From The July 2003 Issue of Functional Foods & Nutraceuticals
This vitamin's eight compounds garner a corner of the antioxidant market.
Andreas M Papas, PhD, investigates.
Alpha-tocopherol is synonymous with vitamin E because it is the predominant form in human and animal tissues. But the vitamin E family is comprised of eight compounds.
Eight natural compounds have vitamin E activity. These are the four tocopherols, designated as alpha, beta, gamma and delta, and four tocotrienols also designated as alpha, beta, gamma and delta. Yet, alpha-tocopherol has become synonymous with vitamin E. It is the most bioactive form based on the rat foetal resorption test, the classical assay for vitamin E activity. Recent research, however, shows that the other tocopherols and tocotrienols have important and unique antioxidant and other biological effects in nutrition and health. [1,2] This paper will review the biological function of tocopherols and tocotrienols and their role in health and disease.
Natural Vs Synthetic Alpha-tocopherol
Alpha-tocopherol is produced commercially both in the natural and synthetic forms. All molecules in d-alpha-tocopherol, the naturally occurring form, are identical. In contrast, the synthetic dl-alpha-tocopherol is a mixture of eight different stereoisomers. Of these eight, only one is identical to the natural form. [1,2]
The US Food and Drug Administration (FDA) and the United States Pharmacopoeia (USP) recognise the natural d-alpha-tocopherol as 36 per cent more potent than the synthetic dl-alpha-tocopherol. Recent studies in humans using powerful new techniques indicate that the relative potency of natural d-alpha-tocopherol is underestimated. [3,4] On the basis of these studies, the Food and Nutrition Board recommended that the biopotency of the d-alpha-tocopherol is twice that of the synthetic dl form. 
One International Unit (IU) is defined as one milligram of synthetic dl-alpha-tocopheryl acetate. For nutritional supplements, the claimed IU content is from alpha-tocopherol content. The other tocopherols and tocotrienols are assumed to have zero IU value.
The Food and Nutrition Board replaced the IU with the alpha-tocopherol equivalent (a-TE). One a-TE is one milligram of natural d-alpha-tocopherol. It also allowed credit for beta- and gamma-tocopherols and alpha-tocotrienols for foods only, not supplements. [1,2] Yet vitamin E content of nutritional supplements and in fortified foods continues to be expressed as IU.
It is important to note that IU provides partial information on the true vitamin E value of a product. Specifically, IUs do not tell us whether:
The product contains only alpha-tocopherol, or in addition to other tocopherols and tocotrienols.
The alpha-tocopherol is natural or synthetic, as listed on the label.
The alpha-tocopherol is esterified.
Underscoring the importance of viewing vitamin E as a family of compounds is the evidence that gamma-tocopherol and tocotrienols have unique functions different from those of alpha-tocopherol.
Gamma-tocopherol appears to be more potent than alpha-tocopherol in increasing superoxide dismutase (SOD) activity in plasma and arterial tissues. [6 ]
While both alpha- and gamma-tocopherol increase nitric oxide (NO) generation and nitric oxide synthase (cNOS) activity, only the gamma-tocopherol increased cNOS protein expression. NO is important for cardiovascular health; in atherosclerosis, the endothelium has a reduced capacity to produce NO. 
Gamma-tocopherol has been reported to be more effective than alpha-tocopherol in quenching nitrogen radicals. 
Gamma-tocopherol and its major metabolite reduced PGE2 synthesis in both lipopolysaccharide-stimulated macrophages and IL-1b-treated human epithelial cells. In contrast, alpha-tocopherol slightly reduced PGE2 formation in macrophages, but had no effect in epithelial cells.  We reported preferential uptake of gamma-tocopherol and potential synergy with alpha-tocopherol in macrophages. 
A metabolic product of gamma-tocopherol, code-named LLU-a, appeared to be a natriuretic factor.  A natriuretic substance increases the rate of excretion of sodium ion in the urine, which would appear to have an effect on blood pressure.
Tocotrienols, in particular gamma-tocotrienol, appear to suppress 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), a key enzyme in cholesterol synthesis. 
Laboratory studies in-dicate that tocotrienols may affect the growth and/or proliferation of some types of human breast, melanoma and leukaemia cancer cells. [12,13] Our research indicated that gamma-tocopherol, added to a semi-purified diet, was more effective than alpha-tocopherol in reducing ras-p21 oncogenes in the colonocyte of rats. 
Tocotrienols And Cardiovascular Health
In a five-year study, researchers evaluated 50 patients who had stenosis of the carotid artery.  In this study, one group of 25 patients received approximately 650mg tocotrienols plus tocopherols. In the other group of 25 who received a placebo, 15 patients showed worsening of the stenosis, eight remained stable and two showed some improvement. In the treatment group, three patients got slightly worse and 12 remained stable. Ten patients showed regression of stenosis.
The researchers have also looked at the effect of tocotrienols on total cholesterol, LDL and triglycerides.  Although their data suggest a drop in triglycerides and LDL and increase in HDL, this observation needs to be confirmed in other clinical studies because evidence to date has been mixed. [17,18]
The results from clinical intervention trials have been largely negative, leading to a controversy over the role of vitamin E in heart disease.
In the Cambridge Heart Antioxidant Study (CHAOS), 400 or 800IU vitamin E each day as d-alpha-tocopheryl acetate reduced the risk of suffering a heart attack within a year-and-a-half by 77 per cent compared with the control group. There was no decrease, however, in fatal heart attacks; the number was actually slightly higher in the vitamin E group. 
The Italian study GISSI involved 11,324 men and women who had suffered a heart attack no more than three months before. Whilst fish oil reduced subsequent heart attacks, the effects of dl-alpha-tocopheryl acetate (300mg dl-alpha-tocopheryl acetate) were not significant. 
In the Heart Outcomes Prevention Evaluation Study (HOPE), vitamin E (400IU d-alpha-tocopheryl acetate) was ineffective. 
In evaluating these results, it is important to consider that these studies evaluated only one member of the vitamin E family—alpha-tocopherol—and were limited to a single dose. The emerging information on the role of gamma-tocopherol and tocotrienols indicates that the complete vitamin E of tocopherols plus tocotrienols might be more effective.
Other E Benefits
Cancer: In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study with more than 29,000 elderly male smokers, those taking 50IU vitamin E for six years had 32 per cent fewer diagnoses of prostate cancer and 41 per cent fewer prostate cancer deaths than men who did not take vitamin E. There was also a non-significant 16 percent reduction in colon cancer.  A study at Johns Hopkins University evaluated the alpha-1 and gamma-tocopherols and selenium on prostate cancer. For gamma-tocopherol, men in the highest fifth of blood concentration had a five-fold reduction in the risk of developing prostate cancer than men in the lowest fifth. 
Alzheimer's disease: In a collaborative study at major medical centres across the US, researchers found that in Alzheimer's patients taking large doses of vitamin E (2,000IU/day), progression of the memory-robbing disease was delayed by approximately seven months. 
Ageing and immunity: Vitamin E (300mg dl-alpha-tocopheryl acetate) increased the power of disease-fighting T-cells, improved delayed-type hypersensitivity skin response (DTH) by 65 per cent and antibody response to hepatitis B six-fold in healthy elderly people. It also significantly increased the antibody titer to tetanus vaccine.  In a recent study in The Netherlands, researchers reported no benefit in acute respiratory tract infections in elderly people from vitamin E supplementation. 
Cataracts: Vitamin E, in conjunction with other antioxidants (including vitamin C and carotenoids), appears to reduce the risk of cataracts. [1,2,27]
Skin health: Vitamin E has been shown to reduce the damage to skin from exposure to UV radiation and ozone. [1,2]
Safe And Effective Use Levels
Intake of vitamin E from diet is less than 15mg/day. Rich sources of vitamin E include vegetable oils, nuts and whole grains. The United States Department of Agriculture RDA is 30IU and the NRC RDI is 15IU. It is generally assumed that the vitamin E requirement is for alpha-tocopherol and there is no official RDA for other tocopherols and tocotrienols. Considerably higher doses are believed to be necessary for prevention of disease and promotion of wellness. The most common supplemental doses are 400, 800, 100 and 200IU. But remember, the IU does not indicate whether a supplement has tocopherols other than alpha-tocopherol or tocotrienols, and the other tocopherols and tocotrienols are assumed to have zero IU value.
Vitamin E toxicity is low, probably because it is not stored in the liver. Large doses may exacerbate blood coagulation problems in persons with vitamin K deficiency or those taking anticoagulant drugs. Pro-oxidant effects of vitamin E have been shown in vitro but have not been confirmed in humans. 
Emerging evidence suggests that the other members of the vitamin E family have important antioxidant and other effects, which need to be evaluated further. This research will enhance our understanding of the role of vitamin E in nutrition and health and help improve the formulation of dietary supplements.
Andreas M Papas, PhD, is president of YASOO Health Inc and senior scientific advisor, Cancer Prevention Institute, Harvard School of Epidemiology. He is author of The Vitamin E Factor. firstname.lastname@example.org
1. Papas AM. The Vitamin E Factor, HarperCollins Publishers, Inc., New York, NY. 1999 (www.vitamine-factor.com).
2. Papas AM, Editor. Antioxidant Status, Diet, Nutrition and Health, CRC Press, Boca Raton, 1998.
3. Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue a-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr 1998;67:669-684.
4. Acuff RV, Dunworth RG, Webb LW, et al. Transport of deuterium-labeled tocopherols during pregnancy. Am J Clin Nutr 1998;67:459-464.
5. Food and Nutrition Board. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium and Carotenoids, National Academies Press, Washington, DC 2000.
6. Li D, Saldeen T, Romeo F, Mehta JL. Relative effects of a- and g-tocopherol on low-density lipoprotein oxidation and superoxide dismutase and nitric oxide synthase activity and protein expression in rats. Cardiovasc Pharmacol Ther 1999:219-226.
7. Cooney R, Franke A, Harwood P, et al. G-tocopherol detoxification of nitrogen dioxide: superiority to a-tocopherol. Proc Natl Acad Sci U S A 1993;90:1771-1775.
8. Jiang, Q, Elson-Schwab, I, Courtemanche, C, Ames, BN. g-Tocopherol and its major metabolite, in contrast to a-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci USA. 2000;97:11494-11499.
9. Gao R, Stone WL, Huang T, Papas AM, Qui M. The uptake of tocopherols by RAW 264.7 macrophages. Nutr J. 2002;1:2.
10. Wechter WJ, Kantoci D, Murray ED Jr, et al. A new endogenous natriuretic factor: LLU-a. Proc Natl Acad Sci USA 1996;93:6002-6007.
11. Khor HT, Chieng DY, Ong, KK Tocotrienols inhibit liver HMG-CoA reductase activity in the guinea pig. Nutr Res 1995;15: 537-544.
12. Yu W, Simmons-Menchaca M, Gapor A, et al. Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols. Nutr Cancer 1999;33:26-32.
13. Mo H, Elson CE. Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. J Nutr 1999;129:804-13.
14. Stone WL, Papas AM, LeClair IO, et al. The influence of dietary iron and tocopherols on oxidative stress and ras-p21 levels in the colon. Cancer Detect Prev. 2002;26(1):78-84.
15. Watkins TR, Bierenbaum ML, Giampaolo A. Tocotrienols: Biological and Health Effects. In Antioxidant Status, Diet, Nutrition and Health, Papas AM editor, CRC Press, Boca Raton, 1998;479-96
16. Kooyenga DK, Watkins TR, Geller M, et al. Hypocholesterolemic and antioxidant effects of rice bran oil non-saponifiables in hypercholesterolemic subjects. Journal of Enironmental and Nutritional Interactions 1999; 3:1-8.
17. Mensink RP, van Houwelingen AC, Kromhout D, Hornstra G. A vitamin E concentrate rich in tocotrienols had no effect on serum lipids, lipoproteins, or platelet function in men with mildly elevated serum lipid concentrations. Am J Clin Nutr. 1999;69:213-9.
18. Mustad VA, Smith CA, Ruey PP, Edens NK, DeMichele SJ. Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia. Am J Clin Nutr. 2002;76:1237-43.
19. Stephens NG, Parsons A, Schofield PM, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.
20. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999; 354:447-55.
21. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:154-60.
22. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with a-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998;90:440-446.
23. Helzlsouer, KJ, Huang, H-Y, Alberg, AJ, et al. Association between a-tocopherol, g-tocopherol, selenium and subsequent prostate cancer. J Natl Cancer Inst 2000:92; 2018-2023.
24. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, a-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 1997: 336:1216-1222.
25. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA 1997;277:1380-1386.
26. Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial. JAMA. 2002;288:715-21.
27. Robertson J McD, Donner AP, Trevithick JR. A possible role for vitamins C and E in cataract prevention. Am J Clin Nutr 1991 Supplement;35:346S-351S.
28. Diplock AT. Safety of antioxidant vitamins and beta-carotene. Am J Clin Nutr 1995 Dec;62(6 Suppl):1510S-1516S