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Vitamin E: An Important & Controversial Nutrient

Vitamin E is a fat-soluble vitamin with a well-established need in human health. Over the past decade or so, however, there has been a great deal of controversy surrounding whether supplementation with vitamin E increases or decreases the risk of heart disease and prostate cancer. This article will review the functions of vitamin E and research on the role of supplementation in human health, as well as address the aforementioned controversy.

Vitamin E Defined

From a scientific perspective, vitamin E is not just one compound (as is the case with other vitamins such as vitamin C), but rather a family of eight isomers, which include alpha-, beta-, gammaand delta-e tocopherols. In this context, the term isomer refers to compounds with the same structural formula but different spatial arrangements of atoms.1 The other four isomers are alpha-, beta-, gamma- and delta- tocotrienols (a family of natural compounds related to tocopherols). However, according to the Food and Nutrition Board, Institute of Medicine, vitamin E is defined as one specific compound, alpha-tocopherol.The reason for this is that alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body and found in the largest quantities in blood and tissues.2 Consequently, alpha-tocopherol is the only form that meets the latest recommended dietary allowance (RDA) and daily value (DV) for vitamin E. Nevertheless, the other tocopherols and tocotrienols do have value to human health.

Forms & Bioavailability

Vitamin E is measured in international units (IU), a unit of measurement based on biological activity or effect rather than weight (as is the case with nutrients measured in milligrams). Keeping this in mind, it is interesting to note that synthetic vitamin E (dl-alpha-tocopherol) is less bioavailable and only half the biological activity of natural vitamin E (d-alpha-tocopherol).3 That means that it takes twice as many milligrams of synthetic E to provide the same biological activity as would be found in natural E. Additionally, vitamin E is also available as tocopheryl esters using acetic or succinic acid. Alpha-tocopheryl acetate and succinate are more stable and easy to use in vitamin supplements. The bioavailability of alpha-tocopherol from succinate and acetate is equivalent to that of free alpha-tocopherol.4 For the rest of this article, the term “vitamin E” shall be considered to mean alphatocopherol or alpha-tocopheryl, unless otherwise stated.

Functions

The primary function of vitamin E is as an antioxidant. Since lipids (fats) are part of all cell membranes, fat-soluble vitamin E is ideally suited to quench free radicals that would otherwise compromise the integrity of cell membranes.Vitamin E also protects LDL cholesterol from oxidation, which is important since oxidized LDLs have been implicated in the development of cardiovascular diseases.5

In addition to its role as an antioxidant, vitamin E has also been shown to: 1) inhibit the activity of protein kinase C, a Cell-signaling molecule (may increase expression of oncogenes which promote cancer progression6), 2) affect the expression and activities of molecules and enzymes in immune and inflammatory cells, and 3) inhibit platelet aggregation and to enhance vasodilation (which promotes circulation).7,8 Finally research has shown that supplemental vitamin E was able to improve measures of immune function in the elderly9,10, improve oxidative stress, improve insulin action and glucose disposal in diabetes11-15 and slow progression of Alzheimer’s in individuals with moderate neurological impairment.16

Intake

According to the National Health and Nutrition Examination Survey (NHANES) 2003-06, Americans’ average dietary intake of vitamin E from food (including enriched and fortified sources) is 6.9 mg/day (10.35 IU). This intake is well below the current RDA of 15 mg/day (22. 5 IU). This means that more than 90 percent of Americans do not meet RDA for vitamin E.17 If you compare it to the 30 IU DV for vitamin E, the results are even worse.

Cardiovascular Disease

Two large studies found that men and women who supplemented with at least 100 IU of natural vitamin E daily had significantly reduced risk of heart disease.
18,19 A randomized, placebo-controlled, intervention trial of 39,876 women found that daily supplementation with 600 IU of natural vitamin E every other day for 10 years decreased cardiovascular-related deaths by 24 percent, but had no effect on the incidence of various cardiovascular events20 except for a 21 percent reduction in risk of venous blood clot.21 In addition, men who took at least 100 IU of natural vitamin E daily had a reduction in the progression of coronary artery atherosclerosis compared to those who took less vitamin E.22 Also, a randomized, placebo- controlled, intervention trial found that supplementing with 400 IU or 800 IU of synthetic vitamin E daily for 18 months reduced the occurrence of nonfatal heart attacks by 77 percent in heart patients.23

By contrast, a large randomized trial found that supplementation with 400 IU of synthetic vitamin E every other day for eight years had no significant effect on the risk of major cardiovascular events.24 Likewise, three other trials did not find significant risk reductions in cardiovascular disease with vitamin E supplementation in the following ranges: 37.5 IU (natural)25, 400 IU (natural) (47) 26 or 225 IU (synthetic).27 In a study of vascular disease in diabetes patients, daily supplementation with 400 IU of natural vitamin E for about seven years had no effect on major cardiovascular events, but there was a slightly increased risk of heart failure.28

In an effort to determine an effective dose level, a clinical study29 was conducted with individuals with high cholesterol and oxidative stress levels using placebo or the following daily doses of natural vitamin E: 100, 200, 400, 800, 1,600 or 3,200 IU/day for 16 weeks. A reduction in oxidative stress occurred only at 1,600 and 3,200 IU/day, both of which are above the 1,500 IU/day tolerable upper intake level (UL) for vitamin E.

So how does one interpret this seemingly contradictory research on vitamin E and cardiovascular disease when the jury still seems to be out? There are at least a couple of possibilities. One is that doses in the 100 IU range seem to consistently have had benefit for reduction of cardiovascular disease risk when larger or smaller doses did not. Another way is to take the research as an indication that vitamin E should be combined with other antioxidants rather than taken alone.(See the section on prostate cancer for elucidation on this concept.)

Yet another explanation may be that Tocotrienols, rather than alpha-tocopherol, offer better protection against the risk of cardiovascular disease. A two-month, randomized, placebo-controlled, blinded end point clinical study30 examined the effects of placebo and 50, 100 and 200 mg daily of Tocomin Suprabio, a self-emulsifying palm oil-based preparation of the tocotrienols. Results showed that those in Tocomin Suprabio groups had a significantly reduced augmentation index (AI, a measure of arterial stiffness) compared to the placebo group, which did not show any reduction in their AI.Another 30-day study combining tocopherols, palm-based tocotrienols and palm olein showed a reduction in serum total cholesterol and low-densitylipoprotein cholesterol concentrations in all the volunteers.31

Prostate Cancer

A placebo-controlled intervention study that was designed to look at the effect of vitamin E supplementation on lung cancer development noted a 34 percent reduction in the incidence of prostate cancer in smokers given daily supplements of 37.5 IU/day synthetic vitamin E. 32 A meta-analysis that combined the results of this study with three other randomized controlled trials associated vitamin E supplement use with a 15 percent lower risk of prostate cancer.33

Conversely, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) involved 35,000 men randomly assigned to receive either: 1) selenium (L-(+)-selenomethionine) plus synthetic vitamin E (dl-alpha-tocopheryl acetate),
2) selenium plus placebo, 3) synthetic vitamin E plus placebo or 4) two placebos.When originally published in 200834, the results indicated that after almost five and half years, no significant differences were observed between any of the groups in relation to prostate cancer risk. However, subsequently an analysis of the study’s participants published in JAMA35 indicated that synthetic vitamin E supplements alone were associated with a 17 percent increase in the risk of prostate cancer, but that no increase in risk was observed in the combination selenium-vitamin E group.

In the opinion of this author, what the JAMA analysis really shows is that men Should take selenium with their vitamin E. In fact, the JAMA analysis is reminiscent of the flawed 1994 study in which smokers using beta-carotene were thought to be at a greater risk of lung cancer36, although a more thorough follow- up analysis which looked at the diets and other dietary supplements taken revealed that the smokers’ actual danger was due to low total antioxidant levels; not to the fact that they took beta-carotene.37 This makes sense given the fact that antioxidants function interdependently, and so should be taken together. This is consistent with comments from Dr. Duffy MacKay of Council for Responsible Nutrition (CRN) about the JAMA analysis: “This reinforces the theory that vitamins work synergistically and that drug-like trials of nutrients, when used in isolation from other nutrients, may not be the most appropriate way to study them.”38

References:

1 Seager SL, Slabaugh MR. Chemistry for Today: General, Organic, and Biochemistry, Fourth Edition. Pacific Grove, California: Brooks/Cole; 2000:364.

2 Traber MG. Utilization of vitamin E. Biofactors.1999;10(2-3):115-120.

3 Food and Nutrition Board, Institute of Medicine.Vitamin E. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington D.C.: National Academy Press; 2000:186-283.

4 Food and Nutrition Board, Institute of Medicine.Vitamin E. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington D.C.: National Academy Press; 2000:186-283.

5 Traber MG. Vitamin E. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. Philadelphia: Lippincott Williams & Wilkins; 2006:396-411.

6 Yamasaki T, Takahashi A, Pan J, Yamaguchi N, Yokoyama KK. Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Junmediated Activation of Transcription. J Biol Chem. March 2009;284(13):8567–81.

7 Food and Nutrition Board, Institute of Medicine.Vitamin E. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington D.C.: National Academy Press; 2000:186-283.

8 Traber MG. Does vitamin E decrease heart attack risk? Summary and implications with respect to dietary recommendations. J Nutr. 2001;131(2):395S-397S.

9 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(17):1380-1386.

10 Meydani SN, Leka LS, Fine BC, et al. Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. JAMA.2004;292(7):828-836.

11 Davi G, Ciabattoni G, Consoli A, et al. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation.1999;99(2):224-229.

12 Davi G, Ciabattoni G, Consoli A, et al. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation.1999;99(2):224-229.

13 Paolisso G, D’Amore A, Giugliano D, Ceriello A, Varricchio M, D’Onofrio F. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and noninsulin- dependent diabetic patients. Am J Clin Nutr.1993;57(5):650-656.

14 Paolisso G, Di Maro G, Galzerano D, et al.Pharmacological doses of vitamin E and insulin action in elderly subjects. Am J Clin Nutr. 1994;59(6):1291-1296.

15 Jain SK, McVie R, Jaramillo JJ, Palmer M, Smith T. Effect of modest vitamin E supplementation on blood glycated hemoglobin and triglyceride levels and red cell indices in type I diabetic patients. J Am Coll Nutr.1996;15(5):458-461.

16 Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med. 1997;336(17):1216-1222.

17 Fulgoni VL 3rd, Keast DR, Bailey, Dwyer J. Foods, fortificants, and supplements: where do Americans get their nutrients? J Nutr. 2011;141(10):18-47-1854.

18 Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med.1993;328(20):1450-1456.

19 Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med.
1993;328(20):1444-1449.

20 Lee IM, Cook NR, Gaziano JM, 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(1):56-65.

21 Glynn RJ, Ridker PM, Goldhaber SZ, Zee RY, Buring JE. Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: report from the Women’s Health Study. Circulation.
2007;116(13):1497-1503.

22 Azen SP, Qian D, Mack WJ, et al. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation. 1996;94(10):2369-2372.

23 Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet.1996;347(9004):781-786.

24 Sesso HD, Buring JE, Christen WG, 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(18):2123-2133.

25 Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997;349(9067):1715-1720.

26 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(3):154-160.

27 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. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico.Lancet. 1999;354(9177):447-455.

28 Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA.2005;293(11):1338-1347.

29 Roberts LJ 2nd, Oats JA, Linton MF, et al. The relationship between dose of vitamin E and suppression of oxidative stress in humans. Free Radic Biol Med.
2007;43(10):1388-1393.

30 Rasool AH, Rahman AR, Yuen KH, Wong AR.Arterial compliance and vitamin E blood levels with a self emulsifying preparation of tocotrienol rich vitamin E. Arch Pharm Res. 2008 Sep;31(9):1212-7.

31 Tan DT, Khor HT, Low WH, Ali A, Gapor A. Effect of a palm-oil-vitamin E concentrate on the serum and lipoprotein lipids in humans. Am J Clin Nutr. 1991 Apr;53(4 Suppl):1027S-1030S.

32 Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90(6):440-446.

33 Alkhenizan A, Hafez K. The role of vitamin E in the prevention of cancer: a meta-analysis of randomized controlled trials. Ann Saudi Med. 2007;27(6):409-414.

34 Scott M. Lippman SM, Klein EA, Goodman PJ, et al.Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. 2009;301(1):39-51. Published online December 9, 2008. Doi:10. 1001/jama.2008.864.

35 Klein IM, Thompson Jr CM, Tangen JJ, et al.Vitamin E and the Risk of Prostate Cancer: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA.2011; 306(14):1549-1556.

36 Authors not listed.The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med.1994;330:1029–35.

37 Wright ME, Mayne ST, Stolzenberg-Solomon RZ, et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. Am J Epidemiol. 2004;160(1):68-76

38 JAMA Study Links Vitamin E, Prostate Cancer.Natural Product Insider. Retreived October 12, 2011 from www.naturalproductsinsider.com.

Gene Bruno, MS, MHS, the dean of academics for Huntington College of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications.

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