Vitamin E in Disease Prevention – A Critical Appraisal of Vitamin E Supplementation Trials

Zusammenfassung

Da eine Vielzahl degenerativer Erkrankungen mit einer gesteigerten Produktion reaktiver Spezies assoziiert scheint, wurde hypothetisiert, dass Antioxidanzien wie z. B. Vitamin E, in der Prävention und möglicherweise sogar Therapie dieser Erkrankungen protektiv sein könnten. Obwohl in einigen Beobachtungsstudien teilweise ein inverser Zusammenhang zwischen der Vitamin-E-Aufnahme und der Inzidenz koronarer Herzerkrankungen gefunden wurde, konnte diese Hypothese in darauffolgenden groß angelegten Vitamin-E-Supplementationsstudien, nicht bestätigt werden. Es bleibt zu bedenken, dass in einer Vielzahl dieser Studien Probanden nicht unter Berücksichtigung von Biomarkern des oxidativen Stresses und / oder des antioxidativen Status (z. B. Vitamin-E-Plasmaspiegel) rekrutiert wurden. Darüber hinaus könnte es sinnvoll sein, dass auch der Genotyp der Probanden sowohl bei der Versuchsplanung als auch der Auswertung von Vitamin-E-Supplementationsstudien vermehrt Berücksichtigung findet. Einige Untergruppen der Bevölkerung, wie z. B. Träger des Apolipoprotein-E4-Genotyps sowie Diabetiker, die das Haptoglobin-2-2-Allel tragen, könnten möglicherweise von einer höheren Vitamin-E-Zufuhr profitieren. Angesichts der Tatsache, dass die meisten groß angelegten Interventionsstudien keinen positiven Einfluss von hochdosiertem Vitamin E auf Krankheits- oder Mortalitätsrisiken nachweisen konnten, sind generelle Empfehlungen für eine Vitamin-E-Supplementierung (> 400 IU / d) derzeit nicht gerechtfertigt. Es erscheint zunächst erforderlich, die noch immer unbekannte(n) essenzielle(n) Funktion(en) von Vitamin E systematisch aufzuklären und dessen optimalen Zufuhrbereich abzuleiten.

Abstract

Many degenerative disorders may result in an excess formation of free radical species. Consequently, it has been hypothesised that antioxidants, such as vitamin E, may be helpful in the prevention or even treatment of these conditions. A number of observational studies promisingly reported inverse correlations between heart disease-risk and vitamin E consumption, but subsequent large-scale vitamin E supplementation trials failed to confirm this and revealed inconsistent results concerning long-term high-dosage vitamin E-supplementation and disease prevention in humans. However, many of these trials were unable to detect benefits from supplemental vitamin E, possibly because the study design and subject selection criteria were not optimized to test the hypothesis that vitamin E may reduce oxidative damage and associated degenerative diseases. These studies often neglected to include subjects based on vitamin E status or levels of oxidative stress. Future vitamin E supplementation trials should furthermore take into account genotype differences during study design, screening and data evaluation. Specific subgroups of the population, such as carriers of the ApoE4 genotype and diabetics carrying the haptoglobin 2–2 allele, may be responsive towards dietary vitamin E supplementation. However, in light of the fact that many large-scale, high-dosage vitamin E supplementation trials did not report a decrease in disease or mortality risks, general recommendations for a vitamin E supplementation (> 400 IU / d) are not justified. It is time to return to the bench to investigate the as yet unknown essential function(s) of vitamin E and to establish the intake range most suitable to support optimum health.

Schlüsselwörter

Vitamin E - Tocopherol - Krankheitsprävention - Humanstudien - Genotyp

Key words

vitamin E - tocopherol - disease prevention - human trials - genotype

References

• 1 Evans H M, Bishop K S. On the existence of a hitherto unrecognized dietary factor essential for reproduction.  Science. 1922;  56 650-651
• 2 Mason K E. The first two decades of vitamin E.  Fed Proc. 1977;  36 1906-1910
• 3 Evans H M, Emerson O H, Emerson G A. The isolation from wheat germ oil of an alcohol, α-tocopherol, having the properties of vitamin E.  J Biol Chem. 1936;  113 319-332
• 4 Kamal-Eldin A, Appelqvist L Å. The Chemistry and Antioxidant Properties of Tocopherols and Tocotrienols.  Lipids. 1996;  31 671-701
• 5 Lampi A M, Kamal-Eldin A, Piironen V. Tocopherols and Tocotrienols from Oil and Cereal Grains. In: Shi J, Mazza G, Le Maguer M, eds Functional Foods – Biochemical and Processing Aspects. Boca Raton; CRC Press 2002: 1-38
• 6 Munne-Bosch S, Alegre L. The function of tocopherols and tocotrienols in plants.  Critical Reviews in Plant Sciences. 2002;  21 31-57
• 7 Packer L, Obermüller-Jevic U C. Vitamin E: An Introduction. In: Packer L, Traber MG, Kraemer K, Frei B, eds The Antioxidant Vitamins C and E. Champaign, IL, USA; AOCS Press 2002: 133-151
• 8 Nationale Verzehrsstudie II: Ergebnisbericht, Teil 2. Karlsruhe; Max-Rubner-Institut 2008 (URL: http://www.was-esse-ich.de/uploads/media/NVSII_Ergebnisbericht_Teil2.pdf)
• 9 Deutsche Gesellschaft für Ernährung (DGE) .Reference values for nutrient intake. 1st ed. Frankfurt/Main; Umschau/Braus 2000
• 10 Mensink G B, Beitz R. Food and nutrient intake in East and West Germany, 8 years after the reunification – The German Nutrition Survey 1998.  Eur J Clin Nutr. 2004;  58 1000-1010
• 11 Maras J E, Bermudez O I, Qiao N. et al . Intake of alpha-tocopherol is limited among US adults.  J Am Diet Assoc. 2004;  104 567-575
• 12 Food and Nutrition Board of the Institute of Medicine .Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC; National Academy Press 2000: 506
• 13 Olcott H S, Emerson O H. Antioxidants and the Autoxidation of Fats. IX. The Antioxidant Properties of the Tocopherols.  J Am Chem Soc. 1937;  59 1008-1009
• 14 Dam H. Vitamin E as an in vivo antioxidant.  Experientia. 1952;  1 195-213
• 15 Azzi A, Ricciarelli R, Zingg J M. Non-antioxidant molecular functions of alpha-tocopherol (vitamin E).  FEBS Lett. 2002;  519 8-10
• 16 Rimbach G, Minihane A M, Majewicz J. et al . Regulation of cell signalling by vitamin E.  Proc Nutr Soc. 2002;  61 415-425
• 17 Packer L, Weber S U, Rimbach G. Molecular aspects of α-tocotrienol antioxidant action and cell signalling.  J Nutr. 2001;  131 369S-373S
• 18 Barella L, Muller P Y, Schlachter M. et al . Identification of hepatic molecular mechanisms of action of alpha-tocopherol using global gene expression profile analysis in rats.  Biochim Biophys Acta. 2004;  1689 66-74
• 19 Muller P Y, Netscher T, Frank J. et al . Comparative quantification of pharmacodynamic parameters of chiral compounds (RRR- vs. all-rac-alpha tocopherol) by global gene expression profiling.  J Plant Physiol. 2005;  162 811-817
• 20 Nier B, Weinberg P D, Rimbach G. et al . Differential gene expression in skeletal muscle of rats with Vitamin E deficiency.  IUBMB Life. 2006;  58 540-548
• 21 Rimbach G, Fischer A, Stoecklin E. et al . Modulation of hepatic gene expression by alpha-tocopherol in cultured cells and in vivo.  Ann N Y Acad Sci. 2004;  1031 102-108
• 22 Rota C, Barella L, Minihane A M. et al . Dietary alpha-tocopherol affects differential gene expression in rat testes.  IUBMB Life. 2004;  56 277-280
• 23 Rota C, Rimbach G, Minihane A M. et al . Dietary vitamin E modulates differential gene expression in the rat hippocampus: Potential implications for its neuroprotective properties.  Nutritional Neuroscience. 2005;  8 21-29
• 24 Gaedicke S, Zhang X, Schmelzer C. et al . Vitamin E dependent microRNA regulation in rat liver.  FEBS Lett. 2008;  582 3542-3546
• 25 Davies K J. Oxidative stress: the paradox of aerobic life.  Biochem Soc Symp. 1995;  61 1-31
• 26 Ceriello A, Motz E. Is Oxidative Stress the Pathogenic Mechanism Underlying Insulin Resistance, Diabetes, and Cardiovascular Disease? The Common Soil Hypothesis Revisited.  Arterioscler Thromb Vasc Biol. 2004;  24 816-823
• 27 Keaney Jr J F, Larson M G, Vasan R S. et al . Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study.  Arterioscler Thromb Vasc Biol. 2003;  23 434-439
• 28 Rimm E B, Stampfer M J, Ascherio A. et al . Vitamin E consumption and the risk of coronary heart disease in men.  The New England journal of medicine. 1993;  328 1450-1456
• 29 Stampfer M J, Hennekens C H, Manson J E. et al . Vitamin E consumption and the risk of coronary disease in women.  The New England journal of medicine. 1993;  328 1444-1449
• 30 Gey K F, Puska P, Jordan P. et al . Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology.  Am J Clin Nutr. 1991;  53 326S-334S
• 31 Riemersma R A, Wood D A, Macintyre C C. et al . Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene.  Lancet. 1991;  337 1-5
• 32 Jialal I, Devaraj S. Scientific evidence to support a vitamin e and heart disease health claim: research needs.  J Nutr. 2005;  135 348-353
• 33 Bjelakovic G, Nikolova D, Gluud L L. et al . Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis.  JAMA. 2007;  297 842-857
• 34 Miller 3rd  E R, Pastor-Barriuso R, Dalal D. et al . Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality.  Ann Intern Med. 2005;  142 37-46
• 35 Bell S J, Grochoski G T. How safe is vitamin E supplementation?.  Crit Rev Food Sci Nutr. 2008;  48 760-774
• 36 Hathcock J N, Azzi A, Blumberg J. et al . Vitamins E and C are safe across a broad range of intakes.  Am J Clin Nutr. 2005;  81 736-745
• 37 Block G, Jensen C D, Morrow J D. et al . The effect of vitamins C and E on biomarkers of oxidative stress depends on baseline level.  Free Radic Biol Med. 2008;  45 377-384
• 38 Roberts 2nd  L J, Oates J A, Linton M F. et al . The relationship between dose of vitamin E and suppression of oxidative stress in humans.  Free Radic Biol Med. 2007;  43 1388-1393
• 39 Landes N, Pfluger P, Kluth D. et al . Vitamin E activates gene expression via the pregnane X receptor.  Biochem Pharmacol. 2003;  65 269-273
• 40 Cholerton S, Daly A K, Idle J R. The role of individual human cytochromes P450 in drug metabolism and clinical response.  Trends in pharmacological sciences. 1992;  13 434-439
• 41 Mustacich D J, Leonard S W, Devereaux M W. et al . α-Tocopherol regulation of hepatic cytochrome P450 s and ABC transporters in rats.  Free Radic Biol Med. 2006;  41 1069-1078
• 42 Hundhausen C, Frank J, Rimbach G. et al . Effect of Vitamin E on Cytochrome P450 mRNA Levels in Cultured Hepatocytes (HepG2) and in Rat Liver.  Cancer Genomics & Proteomics. 2006;  3 183-190
• 43 Kluth D, Landes N, Pfluger P. et al . Modulation of Cyp3a11 mRNA expression by alpha-tocopherol but not gamma-tocotrienol in mice.  Free Radic Biol Med. 2005;  38 507-514
• 44 Traber M G, Elsner A, Brigelius-Flohé R. Synthetic as compared with natural vitamin E is preferentially excreted as α-CEHC in human urine: studies using deuterated α-tocopheryl acetates.  FEBS Lett. 1998;  437 145-148
• 45 Jeanes Y M, Hall W L, Ellard S. et al . The absorption of vitamin E is influenced by the amount of fat in a meal and the food matrix.  Br J Nutr. 2004;  92 575-579
• 46 Leonard S W, Good C K, Gugger E T. et al . Vitamin E bioavailability from fortified breakfast cereal is greater than that from encapsulated supplements.  Am J Clin Nutr. 2004;  79 86-92
• 47 Bruno R S, Leonard S W, Park S I. et al . Human vitamin E requirements assessed with the use of apples fortified with deuterium-labeled alpha-tocopheryl acetate.  Am J Clin Nutr. 2006;  83 299-304
• 48 Frank J. Beyond vitamin E supplementation: an alternative strategy to improve vitamin E status.  J Plant Physiol. 2005;  162 834-843
• 49 Frank J, Lee S, Leonard S W. et al . Sex differences in the inhibition of gamma-tocopherol metabolism by a single dose of dietary sesame oil in healthy subjects.  Am J Clin Nutr. 2008;  87 1723-1729
• 50 Hall W L, Jeanes Y M, Lodge J K. Hyperlipidemic Subjects Have Reduced Uptake of Newly Absorbed Vitamin E into Their Plasma Lipoproteins, Erythrocytes, Platelets, and Lymphocytes, as Studied by Deuterium-Labeled {alpha}-Tocopherol Biokinetics.  J Nutr. 2005;  135 58-63
• 51 Weisgraber K H, Rall Jr S C, Mahley R W. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms.  J Biol Chem. 1981;  256 9077-9083
• 52 Singh P P, Singh M, Mastana S S. APOE distribution in world populations with new data from India and the UK.  Annals of human biology. 2006;  33 279-308
• 53 Eichner J E, Dunn S T, Perveen G. et al . Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review.  Am J Epidemiol. 2002;  155 487-495
• 54 McCarron M O, Delong D, Alberts M J. APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis.  Neurology. 1999;  53 1308-1311
• 55 Song Y, Stampfer M J, Liu S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease.  Ann Intern Med. 2004;  141 137-147
• 56 Humphries S E, Talmud P J, Hawe E. et al . Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study.  Lancet. 2001;  358 115-119
• 57 Lahoz C, Schaefer E J, Cupples L A. et al . Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study.  Atherosclerosis. 2001;  154 529-537
• 58 Talmud P J. Gene-environment interaction and its impact on coronary heart disease risk.  Nutr Metab Cardiovasc Dis. 2007;  17 148-152
• 59 Talmud P J, Stephens J W, Hawe E. et al . The significant increase in cardiovascular disease risk in APOEϵ4 carriers is evident only in men who smoke: potential relationship between reduced antioxidant status and ApoE4.  Annals of human genetics. 2005;  69 613-622
• 60 Mabile L, Lefebvre C, Lavigne J. et al . Secreted apolipoprotein E reduces macrophage-mediated LDL oxidation in an isoform-dependent way.  J Cell Biochem. 2003;  90 766-776
• 61 Miyata M, Smith J D. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides.  Nat Genet. 1996;  14 55-61
• 62 Dietrich M, Hua Y, Block G. et al . Associations between apolipoprotein E genotype and circulating F2-isoprostane levels in humans.  Lipids. 2005;  40 329-334
• 63 Tsuda M, Sanada M, Nakagawa H. et al . Phenotype of apolipoprotein E influences the lipid metabolic response of postmenopausal women to hormone replacement therapy.  Maturitas. 2001;  38 297-304
• 64 Lodge J K, Hall W L, Jeanes Y M. et al . Physiological factors influencing vitamin E biokinetics.  Ann N Y Acad Sci. 2004;  1031 60-73
• 65 Mas E, Dupuy A M, Artero S. et al . Functional Vitamin E deficiency in ApoE4 patients with Alzheimer's disease.  Dement Geriatr Cogn Disord. 2006;  21 198-204
• 66 Jofre-Monseny L, Huebbe P, Stange I. et al . Influence of apolipoprotein E genotype and dietary alpha-tocopherol on redox status and C-reactive protein levels in apolipoprotein E3 and E4 targeted replacement mice.  Br J Nutr. 2008;  100 44-53
• 67 Bowman B H, Kurosky A. Haptoglobin: the evolutionary product of duplication, unequal crossing over, and point mutation.  Advances in human genetics. 1982;  12 189-261, 453–454
• 68 Miller Y I, Altamentova S M, Shaklai N. Oxidation of low-density lipoprotein by hemoglobin stems from a heme-initiated globin radical: antioxidant role of haptoglobin.  Biochemistry. 1997;  36 12 189-12 198
• 69 Melamed-Frank M, Lache O, Enav B I. et al . Structure-function analysis of the antioxidant properties of haptoglobin.  Blood. 2001;  98 3693-3698
• 70 Carter K, Worwood M. Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases.  International journal of laboratory hematology. 2007;  29 92-110
• 71 Asleh R, Marsh S, Shilkrut M. et al . Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease.  Circ Res. 2003;  92 1193-1200
• 72 Bamm V V, Tsemakhovich V A, Shaklai M. et al . Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL.  Biochemistry. 2004;  43 3899-3906
• 73 Tseng C F, Lin C C, Huang H Y. et al . Antioxidant role of human haptoglobin.  Proteomics. 2004;  4 2221-2228
• 74 Brouwers A, Langlois M, Delanghe J. et al . Oxidized low-density lipoprotein, iron stores, and haptoglobin polymorphism.  Atherosclerosis. 2004;  176 189-195
• 75 Bernard D, Christophe A, Delanghe J. et al . The effect of supplementation with an antioxidant preparation on LDL-oxidation is determined by haptoglobin polymorphism.  Redox Rep. 2003;  8 41-46
• 76 Levy A P, Hochberg I, Jablonski K. et al . Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study.  Journal of the American College of Cardiology. 2002;  40 1984-1990
• 77 Burbea Z, Nakhoul F, Zoabi R. et al . Haptoglobin phenotype as a predictive factor of mortality in diabetic haemodialysis patients.  Annals of clinical biochemistry. 2004;  41 469-473
• 78 Levy A P, Friedenberg P, Lotan R. et al . The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women.  Diabetes Care. 2004;  27 925-930
• 79 Waters D D, Alderman E L, Hsia J. et al . Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial.  JAMA. 2002;  288 2432-2440
• 80 Yusuf S, Dagenais G, Pogue J. et al . Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.  The New England journal of medicine. 2000;  342 154-160
• 81 Levy A P, Gerstein H C, Miller-Lotan R. et al . The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes.  Diabetes Care. 2004;  27 2767
• 82 Milman U, Blum S, Shapira C. et al . Vitamin E Supplementation Reduces Cardiovascular Events in a Subgroup of Middle-Aged Individuals With Both Type 2 Diabetes Mellitus and the Haptoglobin 2–2 Genotype – A Prospective Double-Blinded Clinical Trial.  Arterioscler Thromb Vasc Biol. 2008;  28 341-347
• 83 Döring F, Rimbach G, Lodge J K. In silico search for single nucleotide polymorphisms in genes important in vitamin E homeostasis.  IUBMB Life. 2004;  56 615-620
• 84 Borel P, Moussa M, Reboul E. et al . Human plasma levels of vitamin E and carotenoids are associated with genetic polymorphisms in genes involved in lipid metabolism.  J Nutr. 2007;  137 2653-2659
• 85 Sundl I, Guardiola M, Khoschsorur G. et al . Increased concentrations of circulating vitamin E in carriers of the apolipoprotein A5 gene – 1131T>C variant and associations with plasma lipids and lipid peroxidation.  J Lipid Res. 2007;  48 2506-2513
• 86 Testa R, Bonfigli A R, Sirolla C. et al . Effect of 4G/5G PAI-1 polymorphism on the response of PAI-1 activity to vitamin E supplementation in Type 2 diabetic patients.  Diabetes, nutrition & metabolism. 2004;  17 217-221
• 87 Hoppe P P, Krennrich G. Bioavailability and potency of natural-source and all-racemic α-tocopherol in the human: a dispute.  Eur J Nutr. 2000;  39 183-193
• 88 O'Byrne D, Grundy S, Packer L. et al . Studies of LDL oxidation following α-, γ-, or δ-tocotrienyl acetate supplementation of hypercholesterolemic humans.  Free Radic Biol Med. 2000;  29 834-845
• 89 Hensley K, Benaksas E J, Bolli R. et al . New Perspectives on Vitamin E: γ-Tocopherol and Carboxyethylhydroxychroman Metabolites in Biology and Medicine.  Free Radic Biol Med. 2004;  36 1-15
• 90 Cooney R V, Custer L J, Okinaka L. et al . Effects of dietary sesame seeds on plasma tocopherol levels.  Nutr Cancer. 2001;  39 66-71
• 91 The alpha-Tocopherol, beta Carotene Cancer Prevention Study Group . The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.  The New England journal of medicine. 1994;  330 1029-1035
• 92 Salonen J T, Nyyssonen K, Salonen R. et al . Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis.  Journal of internal medicine. 2000;  248 377-386
• 93 Sesso H D, Buring J E, Christen W G. et al . Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial.  JAMA. 2008;  300 2123-2133
• 94 de Gaetano G. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project.  Lancet. 2001;  357 89-95
• 95 Hodis H N, Mack W J, LaBree L. et al . Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS).  Circulation. 2002;  106 1453-1459
• 96 Lee I M, Cook N R, Gaziano J M. et al . Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.  JAMA. 2005;  294 56-65
• 97 Stephens N G, Parsons A, Schofield P M. et al . Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS).  Lancet. 1996;  347 781-786
• 98 Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico . Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial.  Lancet. 1999;  354 447-455
• 99 Boaz M, Smetana S, Weinstein T. et al . Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial.  Lancet. 2000;  356 1213-1218
• 100 Cook N R, Albert C M, Gaziano J M. et al . A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study.  Archives of internal medicine. 2007;  167 1610-1618