Vitamin E

The term vitamin E describes a family of eight antioxidants, four tocopherols, alpha-, beta-, gamma- and delta-, and four tocotrienols (also alpha-, beta-, gamma- and delta-). Alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore, the form of vitamin E found in the largest quantities in the blood and tissue. Because alpha-tocopherol is the form of vitamin E that appears to have the greatest nutritional significance, it will be the primary topic of the following discussion. It is also the only form that meets the latest Recommended Dietary Allowance (RDA) for vitamin E.

Function

Alpha-tocopherol

The main function of alpha-tocopherol in humans appears to be that of an antioxidant.  Free radicals are formed primarily in the body during normal metabolism and also upon exposure to environmental factors such as cigarette smoke or pollutants. Fats, which are an integral part of all cell membranes, are vulnerable to destruction through oxidation by free radicals.  The fat-soluble vitamin, alpha-tocopherol, is uniquely suited to intercepting free radicals and preventing a chain reaction of lipid destruction.  Aside from maintaining the integrity of cell membranes throughout the body, alpha-tocopherol also protects the fats in low density lipoproteins (LDLs) from oxidation.  Lipoproteins are particles composed of lipids and proteins, which are able to transport fats through the blood stream.  LDL transport cholesterol from the liver to the tissues of the body.  Oxidized LDLs have been implicated in the development of cardiovascular diseases (See Disease Prevention).  When a molecule of alpha-tocopherol neutralizes a free radical, it is altered in such a way that its antioxidant capacity is lost.  However, other antioxidants, such as vitamin C, are capable of regenerating the antioxidant capacity of alpha-tocopherol.

Several other functions of alpha-tocopherol have been identified, which likely are not related to its antioxidant capacity. Alpha-tocopherol is known to inhibit the actvity of protein kinase C, an important cell signaling molecule, as well as to affect the expression and activity of immune and inflammatory cells. Additionally, alpha-tocopherol has been shown to inhibit platelet aggregation and to enhance vasodilation.

Gamma-tocopherol

The function of gamma-tocopherol in humans is presently unclear. Although the most common form of vitamin E in the American diet is gamma-tocopherol (see Food Sources), blood levels of gamma-tocopherol are generally ten times lower than those of alpha-tocopherol.  This phenomenon appears due to the action of the alpha-tocopherol transfer protein (a-TTP) in the liver, which preferentially incorporates alpha-tocopherol into lipoproteins that are circulated in the blood and ultimately deliver alpha-tocopherol to different tissues in the body. See the Linus Pauling Institute Newsletter for more information about a-TTP and vitamin E adequacy. Because gamma-tocopherol is initially absorbed in the same manner as alpha-tocopherol, small amounts are detectable in blood and tissue.  Products of the metabolism of tocopherols, known as metabolites, can be detected in the urine. More gamma-tocopherol metabolites are excreted in the urine than alpha-tocopherol metabolites, suggesting less gamma-tocopherol is needed for use by the body. Limited research in the test tube and in animals indicates that gamma-tocopherol or its metabolites may play a role in the protection of the body from damage by free radicals, but these effects have not been convincingly demonstrated in humans. Recently, concern has been raised regarding the fact that taking alpha-tocopherol supplements lowers gamma-tocopherol levels in the blood.  However, no adverse effects of moderate alpha-tocopherol supplementation have been demonstrated, while many benefits have been documented (see Disease Prevention and Disease Treatment). In one recent prospective study, increased plasma gamma-tocopherol levels were associated with a significantly reduced risk of developing prostate cancer, while significant protective associations for increased levels of plasma alpha-tocopherol and toenail selenium were found only when gamma-tocopherol levels were also high. These limited findings, in addition to the fact that taking alpha-tocopherol supplements lower gamma-tocopherol levels in the blood, have led some scientists to call for additional research on the effects of dietary and supplemental gamma-tocopherol on health. For more information see the article, Which Form of Vitamin E, Alpha- or Gamma-Tocopherol, is Better? in the Linus Pauling Institute Research Report.

Deficiency

Vitamin E deficiency has been observed in individuals with severe malnutrition, genetic defects affecting the alpha-tocopherol transfer protein, and fat malabsorption syndromes.  For example, children with cystic fibrosis or cholestatic liver disease, who have an impaired capacity to absorb dietary fat and therefore fat-soluble vitamins, may develop symptomatic vitamin E deficiency.  Severe vitamin E deficiency results mainly in neurological symptoms, including impaired balance and coordination (ataxia), injury to the sensory nerves (peripheral neuropathy), muscle weakness (myopathy), and damage to the retina of the eye (pigmented retinopathy). For this reason, people who develop peripheral neuropathy, ataxia or retinitis pigmentosa should be screened for vitamin E deficiency.  The developing nervous system appears to be especially vulnerable to vitamin E deficiency because children with severe vitamin E deficiency from birth, who are not treated with vitamin E, develop neurological symptoms rapidly. In contrast, individuals who develop malabsorption of vitamin E in adulthood may not develop neurological symptoms for 10-20 years.  It should be noted that symptomatic vitamin E deficiency in healthy individuals who consume diets low in vitamin E has never been reported.

Although true vitamin E deficiency is rare, suboptimal intake of vitamin E is relatively common in the U.S. The National Health and Nutrition Examination Survey III (NHANES III) examined the dietary intake and blood levels of alpha-tocopherol in 16,295 multi-ethnic adults over the age of 18. Twenty seven % of white participants, 41% of African Americans, 28% of Mexican Americans and 32% of the other participants were found to have blood levels of alpha-tocopherol less than 20 micromoles/liter, a value chosen because the literature suggests an increased risk for cardiovascular disease below this level.

Disease Prevention

Cardiovascular disease

The results of at least five large observational studies suggest that increased vitamin E consumption is associated with decreased risk of myocardial infarction (heart attack) or death from heart disease in both men and women.  Each study was a prospective study which measured vitamin E consumption in presumably healthy people and followed them for a number of years to determine how many of them were diagnosed with, or died as a result of heart disease.  In two of the studies, those individuals who consumed more than 7 mg of alpha-tocopherol in food were only approximately 35% as likely to die from heart disease as those who consumed less than 3-5 mg of alpha-tocopherol.  Two other large studies found a significant reduction in the risk of heart disease only in those women and men who consumed alpha-tocopherol supplements of at least 100 IU (67 mg of RRR-alpha-tocopherol) daily. More recently, several studies have observed plasma or red blood cell levels of alpha-tocopherol to be inversely associated with the presence or severity of carotid atherosclerosis detected using ultrasonography. In contrast, intervention studies with vitamin E supplements in patients with heart disease have not shown vitamin E to be effective in preventing heart attacks or death (see Disease Treatment).

Cataracts

Cataracts appear to be formed by the oxidation of proteins in the lens of the eye, which may be prevented by antioxidants such as alpha-tocopherol.  To date, ten observational studies have examined the association between vitamin E consumption and the incidence and severity of cataracts. Of these studies, five found increased vitamin E intake to be associated with protection from cataracts, while five reported no association. A recent intervention trial of a daily antioxidant supplement containing 500 mg of vitamin C, 400 IU of vitamin E, and 15 mg of beta-carotene in 4,629 men and women found that the antioxidant supplement was no different than a placebo in its effects on the development and progression of age-related cataracts over a 7-year period. Another intervention trial found that a daily supplement of 50 mg of synthetic alpha-tocopherol daily (equivalent to 25 mg of RRR- alpha-tocopherol) did not alter the incidence of cataract surgery in male smokers. Presently, the relationship between vitamin E intake and the development of cataracts requires further clarification before specific recommendations can be made.

Immune Function

Alpha-tocopherol has been shown to enhance specific aspects of the immune response that appear to decline as people age.  For example, 200 mg of synthetic alpha-tocopherol (equivalent to 100 mg of RRR-alpha-tocopherol) daily for several months increased the formation of antibodies in response to hepatitis B vaccine and tetanus vaccine in elderly adults. Whether alpha-tocopherol associated enhancements in the immune response actually translate to increased resistance to infections such as the flu (influenza virus) in older adults remains to be determined.

Cancer

Many types of cancer are thought to result from oxidative damage to DNA caused by free radicals.  The ability of alpha-tocopherol to neutralize free radicals has made it the subject of a number of cancer prevention studies.  However, several large prospective studies have failed to find significant associations between alpha-tocopherol intake and the incidence of lung cancer or breast cancer.  A placebo-controlled intervention study designed to look at the effect of alpha-tocopherol supplementation on lung cancer in smokers found a 34% reduction in the incidence of prostate cancer in smokers given supplements of 50 mg of synthetic alpha-tocopherol (equivalent to 25 mg of RRR-alpha-tocopherol) daily.  Because of these findings a large randomized, placebo-controlled intervention study is currently being conducted to examine the effect of alpha-tocopherol supplementation on prostate cancer risk.

Disease Treatment

Cardiovascular disease

Observational studies have suggested that supplemental alpha-tocopherol might have value in the treatment of cardiovascular disease.  For example, a small observational study of men who had previously undergone a coronary artery bypass surgery found a reduction in the progression of coronary artery atherosclerosis by angiography in those men who took at least 100 IU of alpha-tocopherol (67 mg of RRR-alpha-tocopherol) daily.  A randomized, placebo-controlled intervention trial in Great Britain (the CHAOS study) found that supplementing heart diseasepatients with either 400 or 800 IU  of synthetic alpha-tocopherol (equivalent to 268 or 536 mg of RRR-alpha-tocopherol) for an average of 18 months resulted in a dramatic 77% reduction in nonfatal heart attacks.  However, total deaths from heart disease were not significantly reduced. Chronic renal dialysis patients are at much greater risk of dying from cardiovascular disease than the general population, and there is evidence that they are also under increased oxidative stress. Supplementation of renal dialysis patients with 800 IU of natural alpha-tocopherol (536 mg of RRR-alpha-tocopherol) for an average of 1.4 years resulted in a significantly reduced risk of heart attack compared to placebo. In contrast, three other intervention trials failed to find significant risk reductions with alpha-tocopherol supplementation.  One study, which was designed mainly to examine cancer prevention, found that 50 mg of synthetic alpha-tocopherol daily (equivalent to 25 mg of RRR-alpha-tocopherol) resulted in a non-significant decrease in nonfatal heart attacks in those participants who had had previous heart attacks. However, two other large trials found that daily supplements of 400 IU of natural alpha-tocopherol (equivalent to 268 mg RRR-alpha-tocopherol) and 300 mg of synthetic alpha-tocopherol (equivalent to 150 mg of RRR-alpha-tocopherol) in individuals with evidence of cardiovascular disease (previous heart attack, stroke, or evidence of vascular disease) did not significantly change the risk of a subsequent heart attack or stroke. The results of several other large intervention trials, which are presently in progress may clarify the role of alpha-tocopherol supplementation in the treatment of cardiovascular disease.

A more thorough discussion of the complex issues involved in analyzing the results of recent trials of vitamin E in heart disease can be found in the Fall/Winter 1999 issue of the Linus Pauling Institute Newsletter: Fish Oil, Vitamin E, Genes, Diet, and CHAOS. For a discussion of some of the limitations of the HOPE study see the article, Vitamin E: Hope or Hopeless, in the Spring/Summer 2000 issue of the Linus Pauling Institute Newsletter.

Diabetes mellitus

Alpha-tocopherol supplementation of individuals with diabetes has been proposed because diabetes appears to increase oxidative stress and because cardiovascular complications (heart attack and stroke) are among the leading causes of death in diabetics.  A recent study found a biochemical marker of oxidative stress to be elevated in diabetic individuals.  Supplementation with 600 mg of synthetic alpha-tocopherol daily (equivalent to 300 mg of RRR-alpha-tocopherol) for 14 days resulted in a reduction in the oxidative stress marker.  Studies of the effect of alpha-tocopherol supplementation on blood glucose control have been contradictory.  One study reported improved control of blood glucose levels with supplementation of only 100 IU of synthetic alpha-tocopherol daily (equivalent to 45 mg RRR-alpha-tocopherol), while studies using 900 to 1,600 IU of synthetic alpha-tocopherol daily (equivalent to 405 to 720 mg RRR-alpha-tocopherol) found either minimal or no improvement, respectively. Although there is reason to suspect that alpha-tocopherol supplementation may be beneficial for individuals with diabetes, evidence from well-controlled clinical trials is lacking.

Dementia (impaired cognitive function)

The brain is particularly vulnerable to oxidative stress, which is thought to play a role in the pathology of neurodegenerative diseases, such as Alzheimer's disease. In a large placebo-controlled intervention trial, supplementation of individuals who had moderate neurological impairment with 2,000 IU of synthetic alpha-tocopherol daily for two years (equivalent to 900 mg/day of RRR-alpha-tocopherol) resulted in a significant slowing of the progression of Alzheimer's dementia. After Alzheimer's disease, vascular dementia (dementia resulting from strokes) is the most common cause of dementia in the U.S. A case-control study examining risk factors for vascular dementia in elderly Japanese-American men found that supplemental vitamin E and vitamin C intake was associated with a significantly decreased risk of vascular and other types of dementia, but not Alzheimer's dementia. Among those without dementia, vitamin E supplement use was associated with better scores on cognitive tests. Although these findings are promising, further studies are required to determine the role of alpha-tocopherol supplementation in the treatment of Alzheimer's disease and other types of dementia.

Cancer

Cancer cells proliferate rapidly and are resistant to death by apoptosis (programmed cell death). Cell culture studies indicate that the vitamin E ester, alpha-tocopheryl succinate, can inhibit proliferation and induce apoptosis in a number of cancer cell lines. The ester form, alpha-tocopheryl succinate, not alpha-tocopherol, is required to effectively inhibit proliferation or induce cancer cell death. Although the mechanisms for the effects of alpha-tocohpheryl succinate on cancer cells are not yet clear, the fact that the ester form has no antioxidant activity argues against an antioxidant mechanism. Limited data from animal models of cancer indicate that alpha-tocopheryl succinate administered by injection may inhibit tumor growth, but much more research is required to determine whether alpha-tocopheryl succinate will be a useful adjunct to cancer therapy in humans. Certainly, administration by injection will be necessary for any benefit, because alpha-tocopheryl succinate is cleaved to form alpha-tocopherol in the intestine when taken orally. There is currently no evidence in humans that taking oral alpha-tocopheryl succinate supplements delivers alpha-tocopheryl succinate to tissues.

Safety

Toxicity

Few side effects have been noted in adults taking supplements of less than 2,000 mg of alpha-tocopherol daily (RRR- or all-rac-alpha-tocopherol).  However, most studies of toxicity or side effects of alpha-tocopherol supplementation have lasted only a few weeks to a few months, and side effects occurring as a result of long-term alpha-tocopherol supplementation have not been adequately studied.  The most worrisome possibility is that of impaired blood clotting resulting in an increased likelihood of hemorrhage in some individuals. The Food and Nutrition Board of the Institute of Medicine established a tolerable upper intake level (UL) for alpha-tocopherol supplements, based on the prevention of hemorrhage (see table below).  The Board felt that 1,000 mg/day of alpha-tocopherol of any form (equivalent to 1,500 IU/day of RRR-alpha-tocopherol or 1,100 IU/day of all-rac-alpha-tocopherol) would be the highest dose unlikely to result in hemorrhage in almost all adults.  Although only certain isomers of alpha-tocopherol are retained in the circulation, all forms are absorbed, and the liver must break them down and eliminate them. The rationale that any form of alpha-tocopherol (natural or synthetic) that can be absorbed could potentially have adverse effects is the basis for a UL that refers to all forms of alpha-tocopherol.

Some physicians recommend that high-dose vitamin E supplementation be discontinued one month before elective surgery to decrease the risk of hemorrhage. Premature infants appear to be especially vulnerable to adverse effects of alpha-tocopherol supplementation, which should be used only under controlled supervision by a pediatrician. Supplementation with 400 IU/day of vitamin E has been found to accelerate the progression of retinitis pigmentosa that is not associated with vitamin E deficiency.

Vitamin E Supplementation and All-Cause Mortality

A recent meta-analysis that combined the results of 19 clinical trials of vitamin E supplementation for various diseases, including heart disease, end-stage renal failure and Alzheimer's disease, reported that adults who took supplements of 400 IU/day or more were 6% more likely to die from any cause than those who did not take vitamin E supplements. However, further breakdown of the risk by vitamin E dose and adjustment for other vitamin and mineral supplements revealed that the increased risk of death was statistically significant only at a dose of 2,000 IU/day, which is higher than the UL for adults. Furthermore, three other meta-analyses that combined the results of randomized controlled trials designed to evaluate the efficacy of vitamin E supplementation for the prevention or treatment of cardiovascular disease found no evidence that vitamin E supplementation up to 800 IU/day significantly increased or decreased cardiovascular disease mortality or all-cause mortality. At present, there is no convincing evidence that vitamin E supplementation up to 800 IU/day increases the risk of death from cardiovascular disease or other causes.

Drug interactions

Individuals on anticoagulant therapy (blood thinners) or individuals who are vitamin K deficient should not take alpha-tocopherol supplements without close medical supervision because of the increased risk of hemorrhage. A number of medications may decrease the absorption of vitamin E, including cholestyramine, colestipol, isoniazid, mineral oil, orlistat, sucralfate, and the fat substitute, olestra. Anticonvulsant drugs such as phenobarbitol, phenytoin, or carbamazepine may decrease plasma levels of vitamin E.

Antioxidants and HMG-CoA reductase inhibitors (statins)

A 3-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low HDL levels found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, such as myocardial infarction and stroke. Surprisingly, when an antioxidant combination (1000 mg vitamin C, 800 IU alpha-tocopherol, 100 mcg of selenium, and 25 mg beta-carotene daily) was taken with the simvastatin-niacin combination, the protective effects were diminished. However, in a much larger randomized controlled trial of simvastatin and an antioxidant combination (600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily) in more than 20,000 men and women with coronary artery disease or diabetes, the antioxidant combination did not adversely affect the cardioprotective effects of simvastatin therapy over a 5-year period. These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplementation and cholesterol-lowering agents, such as HMG-CoA reductase inhibitors (statins).

Linus Pauling Institute Recommendation

Scientists at the Linus Pauling Institute feel there exists credible evidence that taking a supplement of 200 IU of natural source d-alpha-tocopherol (RRR-alpha-tocopherol) daily with a meal may help protect adults from chronic diseases like heart disease, stroke, neurodegenerative diseases, and some types of cancer. The amount of alpha-tocopherol required for such beneficial effects appears to be much greater than that which could be achieved through diet alone (see Sources). Since supplements containing 200 IU of d-alpha-tocopherol are often as expensive as supplements containing 400 IU of d-alpha-tocopherol, a less expensive alternative may be to take 400 IU of d-alpha-tocopherol every other day. Alpha-tocopherol supplements are unlikely to be absorbed unless taken with food.

Older adults (65 years and older)

The Linus Pauling Institute's recommendation of a supplement providing 200 IU of natural source d-alpha-tocopherol daily (or 400 IU of d-alpha-tocopherol every other day) with a meal is also appropriate for generally healthy older adults.

Reference: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminE/