 10 days. The dose canbe reduced gradually to 10 g (400IU) per day after one month oftherapy.Vitamin D analogues are used in thetreatment of psoriasis.Vitamin D is discussed as a preven-tion factor for a number of diseases.Results from epidemiological studiesand evidence from animal modelssuggest that the risk of severalautoimmune diseases (multiple scle-rosis, insulin-dependent diabetesmellitus, rheumatoid arthritis) maybe decreased by adequate vitamin Dintake.Vitamin D plays an important role inthe prevention of osteoporosisbecause vitamin D insufficiency canbe an important contributing factorin this disease. A prospective studyamong 72,000 postmenopausalwomen over 18 years indicated thatwomen consuming at least 600 IUvitamin D/day from food plus sup-plements had a 37% lower risk ofhip fracture. Evidence from mostclinical trials suggests that vitamin Dsupplementation slows bone densitylosses and decreases the risk ofosteoporotic fracture in men andwomen. Various surveys and studies suggestthat poor vitamin D intake or statusis associated with an increased riskof colon, breast and prostate cancer.

24

RecommendedDietary Allowance(RDA)

Establishing an RDA for vitamin D isdifficult because vitamin D can beendogenously produced in the bodythrough exposure to sunlight.Healthy people regularly exposed tothe sun have no dietary requirementfor vitamin D, under appropriateconditions. As this is rarely the casein temperate zones, however, adietary supply is needed.In 1997, the Food and NutritionBoard based adequate intake levels(AI) on the assumption that no vita-min D is produced by UV light in theskin. An AI of 5 g (200 IU)/day isrecommended for infants, childrenand adults (ages 19-50 years). Forthe elderly, higher intakes are rec-ommended to maintain normal calci-um metabolism and maximise bonehealth. In other countries, adult rec-ommendations range from 2.5 g(100 IU) to 10 g (400 IU).

SafetyHypervitaminosis D is a potentiallyserious problem as it can causepermanent kidney damage, growthretardation, calcification of softtissues and death. Mild symptoms ofintoxication are nausea, weakness,constipation and irritability. In gener-al, the toxic dose for adults isaround 1.25 mg (50,000 IU) per day.However, certain individuals have anincreased sensitivity to vitamin Dand present with toxic symptomsafter 50 g (2,000 IU) per day.Hypervitaminosis D is not associatedwith overexposure to the sunbecause a regulating mechanismprevents overproduction of vitaminD.

The Food and Nutrition Board (FNB)and the EU Scientific Committee onFood have set the tolerable upperintake level (UL) for vitamin D at 50g/day for adolescents and adults.

Supplements andfood fortificationMonopreparations of vitamin D andrelated compounds are available astablets, capsules, oily solutions andinjections. Vitamin D is also incorpo-rated in combinations with vitamin A,calcium, and in multivitamins.In many countries, milk and milkproducts, margarine and vegetableoils fortified with vitamin D serve asa major dietary source of the vita-min.

Industrial production

Cholecalciferol is produced com-mercially by the action of ultravioletlight on 7-dehydrocholesterol, whichis obtained from cholesterol by vari-ous methods. Ergocalciferol is pro-duced in a similar manner fromergosterol, which is extracted fromyeast. Starting material for the pro-duction of caIcitriol is the cholesterolderivative pregnenolone.

Current recommendations in the USA

RDA*

Infants 5 g (AI)

Children 1-18 years 5 g (AI)

Males 19-50 years 5 g (AI)

Females 19-50 years 5 g (AI)

Males 51- 70 years 10 g (AI)

Females 51-70 years 10 g (AI)

Males . 70 years 15 g (AI)

Females . 70 years 15 g (AI)

Pregnancy 5 g (AI)

Lactation 5 g (AI)

*The Dietary Reference Intakes (DRIs) are actually

a set of four reference values: Estimated Average

Requirements (EAR), Recommended Dietary

Allowances (RDA), Adequate Intakes (AI), and

Tolerable Upper Intake Levels, (UL) that have

replaced the 1989 Recommended Dietary

Allowances (RDAs). The RDA was established as

a nutritional norm for planning and assessing

dietary intake, and represents intake levels of

essential nutrients considered to meet adequately

the known needs of practically all healthy people

History

1645 Whistler writes the first scientific description of rickets.

1865 In his textbook on clinical medicine, Trousseau recommends codliver oil as treatment for rickets. He also recognises the impor-tance of sunlight and identifies osteomalacia as the adult form ofrickets.

1919 Mellanby proposes that rickets is due to the absence of a fat-soluble dietary factor.

1922 McCollum and coworkers establish the distinction betweenvitamin A and the antirachitic factor.

1925 McCollum and coworkers name the antirachitic factor vitamin D.Hess and Weinstock show that a factor with antirachitic activityis produced in the skin by ultraviolet irradiation.

1936 Windaus identifies the structure of vitamin D in cod liver oil.

1937 Schenck obtains crystallised vitamin D3 by activation of 7-dehy-dro-cholesterol.

1968 Haussler and colleagues report the presence of an activemetabolite of vitamin D in the intestinal mucosa of chicks.

1969 Haussler and Norman discover calcitriol receptors in chickintestine.

1970 Fraser and Kodicek discover that calcitriol is produced in thekidney.

1971 Norman and coworkers identify the structure of calcitriol.

1973 Fraser and associates discover the presence of an inborn errorof vitamin D metabolism that produces rickets resistant tovitamin D therapy.

1978 De Luca's group discovers a second form of vitamin D-resistantrickets (Type II).

1981 Abe and colleagues in Japan demonstrate that calcitriol isinvolved in the differentiation of bone-marrow cells.

1983 Provvedini and colleagues demonstrate the presence of calcitriolreceptors in human leukocytes.

1984 The same group presents evidence that calcitriol has a regulato-ry role in immune function.

1986 Morimoto and associates suggest that calcitriol may be useful inthe treatment of psoriasis.

25

26

Elmer V. McCollum

Adolf Windaus

Sir Edward Mellanby

1989 Baker and associates show that the vitamin D receptor belongsto the steroid-receptor gene family.

1994 The U.S. Food and Drug Administration approves a vitamin D-based topical treatment for psoriasis, called calcipotriol.

2003 A prospective study from Feskanich and coworkers among72,000 postmenopausal women in the U.S. over 18 years indi-cated that women consuming at least 600 IU vitamin D/day fromfood plus supplements had a 37% lower risk of hip fracture.

2006 Researchers from the Harvard School of Public Health examinedcancer incidence and vitamin D exposure in over 47,000 men inthe Health Professionals Follow-Up Study. They found that a highlevel of vitamin D (~1500 IU daily) was associated with a 17%reduction in all cancer incidences and a 29% reduction in totalcancer mortality with even stronger effects for digestive-systemcancers.

27

Vitamin E

SynonymsTocopherol

ChemistryA group of compounds composed of a substituted chromanol ring with aC16 side chain saturated in tocopherols, with 3 double bonds intocotrienols.

CH3

CH3

CH3H3C

HO

OCH3 CH3 CH3

CH3

Molecular formula of a-tocopherol

Vitamin E crystals in polarised light

28

Introduction

The term vitamin E covers eight fat-soluble compounds found in nature.Four of them are called tocopherolsand the other four tocotrienols. Theyare identified by the prefixes a, b, gand d. a-Tocopherol is the mostcommon and biologically the mostactive of these naturally occurringforms of vitamin E. Natural toco-pherols occur in RRR-configurationonly (RRR-a-tocopherol was former-ly designated as d-a-tocopherol).The chemical synthesis of a-toco-pherol results in a mixture of eightdifferent stereoisomeric forms whichis called all-rac-a-tocopherol (or dl-a-tocopherol). The biological activityof the synthetic form is lower thanthat of the natural form.The name tocopherol derives fromthe Greek words tocos, meaningchildbirth, and pherein, meaning tobring forth. The name was coined tohighlight its essential role in thereproduction of various animalspecies.The ending -ol identifies the sub-stance as being an alcohol.The importance of vitamin E inhumans was not accepted until fair-ly recently. Because its deficiency isnot manifested by a well-recognised,widespread vitamin deficiency dis-ease such as scurvy (vitamin Cdeficiency) or rickets (vitamin D defi-ciency), science only began torecognise the importance of vitaminE at a relatively late stage.

Functions

The major biological function of vita-min E is that of a lipid soluble antiox-idant preventing the propagation offree-radical reactions. Free radicalsare formed in normal metabolicprocesses and upon exposure toexogenous toxic agents (e.g. ciga-rette smoke, pollutants). Vitamin E islocated within the cellular mem-

branes. It protects polyunsaturatedfatty acids (PUFAs) and other com-ponents of cellular membranes fromoxidation by free radicals. Apartfrom maintaining the integrity of thecell membranes in the human body,it also protects low density lipo-protein (LDL) from oxidation. Recently, non-antioxidant functionsof a-tocopherol have been identi-fied.a-Tocopherol inhibits protein kinaseC activity, which is involved in cellproliferation and differentiation.Vitamin E inhibits platelet aggrega-tion and enhances vasodilation.Vitamin E enrichment of endothelialcells downregulates the expressionof cell adhesion molecules, therebydecreasing the adhesion of bloodcell components to the endothelium.

Main functions in a nutshell: Major fat soluble antioxidant of

the body Non-antioxidant functions in cell

signalling, gene expression andregulation of other cell functions

Dietary sources

Vegetable oils (olive, soya beans,palm, corn, safflower, sunflower,etc.), nuts, whole grains and wheatgerm are the most importantsources of vitamin E. Other sources

are seeds and green leafy vegeta-bles. The vitamin E content of veg-etables, fruits, dairy products, fishand meat is relatively low.The vitamin E content in foods isoften reported as a-tocopherolequivalents (a-TE). This term wasestablished to account for the differ-ences in biological activity of thevarious forms of vitamin E. 1 mg ofa-tocopherol is equivalent to 1 TE.Other tocopherols and tocotrienolsin the diet are assigned the followingvalues: 1 mg b-tocopherol = 0.5 TE;1 mg g-tocopherol = 0.1 TE; 1 mgd-tocopherol = 0.03 TE; 1 mg a-tocotrienol = 0.3 TE; 1 mg b-tocotrienol = 0.05 TE.

Food Vitamin E (mg a-TE/100g)

Wheat germ oil 174

Sunflower oil 63

Hazelnut 26

Rape seed oil 23

Soya bean oil 17

Olive oil 12

Peanuts 11

Walnuts 6

Butter 2

Spinach 1.4

Tomatoes 0.8

Apples 0.5

Milk (whole) 0.14

Vitamin E content of foods

(Souci, Fachmann, Kraut)

29

Absorption andbody stores

Vitamin E is absorbed together withlipids in the small intestine, depend-ing on adequate pancreatic functionand biliary secretion. Tocopherolesters which are present in foodsupplements and processed foodare hydrolysed before absorption.Vitamin E is incorporated intochylomicrons and transported viathe lymphatic system to the liver.a-Tocopherol is the vitamin E formthat predominates in blood and tis-sue. This is due to the action of aliver protein (a-tocopherol transferprotein) preferentially incorporatinga-tocopherol into the lipoproteinswhich deliver it to the different tis-sues. Vitamin E is found in mosthuman body tissues. The highestvitamin E contents are found in theadipose tissue, liver and muscles.The pool of vitamin E in the plasma,liver, kidneys and spleen turns overrapidly, whereas turnover of the con-tent of adipose tissue is slow.

Measurement

Normal a-tocopherol concentrationsin plasma measured by high per-formance liquid chromatographyrange from 12-45 M (0.5-2 mg/100ml). Plasma a-tocopherol concen-trations of

30

DeficiencyBecause depletion of vitamin E tis-sue stores takes a very long time, noovert clinical deficiency symptomshave been noted in otherwisehealthy adults. Symptoms of vitaminE deficiency are seen in patientswith fat malabsorption syndromes orliver disease, in individuals withgenetic defects affecting the a-toco-pherol transfer protein and in new-born infants, particularly prematureinfants.Vitamin E deficiency results in neuro-logical symptoms (neuropathy),myopathy (muscle weakness) andpigmented retinopathy. Early diag-nostic signs are leakage of muscleenzymes, increased plasma levels oflipid peroxidation products andincreased haemolysis of erythro-cytes (red blood cells). In prematureinfants, vitamin E deficiency is asso-ciated with haemolytic anaemia,intraventricular haemorrhage andretrolental fibroplasia.

Disease prevention andtherapeutic use

Research studies suggest that vita-min E has numerous health benefits.Vitamin E is thought to play a role inpreventing atherosclerosis and car-diovascular diseases (heart diseaseand stroke) due to its effects on anumber of steps in the developmentof atherosclerosis (e.g. inhibition ofLDL oxidation, inhibition of smoothmuscle cell proliferation, inhibition ofplatelet adhesion, aggregation andplatelet release reaction). Recent studies suggest that vitaminE enhances immunity in the elderly,and that supplementation with vita-min E lowers the risk of contractingan upper respiratory tract infection,particularly the common cold. Researchers are investigating the

prophylactic role of vitamin E in pro-tecting against exogenous pollutantsand lowering the risk of cancer andof cataracts.Vitamin E in combination with vita-min C may protect the body fromoxidative stress caused by extremesports (e.g. ultra marathon running).A role of vitamin E supplementationin the treatment of neurodegenera-tive diseases (Alzheimers disease,amyotrophic lateral sclerosis) is alsounder investigation.

RecommendedDietary Allowance(RDA)The recommended daily intake ofvitamin E varies according to age,sex and criteria applied in individualcountries. In the USA, the RDA foradults is 15 mg RRR-a-toco-pherol/day (FNB, 2000). In Europe,adult recommendations range from4 to 15 mg a-TE/day for men andfrom 3 to 12 mg a-TE/day forwomen.The RDA for vitamin E of 15 mg can-

not easily be acquired even with thebest nutritional intentions, yet mostresearch studies show that optimalintake levels associated with healthbenefits tend to be high. Vitamin Eintake should also be adapted tothat of PUFA, which influences therequirement for this vitamin. The ECScientific Committee on Foods (SCF)has suggested a consumption ratioof 0.4 mg a-TE per gram of PUFA.

Safety

Vitamin E has low toxicity. Afterreviewing more than 300 scientificstudies, the US-based Institute ofMedicine (IOM) concluded that vita-min E is safe for chronic use even atdoses of up to 1000 mg per day. Arecently published meta-analysissuggested that taking more than400 IU of vitamin E per day broughta weekly increase in the risk of all-cause mortality. However, much ofthe research was done in patients athigh risk of a chronic disease andthese findings may not be generalis-able to healthy adults. Many humanlong-term studies with higher doses

Current recommendations in the USA

RDA*

Infants # 6 months 4 mg (6 IU)(AI)

Infants 7-12 months 5 mg (7.5 IU)(AI)

Children 1-3 years 6 mg (9 IU)

Children 4-8 years 7 mg (10.5 IU)

Children 9-13 years 11 mg (16.5 IU)

Males $ 14 years 15 mg (22.5 IU)

Females $ 14 years 15 mg (22.5 IU)

Pregnancy 15 mg (22.5 IU)

Lactation 19 mg (28.5 IU)

*The Dietary Reference Intakes (DRIs) are actually

a set of four reference values: Estimated Average

Requirements (EAR), Recommended Dietary

Allowances (RDA), Adequate Intakes (AI), and

Tolerable Upper Intake Levels, (UL) that have

replaced the 1989 Recommended Dietary

Allowances (RDAs). The RDA was established as

a nutritional norm for planning and assessing

dietary intake, and represents intake levels of

essential nutrients considered to meet adequately

the known needs of practically all healthy people

31

of vitamin E have not reported anyadverse effects, and it has beenconcluded that vitamin E intakes ofup to 1600 IU (1073 mg RRR-a-tocopherol) are safe for most adults.The Antioxidant Panel of the Foodand Nutrition Board (FNB, 2000) hasset the UL (tolerable upper intakelevel) for adults at 1000 mg/day ofany form of supplemental a-toco-pherol. In 2003 the EC ScientificCommittee on Foods (SCF) estab-lished the UL of 300 mg a-TE foradults. Also in 2003, the UK Expertgroup on Vitamins and Minerals(EVM; 2003) set the UL at 540 mga-TE for supplemental vitamin E.Pharmacologic doses of vitamin Emay increase the risk of bleeding inpatients treated with anticoagulants.Patients on anticoagulant therapy orthose anticipating surgery shouldavoid high levels of vitamin E.

Supplements, food fortifica-tions and otherapplications

Vitamin E is available insoft gelatine capsules, or aschewable or effervescenttablets, and is found in mostmultivitamin supplements.The most common fortifiedfoods are soft drinks andcereals.

The all-rac-a-toco-pherol form of vitamin Eis widely used as anantioxidant in stabilising edibleoils, fats and fat-containing foodproducts.Research has shown thatvitamin E in combinationwith vitamin C reduces theformation of nitrosamines (a provencarcinogen in animals) in baconmore effectively than vitamin Calone.

Vitamin E has been used topically asan anti-inflammatory agent, toenhance skin moisturisation and toprevent cell damage by UV light.In pharmaceutical products toco-pherol is used, for example, to sta-bilise syrups, aromatic components,and vitamin A or provitamin A com-ponents.a-Tocopherol is used as an antioxi-dant in plastics, technical oils andgreases, and in the purified, so-called white oils, employed in cos-metics and pharmaceuticals.

Industrial production

Vitamin E derived from naturalsources is obtained by moleculardistil lation and, in most cases,subsequent methylation and esterifi-cation of edible vegetable oil prod-ucts. Synthetic vitamin E is pro-duced from fossil plant material bycondensation of trimethylhydro-quinone with isophytol.

Erhard Fernholz

Paul Karrer

Katherine Scott Bishop

32

Herbert Evans

History

1911 Hart and coworkers publish the first report of a suspected anti-sterility factor in animals.

1920 Matthill and Conklin observe reproductive anomalies in rats fedon special milk diets.

1922 Vitamin E is discovered by Evans and Scott Bishop.

1936 Evans and coworkers isolate what turns out to be a-tocopherolin its pure form from wheat germ oil.

1938 Fernholz provides the structural formula of vitamin E and Nobellaureate Karrer synthesises dl-a-tocopherol.

1945 Dam and coworkers discover peroxides in the fat tissue of ani-mals fed on vitamin E-deficient diets. The first antioxidant theoryof vitamin E activity is proposed.

1962 Tappel proposes that vitamin E acts as an in vivo antioxidant toprotect cell lipids from free radicals.

1968 The Food and Nutrition Board of the US National ResearchCouncil recognises vitamin E as an essential nutrient for humans.

1974 Fahrenholtz proposes singlet oxygen quenching abilities of a-tocopherol.

1977 Human vitamin E deficiency syndromes are described.

1980 Walton and Packer propose that vitamin E may prevent thegeneration of potentially carcinogenic oxidative products ofunsaturated fatty acids.

1980 McKay and King suggest that vitamin E functions as an antioxi-dant located primarily in the cell membrane.

1980s Vitamin E is demonstrated to be the major lipid-soluble antioxi-dant protecting cell membranes from peroxidation. Vitamin E isshown to stabilise the superoxide and hydroxyl free radicals.

1990 Effectiveness of vitamin E in inhibiting LDL (low density lipopro-tein) oxidation is shown.

1990 Kaiser and coworkers elucidate the singlet oxygen quenchingcapability of vitamin E.

1991 Azzi and coworkers describe an inhibitory effect of a-tocopherolon the proliferation of vascular smooth muscle cells and proteinkinase C activity.

2004 Barella and coworkers demonstrate that vitamin E regulates geneexpression in the liver and the testes of rats.

33

Vitamin K

SynonymsPhylloquinone, menaquinone

ChemistryCompounds with vitamin K activity are 3-substituted 2-methyl-1,4-naphtho-quinones. Phylloquinone contains a phytyl group, whereas menaquinonescontain a polyisoprenyl side chain with 6 to 13 isoprenyl units at the 3-posi-tion.

CH3

O

O CH3 CH3 CH3

CH3

CH3

Molecular formula of vitamin K1 (phylloquinone)

Vitamin K crystals in polarised light

34

Introduction

In 1929 Henrik Dam observed thatchicks fed on fat-free diets devel-