When choosing a vitamin E supplement, consumers have a bewildering number of options.
Alpha-tocopherol or gamma-tocopherol? Natural or synthetic? What about capsules containing mixed tocopherols? Here?s a look at some of the latest research on this essential nutrient and which forms are best for helping consumers achieve their desired health benefits.
The term vitamin E refers to a group of eight naturally occurring compounds, all with different potencies: alpha-, beta-, gamma- and delta-tocopherol and alpha-, beta-, gamma- and delta-tocotrienol. Within each of these eight compounds are myriad stereoisomers (compounds with the same atoms and bond structure but a different three-dimensional arrangement of atoms).1 Alpha-tocopherol is composed of eight stereoisomers (RRR, RSR, RRS, RSS, SRR, SSR, SRS and SSS).
Synthetic alpha-tocopherol, called all rac-alpha-tocopherol or dl-alpha-tocopherol, consists of all eight stereoisomers in equal amounts, though only the four starting with ?R? are considered biologically active. Synthetic vitamin E can be found in both supplements and fortified foods. In nature, alpha-tocopherol occurs only as RRR-alpha-tocopherol (also called d-alpha-tocopherol). RRR-alpha-tocopherol can also be manufactured from vegetable oil and sold in supplement form (typically labeled as ?natural?). By weight, natural vitamin E (RRR-alpha-tocopherol) is twice as biologically active as the synthetic all rac-tocopherol, which contains four inactive stereoisomers. A ?cocktail? supplement of d-alpha tocopherol with beta, gamma and delta is typically labeled as ?mixed natural tocopherols.?1
Aside from having distinct chemical names, the various forms of vitamin E are associated with different health benefits. The human body appears to differentiate among, and have various uses for, each chemical compound. While the majority of research has focused on alpha-tocopherol, scientific evidence supporting the benefits of gamma-tocopherol is beginning to emerge.
Effects of alpha-tocopherol
For years, alpha-tocopherol has been the showboat among its chemical cousins. It is the main form of vitamin E found in serum and tissues within the human body,2 the most researched in its family and the most chemically and biologically active form.3 With such an impressive resume, it is no wonder that all forms of vitamin E are measured in alpha-tocopherol equivalents.
As an antioxidant, one of alpha-tocopherol?s main functions is to protect cell membranes from the damaging effects of free radicals (harmful oxygen byproducts created during metabolism and upon exposure to pollution, cigarette smoke and other environmental contaminants).4 Free radicals damage DNA, cells and tissues, thereby contributing to the development of degenerative diseases and other health problems.
Alpha-tocopherol and heart disease
Numerous studies in both men and women support an association between alpha-tocopherol intake and a decrease in atherosclerosis risk factors. Studies show that alpha-tocopherol decreases oxidation of low-density lipoprotein,5,6,7,8 inhibits platelet aggregation,9,10 increases vasodilation11,12 and decreases inflammation. Others studies have demonstrated a relationship between endothelial cell functioning and plasma levels of alpha-tocopherol.12,13 However, not all randomized controlled trials or epidemiological studies have shown an association between alpha-tocopherol intake and the prevention of atherosclerosis or cardiac events.
In a double-blind, randomized clinical trial examining the effect of supplementation with all rac-alpha-tocopherol (synthetic vitamin E) on LDL oxidation, 318 healthy men and women (mean age 56.2 years) were given either 267 mg vitamin E or placebo daily and assessed every three months throughout the study. All rac-alpha-tocopherol reduced circulating LDL and decreased the susceptibility of LDL to oxidation compared with placebo. However, vitamin E supplementation was no more effective than placebo in reducing the progression of carotid intima-media thickening (a measurement of the development of atherosclerosis).14
Results of the Women?s Health Study, reported in July 2005 in the Journal of the American Medical Association, suggested that vitamin E decreased some, but not all, cardiovascular risks. For this randomized, controlled trial, 39,876 healthy women (mean age 54.6 years) were placed in one of four groups and given 400 mg all rac-alpha-tocopherol (synthetic vitamin E) or placebo on alternating days, 400 mg all rac-alpha-tocopherol or 100 mg aspirin on alternating days, placebo or 100 mg aspirin on alternating days, or placebo only, and studied for an average of 10.1 years. Results showed a nonsignificant 7 percent reduction in risk for a major cardiovascular event in the vitamin E-supplemented groups and a significant (24 percent) decrease in cardiovascular death in the vitamin E-supplemented groups. However, no differences were noted between groups in risks for heart attack, ischemic or hemorrhagic stroke or cancer.15
One small study compared the effects of natural and synthetic alpha-tocopherol in a variety of doses in preventing LDL oxidation. In this randomized, placebo-controlled study of 79 healthy men and women, subjects were assigned to take placebo or either all rac-alpha-tocopherol or RRR alpha-tocopherol over the course of eight weeks, in doses of 67, 133, 267 or 533 mg daily. There were no significant differences in time to LDL oxidation among the different dosage regimens, indicating that neither form of vitamin E was superior in preventing LDL oxidation. However, doses above 267 mg/day of either all rac-alpha-tocopherol or RRR alpha-tocopherol did significantly delay time to LDL oxidation.16
Alpha-tocopherol and cancer
Researchers have postulated that alpha-tocopherol may help prevent cancer by decreasing free radical-induced oxidative damage to DNA. Studies in this area have had mixed results, though the majority show little to no benefit with alpha-tocopherol supplementation in reducing risks for several types of cancer.15,17 Serum studies suggest that there might be a relationship between gastrointestinal cancer and serum levels of alpha-tocopherol, but not gamma-tocopherol.18
More promising results have been reported in the area of prostate cancer. Data from the ?2005 Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study? indicated that alpha-tocopherol might play a role in the prevention of prostate cancer. A total of 29,133 male smokers from Finland (average age 57 years) were randomly assigned to receive 50 mg alpha-tocopherol, 20 mg beta-carotene, both agents or placebo daily for five to eight years (median 6.1 years). The group taking alpha-tocopherol had a 32 percent decrease in prostate cancer incidence and a 41 percent decrease in mortality from prostate cancer, compared with the placebo group.19
Researchers delved further into the data from this study to determine if serum concentrations of alpha-tocopherol and gamma-tocopherol might play a role in the development of prostate cancer. They randomly selected 100 prostate cancer cases and matched them to 200 controls. Men with higher circulating levels of both alpha- and gamma-tocopherol had a similarly lower prostate cancer risk, indicating that both tocopherols may be involved in prostate cancer prevention.20
However, in the double-blind, randomized ?Prevention Research Veteran Affairs E-Vitamin Nutrition Trial,? daily doses of 400 mg alpha-tocopherol had no effect on biomarkers associated with prostate cancer risk in 44 men with increased prostate-specific antigen and/or abnormal digital rectal examinations. Researchers concluded that while alpha-tocopherol may still play a role in the reduction of prostate cancer risk, its contribution is not hormone-dependent.21
More clinical trials are needed to establish the relationship between alpha-tocopherol and cancer risk. Epidemiological studies usually look at vitamin E consumed in foods or even supplements, but both are hard to quantify. People often forget what they eat, don?t know how much vitamin E their supplement contains or are unsure if they are taking alpha-tocopherol or mixed tocopherols.
The role of gamma-tocopherol
Gamma-tocopherol is the most prevalent form of vitamin E in the diet, found especially in plant seeds, vegetable oils and nuts.22 However, it has received little research attention, primarily because alpha-tocopherol is the predominant form of vitamin E in blood and tissues and is considered a stronger antioxidant.23
Though gamma-tocopherol is considered a weaker antioxidant than alpha-tocopherol, it appears to be better suited for reducing reactive nitrogen oxide species. RNOSs are associated with inflammation and may be involved in the cause or promotion of cancer and cardiovascular disease.24,25 The ability to affect these inflammatory mediators may help decrease the promotion or initiation of those diseases.25
One interesting fact about vitamin E is that supplementation with alpha-tocopherol decreases plasma and tissue stores of gamma-tocopherol,26,27 whereas high intakes of gamma-tocopherol actually increased both gamma-tocopherol and alpha-tocopherol levels in animal studies.28
Gamma-tocopherol and heart disease
Studies investigating the relationship between gamma-tocopherol and disease are typically either epidemiological in nature or measure serum levels of gamma-tocopherol and disease status. One problem with epidemiological studies is that they rely on food records, which involve inherent bias. They also do not differentiate between gamma- and alpha-tocopherol intake, but instead measure overall dietary vitamin E intake. However, studies on blood levels of tocopherols and coronary heart disease indicate that higher levels of gamma-tocopherol may be an important, modifiable factor.
In an attempt to determine if there is a relationship between plasma antioxidant status and atherogenesis, researchers measured a number of antioxidants, including gamma-tocopherol, in 34 patients with CHD and 40 control subjects. Low levels of gamma-tocopherol (but not alpha-tocopherol) were significantly associated with CHD.29 A cross-sectional study of 210 randomly selected, healthy Swedish men also found that low blood levels of gamma-tocopherol were linked with high CHD mortality rates.30
In one clinical trial that looked at the effect of a mixed tocopherol product on several measures of platelet functioning, 46 subjects received either alpha-tocopherol (100 mg all rac-alpha-tocopherol), mixed tocopherols (100 mg gamma-tocopherol, 40 mg delta-tocopherol and 20 mg alpha-tocopherol) or placebo. Those taking mixed tocopherols over the eight-week study had less platelet aggregation and increased nitric oxide release, compared with those taking alpha-tocopherol.31
Epidemiological studies also point to a potential role for gamma-tocopherol in lowering cardiovascular disease risk. In an epidemiological study examining the association between antioxidant intake and death from stroke in 34,492 postmenopausal women, researchers found that death from stroke was significantly and inversely associated with vitamin E intake from food. This study didn?t measure gamma-tocopherol intake directly, but food sources of vitamin E are more often gamma-tocopherol.32
Gamma-tocopherol and cancer
The role of gamma-tocopherol in cancer prevention is not clear. Some but not all studies have related gamma-tocopherol intake to a decreased incidence of certain cancers. For example, results of cell-culture studies in humans and rats have shown that gamma-tocopherol can inhibit proliferation of prostate,33,34 lung,34 colorectal,33 and colon35,36 cancer cells. Epidemiological studies have shown that dietary vitamin E intake is related to lower rates of breast cancer,37,38,39 but these examine total vitamin E intake and do not look separately at alpha- and gamma-tocopherol. Thus, additional research is needed before any conclusions can be drawn about the potential role of gamma-tocopherol in cancer prevention.
How much and what kind of vitamin E?
Vitamin E deficiency is rare in humans and is typically seen only in those with severe malnutrition, genetic defects or fat malabsorption disorders, such as cystic fibrosis.40
But does the average person get enough vitamin E to prevent disease? Probably not. Intake levels are low, and many people don?t even meet the adult daily reference intake of 15 mg/day.41.
Studies showing health benefits typically start with an intake higher than 200 mg/day. Nutritionists usually recommend obtaining micronutrients from food before turning to supplementation, but in the case of vitamin E, one would have to eat more food than is humanly possible to obtain at least 200 mg/day. Therefore, for those who wish to increase vitamin E intake to potentially therapeutic levels, supplements are the only option.
So what type of supplement is best? The majority of clinical trials have examined alpha-tocopherol intake, with research on gamma-tocopherol and other forms lagging behind. However, food offers a mix of tocopherols and tocotreinols that are thought to act synergistically to exert health benefits.42 Given these synergistic relationships and the results of research to date, a mixed-tocopherol product seems to be the best choice.
Marie Spano, M.S., R.D., is a registered dietitian, food industry consultant and spokeswoman for the International Society of Sports Nutrition.
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34. Qing Jiang, et al. Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. Proc Natl Acad Sci 2004;1(51):17825?30.
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