DK1791 Ch04

4
Efcacy of Vitamin E in Human Health and Disease

Sharon V. Landvik
Vitamin E Research and Information Service, Edina, Minnesota
Anthony T. Diplock
United Medical and Dental Schools, University of London, and Guys Hospital, London, England
Lester Packer
University of Southern California School of Pharmacy, Los Angeles, California
I.
INTRODUCTION
Since the discovery of vitamin E in 1922 by Evans and Bishop, its role in human health has been extensively investigated. Vitamin E refers to a group of eight naturally occurring compounds -, -, -, -tocopherols and tocotrienols. -Tocopherol, especially the naturally occurring d- -tocopherol, has the highest biological activity (1,2). Vitamin E is the major chain-breaking antioxidant in body tissues, and it is considered the rst line of defense against lipid peroxidation, protecting cell membranes at an early stage of free radical attack (3,4). Unchecked by an antioxidant, highly unstable free radicals attack cell constituents, particularly those containing polyunsaturated fatty acids, and can damage both the structure and function of cell membranes. Nucleic acids and electron-dense regions of proteins also come under attack (5,6). There is evidence to implicate free radicals in development of degenerative diseases and conditions (7,8). This chapter discusses vitamin E functions, requirements, and clinical deciency states, and current research ndings on the protective role of vitamin E in preventing or minimizing free radical damage associated with cancer, cardiovascular disease, premature aging, cataracts, air pollution, and strenuous exercise.
II.
FUNCTIONS
Vitamin E is natures most effective lipid-soluble antioxidant, protecting unsaturated fatty acids in cell membranes that are important for membrane function and structure (4,6,9). Increased
Copyright 2002 by Taylor & Francis Group, LLC
vitamin E intake may enhance the immune response. Vitamin E regulates platelet aggregation by inhibiting prostaglandin (thromboxane) production. It also has a role in the regulation of protein kinase C (PKC) activation, mitochondrial function, nucleic acid and protein metabolism, and hormonal production. Vitamin E protects vitamin A from destruction in the body and spares selenium (10,11).
III.
CLINICAL DEFICIENCY STATES
Clinical vitamin E deciency states have been observed in individuals with a chronic malabsorption syndrome, premature infants, and patients receiving total parenteral nutrition (3). Conditions interfering with normal digestion, absorption, or transport of dietary fat have been associated with low serum vitamin E concentrations (12). In patients with malabsorption syndromes, such as celiac disease, biliary atresia, and cystic brosis, serum vitamin E concentrations can be less than 20% of normal. Serum vitamin E levels are often too low to measure in patients with abetalipoproteinemia. Hemolysis and a shortened life span of red blood cells have been reported at vitamin E plasma concentrations below 0.5 mg/dL (11). Severe and chronic vitamin E deciency in patient with fat malabsorption can lead to a progressive neurological syndrome, indicating the importance of vitamin E in optimal development and maintenance of the function and integrity of the nervous system and skeletal muscle (13). Characteristics of the neurological syndrome include progressive neuropathy with absent or altered reexes, limb weakness, ataxia, and sensory loss in the legs and arms. Improvement of neurological function has been documented with appropriate vitamin E therapy; progressive neurological damage may be prevented in children with prolonged cholestatic disease by early initiation of vitamin E therapy (14,15). Low birth weight premature infants are vulnerable to vitamin E deciency owing to inadequate body stores, impaired absorption, and reduced transport capacity in the blood because of low levels of low-density lipoproteins (LDL) at birth (16). Plasma vitamin E levels are also frequently low in patients on a total parenteral nutrition regime. Parenteral lipid emulsions contain primarily - and -tocopherol homologues, which are much less biologically active forms than -tocopherol. Plasma vitamin E levels cannot be maintained with high intakes of - and -isomers; thus -tocopherol supplementation is required for patients receiving total parenteral nutrition (17,18).
IV.
REQUIREMENTS
Depending on dietary and lifestyle habits or tissue composition from previous intake patterns, vitamin E requirements of normal adults may vary at least vefold. Even greater variability in vitamin E requirements has been demonstrated in animals with a high polyunsaturated fatty acid intake (3) (Table 1). Serum or plasma vitamin E concentrations are usually considered to be the most convenient and useful measurement of vitamin E status. It is generally accepted that individuals with plasma vitamin E levels of less than 0.5 mg/dL are vitamin E-decient (11). Daily dietary vitamin E intakes of 1030 mg in healthy adults will maintain serum vitamin E concentrations in the normal range (11). In a study of well-nourished adults, mean plasma vitamin E concentrations were 1.06 mg/dL at baseline and doubled to 2.03 mg/dL after daily supplementation with 800 IU vitamin E for 8 weeks (19). Determination of vitamin E requirements must consider whether requirements should reect vitamin E intakes that are adequate to prevent deciency symptoms and allow normal physiological function, or the higher intakes necessary to prevent oxidative damage (3,20).
Table 1 Relation of Vitamin E Requirement with Calculated Relative Susceptibility of Muscle Tissue Lipid to Peroxidation in Rats Fed Diets of Varying Fatty Acid Composition Number of double bonds 1 2 3 4 5 6 Relative oxidative rate 0.025 1 2 4 6 8 Vitamin E requirementa 0.3 2 3 4 5 6
a Proportional to number of double bonds in muscle
lipids, except for monounsaturated fatty acids.
A study of healthy adults showed that daily supplementation of 1000 IU vitamin E for 10 days signicantly decreased breath pentane excretion. Based on these results, it may be inferred that there are undesirably high levels of lipid peroxidation in the body, which can be reduced by vitamin E supplementation (21). These results may be signicant in light of research evidence showing involvement of free radical damage in normal body processes and certain diseases and the role of vitamin E in controlling or preventing lipid peroxidation (4,21).
V.
CANCER
Cancer is believed to be the result of external factors combined with a hereditary disposition to cancer. Most human cancers are considered to be environmentally induced, based on lifestyle patterns, including diet. Free radicals frequently have a role in the process of cancer initiation and promotion. From cell culture and animal studies, it appears that vitamin E and other antioxidants may alter cancer incidence and growth through their action as anticarcinogens, quenching free radicals or reacting with their products, although this is a considerable oversimplication. Although studies do not provide conclusive documentation and a signicant effect of vitamin E is not seen in all experimental models, the majority of studies show a protective effect of vitamin E relative to cancer risk in some sites (2234). Although controlled human studies on the antioxidants and cancer are limited, most available epidemiological evidence suggests that vitamin E and other antioxidants decrease the incidence of certain cancers (Table 2). However, because the range of dietary vitamin E intake within a population may be quite narrow, a protective effect of vitamin E may not be fully demonstrated in all epidemiological studies evaluating serum vitamin E levels and cancer risk (35). An inverse correlation between serum antioxidant levels and subsequent cancer risk was demonstrated in several epidemiological studies in Finland (3538). In a mortality follow-up study in Switzerland, low blood levels of -carotene, vitamin C, and vitamin E were associated with increased risk for certain types of cancer (39). In additional follow-up of the same study, low plasma vitamin E levels were associated with signicantly increased risk for prostate cancer mortality in smokers after exclusion of mortality during the rst 2 years of follow-up (40). Low plasma concentrations of vitamin C and E were associated with an increased risk for lung cancer (41).
Table 2 Human Epidemiological Studies of Vitamin E and Other Antioxidants and Subsequent Cancer Risk Number of subjects with cancer 453 males 51 150
Cancer site All sites All sites Upper gastrointestinal tract Colorectal Reproductive organs Stomach Colon All sites
Country Finland Finland Finland
Findings 0.7 adjusted relative risk of cancer in two highest quintiles of blood vitamin E levels 11.4-fold adjusted relative risk of fatal cancer with low blood vitamin E and selenium levels Relative cancer risk of 2.2 in the three lowest quintiles of serum vitamin E and 3.3 in the lowest quintile of serum selenium No inverse association between serum vitamin E and selenium levels and colorectal cancer risk 1.5-fold higher cancer risk with serum vitamin E levels in the lowest quintile, tenfold higher selenium and vitamin E levels Blood levels of -carotene, vitamin C, and vitamin E were lower in cancer cases than in controls Vitamin E blood levels were lower in cancer cases compared with controls Low blood vitamin E levels associated with increased risk for prostate cancer mortality in smokers; no association between plasma - and -carotene levels and prostate cancer mortality Low vitamin C and vitamin E plasma levels associated with increased lung cancer risk No relation between blood antioxidant levels and subsequent cancer risk 3.4-fold relative risk of lung cancer with serum -carotene levels in the lowest quintile No association between serum vitamin A or E levels and cancer risk Serum -carotene and vitamin E had a protective association with lung cancer
Ref. 35 36 37
Finland Switzerland
313 females 129 males
38 39
Switzerland
290 males
40
41 42 43
All sites Lung Bladder, gastrointestinal tract Nine primary sites
United States United States
111 284 males
United States
436
44
All sites
England
271 males
Breast All sites Lung Lung Lung Lung
England India United States United States Japan Finland
39 females 101 99 59 37 117 males
Lung Lung Lung Lung Cervix Cervix Cervix Ovaries
United Kingdom United States Uruguay United States United States United States United States United States
171 328 541 413 nonsmokers 10 females 189 females 27 females 35 females
Serum vitamin E levels were signicantly lower in subjects diagnosed with cancer within 1 year after blood collection, but not in other cancer subjects Five times greater cancer risk for women with vitamin E blood levels in the lowest fth than in the highest fth Plasma levels of vitamins A, C, and E and -carotene were signicantly lower in cancer patients than in the controls 2.5 times higher cancer risk with serum vitamin E levels in the lowest quintile than in the highest quintile Serum vitamin E and carotenoid levels were signicantly lower in cancer patients than in controls Mean blood vitamin E and selenium levels were signicantly lower in cancer patients than in controls Adjusted risk of cancer in nonsmokers in the lowest tertile of intake compared with the highest tertile was 2.5 for carotenoids and 3.1 for vitamins C and E Serum -carotene, vitamin A, and vitamin E levels were lower in cancer patients than in controls Inverse correlation between upper lobe location of cancer and intake of vitamin E and yelloworange vegetables Cancer risk was 57% lower in the highest quintile of total carotenoid intake and 50% lower in the highest quintile of vitamin E intake -Carotene intake was associated with a signicant reduction in cancer risk; vitamin E supplementation was also protective against cancer Blood -carotene and vitamin E levels were signicantly lower in cancer cases than in controls High vitamin C and vitamin E intake were associated with a signicantly reduced risk of cancer Plasma carotenoid and -tocophenol levels lower in cancer cases No association between serum carotenoid and vitamin E levels and cancer risk
45
46 47 48 49 50 51
52 53 54 55 56 57 58 59
(continued )
Table 2 (Continued ) Number of subjects with cancer 105 females 2569 females 297 females 190 1103 24 86 59 females 1016
Cancer site Breast Breast Breast Mouth and pharynx Mouth and pharynx Oral cavity Oral cavity, pharynx, larynx Upper gastrointestinal tract Stomach
Country United States Italy United States United States United States India The Netherlands United States Italy
Findings Inverse association between serum lycopene levels, but not other antioxidants and cancer risk Inverse association between dietary -carotene and vitamin E intake and cancer risk Cancer risk in highest quartile of intake was 45% lower for vitamin E and -carotene, and 53% lower for lutein and zeaxanthin Lower cancer risk was associated with increased intake of ber, carotene, and vitamins C and E in males and of vitamin C and ber in women Use of vitamin E supplements was associated with a signicantly reduced risk of cancer Plasma vitamin C and vitamin E levels lower in cancer cases Serum levels of vitamins A and E lower in patients with a second primary tumor Lower cancer risk associated with higher intake of carotene and vitamins C and E Fivefold difference in cancer risk between high vitamins C and E intake and low protein and nitrite intake and low vitamins C and E intake and high protein and nitrite intake 68% lower relative risk of cancer for subjects in the highest quintile of total vitamin E intake compared with the lowest quintile Serum levels of vitamin C, vitamin E, and -carotene lower in cancer cases Cancer risk was 33% lower for vitamin E and 42% lower for -carotene in the highest quartile of intakes compared with the lowest quartile Serum vitamin E levels lower in cancer cases 60, 40, and 50% lower cancer risk with high intakes of vitamin C, vitamin E, and fruits and vegetables, respectively
Ref. 60 61 62 63 64 65 66 67 68
Colon Stomach Thyroid Leukemia, lymphoma Prostate
United States Korea Italy India Uruguay
212 59 399 NA 175 males
69 70 71 72 73
In a follow-up of a blood pressure risk study in United States, it was concluded that there was no association between blood antioxidant concentrations and subsequent cancer risk, although blood vitamin E levels were somewhat lower in subjects who later developed cancer, but the vitamin E levels seemed to relate to blood cholesterol levels (42). In a study of men of Japanese ancestry in Hawaii, there was a signicant association between serum -carotene concentrations and subsequent lung cancer risk, but not between serum vitamin A or vitamin E concentrations and subsequent risk of lung, bladder, or gastrointestinal cancers (43). Serum -carotene and vitamin E levels showed a protective association with lung cancer in another study in The United States (44). In the two studies in England, men who had a diagnosis of cancer within 1 year after blood collection had signicantly lower mean serum vitamin E levels than controls, and women with low plasma vitamin E concentrations had a signicantly increased risk of breast cancer (45,46). In a casecontrol study in India of patients with cancer at various sites, plasma levels of vitamin A and E and -carotene were signicantly lower in the cancer patients (47). Blood vitamin E levels were signicantly lower in subjects who subsequently developed lung cancer than in controls in a study in the United States (48). Results of another U. S. study showed that newly diagnosed lung cancer patients had signicantly lower average serum levels of vitamin E and carotenoids than controls (49). Mean blood vitamin E and selenium concentrations were also signicantly lower in a group of patients in Japan with lung cancer than in controls (50). Using dietary intake data based on dietary history interviews in a study in Finland, the age-adjusted relative risk of lung cancer in the lowest tertile of intake compared with the highest tertile was 2.5 for carotenoids and 3.1 for vitamin C and vitamin E (51). In a casecontrol study in United Kingdom, serum -carotene, vitamin A, and vitamin E levels were lower in lung cancer patients than in controls (52). A U. S. study that examined the association between diet and tumor location in patients with lung cancer showed a strong inverse correlation between upper lobe location of cancer and intake of vitamin E and yelloworange vegetables (53). Results of a study in Uruguay showed a 57 and 50% decrease in lung cancer risk with intakes in the highest quartile versus the lowest quartile for total carotenoids and vitamin E, respectively (54). In a study of nonsmokers in the United States, dietary -carotene intake was associated with a signicant reduction in lung cancer risk, and use of vitamin E supplements was also protective against lung cancer (55). There was a signicant reduction in average plasma vitamin E and -carotene levels in women with cervical dysplasia or cancer compared with controls in a U.S. study (56). In a study of the relation of diet to risk of invasive cervical cancer, a high dietary intake of vitamins C and E was associated with a signicantly lower risk of cervical cancer. Use of vitamin A and vitamin E supplements was associated with a slight decrease in cervical cancer risk (57). Plasma levels of carotenoids and -tocopherol, but not -tocopherol, were lower in patients with cervical cancer than in patients with cervical precancer or noncancerous diseases in a U. S. study (58). Serum carotenoid and vitamin E levels were not associated with cancer risk in a U. S. study of patients with ovarian cancer (59). In another U. S. study, serum lycopene levels were inversely associated with breast cancer risk. There was no evidence for a protective effect for vitamin E, - and -carotene, vitamin A, or selenium (60). However, there was a signicant inverse association between dietary vitamin E and -carotene intake and breast cancer risk in a study in Italy (61). A U. S. study of premenopausal women demonstrated a 45% lower breast cancer risk for women in the highest quartile of vitamin E intake compared with those in the lowest quartile. Breast cancer risk was 33% lower for -carotene, 54% lower for -carotene and 53% lower for lutein plus zeaxanthin in the highest quartile of intake compared with the lowest quartile (62).
A multicenter study evaluated the association between diet and incidence of oral and pharyngeal cancer among African Americans. A lower risk of oral and pharyngeal cancer was associated with an increased intake of ber, carotene, and vitamins C and E in men and of vitamin C and ber in women (63). In another study in the United States, individuals who took vitamin E supplements had a signicantly reduced risk of oral and pharyngeal cancer (64). Plasma vitamin C and vitamin E concentrations were signicantly lower in patients with oral cancer than in controls in a study in India (65). Serum levels of vitamins A and E were signicantly lower in patients with a second primary tumor than in patients with a single head and neck cancer in a study in The Netherlands. Serum -carotene levels were depressed in both groups of patients (66). High dietary intakes of carotene and vitamins C and E were related to decreased risk of both oral/pharyngeal/esophageal and stomach cancer in a U. S. study of postmenopausal women. A higher vitamin A intake was associated with a lower risk of stomach cancer only (67). In a study in Italy, the risk of gastric cancer increased with increasing intake of nitrites and protein and decreased in proportion to increased intake of vitamin C and E, -carotene, and vegetable fat (68). In a U. S. study, the relative risk was largely associated with the use of supplemental vitamin E (69). Serum levels of vitamin C, vitamin E, and -carotene were signicantly lower in patients with stomach cancer than in controls in a Korean study (70). In a study that investigated the relation between micronutrient intake and thyroid cancer in Italy, the risk of cancer was 33% lower for vitamin E and 42% lower for -carotene in the highest quartile of intakes compared with the lowest quartile (71). Serum vitamin E concentrations were signicantly lower in leukemia and lymphoma patients than in controls in a study in India (72). In a casecontrol study in Uruguay, prostate cancer risk was decreased 60, 40, and 50% with high intakes of vitamin C, vitamin E, and fruits and vegetables, respectively (73). From results of animal and human studies, it was concluded by the authors that vitamin E and other antioxidants merit continued active research evaluation utilizing epidemiological studies and randomized placebo-controlled clinical trials to evaluate the role of antioxidant supplements in cancer prevention (74). A limited number of intervention trials have evaluated the role of vitamin E and other antioxidants in cancer prevention, with mixed results. In a nutrition intervention trial of 29,584 adults from Linxian, China, cancer mortality was 13% lower, and the mortality rate from stomach and esophageal cancers combined was 10% lower in the group supplemented with -carotene, vitamin E, and selenium for 5 years (75). A clinical trial in the United States of 864 patients who had had a colorectal adenoma removed before entering the study did not demonstrate a benet of vitamins C and E or -carotene in decreasing the incidence of new colorectal adenomas over 4 years (76). In a primary prevention trial of 29,133 male smokers, aged 5069 years, in Finland (ATBC study), there was no reduction in lung cancer incidence among men supplemented with 50 mg of synthetic vitamin E per day for 58 years compared with those who were not. Lung cancer incidence was 18% higher in the group supplemented with 20 mg synthetic -carotene per day (77). This effect may be associated with heavier cigarette smoking and higher intake of alcohol (78). In contrast, prostate cancer incidence was 32% lower and prostate cancer mortality was decreased by 41% among vitamin E-supplemented men. Among -carotene supplemental subjects, prostate cancer incidence was 23% higher and mortality owing to prostate cancer was 15% higher (79). There was a 19% decrease in lung cancer incidence in the highest versus the lowest quartile of baseline serum vitamin E levels in the ATBC study population (80). In a study that evaluated the effects of antioxidant supplementation (800 IU vitamin E, 30 mg -carotene, and 1000 mg vitamin C per day for 9 months) in 79 patients with oral
leukoplakia (precancerous lesions of the oral cavity), 90% of subjects who decreased their use of tobacco or alcohol showed clinical improvement. Approximately 50% of the patients who did not change their use of tobacco or alcohol also showed clinical improvement of lesions (81). In a multicenter trial of the efcacy of vitamin E supplements (800 IU/day for 24 weeks) in patients with oral leukoplakia, 20 of the 43 patients had clinical responses (disappearance or signicant decrease in size of lesions) and 9 had histological responses (improvement in the degree of dysplasia) (82).
VI.
CARDIOVASCULAR DISEASE
It is well established that cholesterol deposited in arteries originates primarily from LDLs and that elevated LDL levels are associated with an increased risk for atherosclerosis. One of the earliest stages in development of atherosclerosis is accumulation in the arteries of foam cells, which are macrophages that have taken up oxidized LDL. These foam cells are lled with liquid droplets of cholesterol and are a key component of the fatty streak lesion (83). LDL is an important target of free radicals, and oxidation of LDL is believed to be an important event in development of atherosclerosis (84). Results of cell and animal research support the hypothesis that oxidative modication of LDL results in an enhanced uptake by macrophages, leading to conversion of macrophages into foam cells, and that antioxidants may protect against LDL oxidation (8587). In isolated cell studies in which high amounts of vitamin E were added to the culture medium, cell-mediated oxidation of LDL was largely prevented over 24 h. Supplementation of plasma with increasing vitamin E concentrations before isolation of LDL resulted in a proportional increase in the duration of the lag phase during which there was no detectable oxidative modication of LDL (83,88). In a study of the oxidation of LDL separated from plasma of healthy subjects, the results demonstrated that vitamins E and C act synergistically as antioxidants to suppress LDL oxidation (84). In studies of healthy, nonsmoking subjects supplemented with vitamin E, there was a signicant increase in resistance of LDL isolated from plasma to induced oxidation (8992). Resistance of LDL to oxidation also increased signicantly in a group of smokers supplemented with vitamin E (93). Research in animals has also investigated possible protective effects of vitamin E on the development and progression of atherosclerosis. In studies of specic types of hens and rabbits that are susceptible to development of atherosclerosis, early aortic lesion development was signicantly inhibited by vitamin E supplementation (9497). Prevention and regression of induced atherosclerosis by vitamin E were studied in male monkeys on an atherosclerosispromoting diet. Stenosis progressed more rapidly and to a greater extent in unsupplemented monkeys compared with vitamin E-treated monkeys. Stenosis in the group of animals with established atherosclerosis signicantly decreased from 33 to 8% after 8 months of vitamin E therapy. According to the researchers, their results show that vitamin E may be effective in both prevention and treatment of atherosclerosis (98). Extensive additional research is required to establish the clinical relevance of the experimental data. The relation between plasma antioxidant levels and incidence of coronary heart disease has been investigated in a number of recent studies in adult populations. In the WJO/MONICA study, comparison was made of plasma antioxidant concentrations of middle-aged men (4059 years of age) from different European populations. There was a high inverse correlation between age-specic mortality from ischemic heart disease and lipid-standardized plasma vitamin E levels (99). In contrast, there was no consistent association between serum selenium, vitamin A, or vitamin E levels and
risk of death from coronary heart disease in prospective epidemiological studies in Finland and The Netherlands (100,101). However, it was noted that the data from the two studies in Finland and The Netherlands must be considered with reservation owing to methodological problems, including lack of standardization for cholesterol and triglycerides (102). The relative risk of heart disease was 32% lower for men and 65% lower for women in the highest tertile of vitamin E intake compared with the lowest tertile in a study in Finland (103). In a U. S. study that evaluated the association between serum antioxidant levels and risk of myocardial infarction, a protective association with serum vitamin E levels was suggested only among individuals with high serum cholesterol concentrations (104). In a study in Poland, plasma vitamin E levels were signicantly lower in patients with stable and unstable angina compared with healthy controls, whereas vitamin E levels in red blood cells were signicantly lower only in patients with unstable angina (105). In a population casecontrol study in the United Kingdom, there was a signicant inverse association between plasma vitamin E concentrations and angina risk. According to the researchers, the results suggest that some populations with a high coronary heart disease incidence may benet from a diet rich in antioxidants, particularly vitamin E (106). Serum and LDL vitamin E levels were signicantly lower in patients with coronary artery disease than in controls in a study in Sweden (107). In a U. S. study of postmenopausal women with no evidence of coronary heart disease, the relative risk of death from coronary heart disease was 58% lower in the two highest quartile of dietary vitamin E intake than in the lowest quartile (108). In a group of subjects 67105 years of age in the United States, use of vitamin E supplements decreased the risk of coronary heart disease mortality by 47% (109). Vitamin E supplementation was associated with a decreased incidence of ischemic heart disease in a study of men in Canada (110). In middle-aged men with previous coronary bypass graft surgery who were placed on a cholesterol-lowering diet and randomized to receive colestipol niacin or placebo, those who took at least 100 IU vitamin E per day from supplements showed signicantly less coronary artery disease progression for all lesions and for mild to moderate lesions than men who took less than 100 IU vitamin E per day (111). In the Harvard-based study of 39,910 male health professionals in the United States, a 36% lower relative risk of coronary heart disease was demonstrated in men who consumed more than 60 IU vitamin E per day compared with men consuming less than 7.5 IU daily. Men who took at least 100 IU vitamin E per day for at least 2 years had a 37% lower relative risk of coronary heart disease than men who did not take vitamin E supplements (112). In the Harvard-based 8-year study of 87,245 healthy nurses in the United States, women in the top fth of vitamin E intake had a 34% lower relative risk of major coronary disease than women in the lowest fth, after adjustment for age and smoking. The relative risk of coronary heart disease (CHD) was 48% lower in women taking vitamin E supplements of more than 100 mg/day for at least 2 years. No protective effect was seen in women whose only source of vitamin E was dietary intake. The researchers in both of the Harvard-based studies noted that these data and other evidence suggest that vitamin E supplements may reduce risk of heart disease (113). In the ATBC study of male smokers in Finland, there was little difference in total incidence or mortality from CHD between the vitamin E-supplemented subjects (56 vs. 67 cases), and rates of hemorrhagic stroke were slightly increased compared with the placebo group (66 vs. 44 cases). However, implications of this study are limited because a criterion for entry into the study was that the study population had smoked at least 20 cigarettes daily for 36 years before the study was begun. (Smoking is an extremely strong risk factor for CHD, stroke, and many
cancers.) The dose of vitamin E was lower than that observed to be protective in prospective studies, and the length of follow-up was relatively short (58 years). The baseline plasma levels of vitamin E among the participants in the study were also quite high, which suggests that any benet derived from vitamin E may have been achieved during the development of the disease (77). Mortality from cerebrovascular disease was 10% lower among subjects supplemented with vitamin E, -carotene, and selenium in the intervention trial in Linxian, China of 29,584 adults (75). A clinical trial in Italy of 11,324 patients who had survived a recent myocardial infarction evaluated the effects of daily supplementation of 1 g of n-3 polyunsaturated fatty acids (sh oil), 300 IU synthetic vitamin E, sh oil and vitamin E, or no supplementation on morbidity and mortality over 3 1/2 years. Treatment with sh oil, but not vitamin E, signicantly decreased the risk of reaching the primary combined endpoint of death, nonfatal myocardial infarction, and stroke during the study period. The effect of the combined treatment of sh oil and vitamin E was similar to the effect for sh oil alone. However, a subgroup analysis of cardiovascular deaths showed a decreased risk for individual components (ranging from a 20% lower risk for all cardiovascular deaths to a 35% lower risk of sudden death) in the vitamin E-supplemented group that was similar to the effects of sh oil supplements (114). The Cambridge Heart Antioxidant Study (CHAOS) evaluated the effect of supplementation with natural source vitamin E (400 or 800 IU/day) or placebo on the risk of myocardial infarction in 2002 patients with angiographic evidence of atherosclerosis. The risk of nonfatal myocardial infarction was reduced by 77% in the vitamin E-supplemented group (115). Increasing research evidence that chronic diseases, such as atherosclerosis, are more easily prevented than cured has led to particular interest in dening the antiatherosclerotic effect of vitamin E and other antioxidants (116). Results of recent research suggest that vitamin E and other antioxidants may be expected to be important factors or even preventers of coronary heart disease (102). The specic protective role of the antioxidants against which subjects with low plasma antioxidant levels are supplemented with vitamin E and other antioxidants is documented (102,106).
VII.
AGING
Approximately 40% of the factors inuencing life expectancy can be controlled, suggesting not only that length of life can be extended, but also that quality of life, particularly in the later years, can be enhanced through better health. One area of aging research implicates free radical-mediated cell damage in development of the pathological changes associated with aging (116). It has been suggested that free-radical generation associated with aging may be a contributory factor in the depressed immune response documented in aged rodents and that improved antioxidant status may have an immunostimulatory effect (117). In a study that evaluated the effect of vitamin E supplementation (800 mg/day for 30 days) or placebo on cell-mediated immune response in 32 healthy adults 60 years of age or older, there was a signicant improvement in delayed-type hypersensitivity skin test response in the vitamin E-supplemented group. Vitamin E supplementation also resulted in enhanced response of isolated lymphocytes to concanavalin A. Immune response was enhanced in most, but not all, of the vitamin E-supplemented subjects (118). Effects on immune response of daily vitamin and trace element supplementation (vitamins A, C, D, and E, B vitamins, -carotene, folate, iron, zinc, copper, selenium, iodine, calcium, and magnesium), or placebo, were investigated in a group of 96 healthy elderly individuals. There was a signicant improvement in several immune-response parameters in the supplemented
group. Infection-related illness was signicantly less frequent in the supplemented group than in the group on placebo. It was concluded that supplementation with modest physiological doses of micronutrients improves immune response and the incidence of infection in the elderly (119). A study of 30 elderly patients who had been hospitalized for over 3 months assessed cellmediated immune function before and following daily antioxidant supplementation (8000 IU vitamin A, 100 mg vitamin C, and 50 mg vitamin E) or placebo for 28 days. There was an improvement in cell-mediated immune function in the antioxidant-supplemented group, but immune function was unchanged in the group receiving placebo. As noted by the researchers, the results suggest that supplementation with slightly higher than RDA levels of the antioxidant vitamins can improve cell-mediated immunity. Additional research is required to determine whether these benets continue with long-term supplementation and are associated with decreased morbidity in long-stay patients (120). A study of 30 older women in Spain assessed the effect of antioxidants (1000 mg vitamin C and 200 mg vitamin E per day for 16 weeks) on immune function. Antioxidant supplementation resulted in a signicant improvement in parameters of immune function and a signicant decrease in lipid peroxide levels in healthy older women and also in older women with coronary heart disease or major depression disorders (121). Vitamin E supplements (200 or 800 mg/day for 235 days) improved certain clinical relevant indexes of cell-mediated immunity in a study of 88 healthy elderly subjects in the United States. The researchers noted that because ageassociated decline in immune response is associated with increased incidence of morbidity and mortality, recommendations to increase vitamin E intake should be considered for the elderly (122). The effects of antioxidants on free radical levels were evaluated in a study in Poland of 100 subjects 60100 years of age. Average blood malondialdehyde (MDA) levels (which may give an index of lipid peroxidation) decreased 26% in subjects receiving 200 IU vitamin E, 13% in the group supplemented with 400 mg vitamin C, and 25% for combined administration of vitamins E and C (123). In a study in Finland, concentrations of serum thiobarbituric acid (TBA) reactants (which may also give an index of lipid peroxidation) were initially higher in a group of elderly nursing home patients, but declined to concentrations found in younger controls after supplementation with vitamins E, C, and B6, selenium, -carotene, and zinc for 3 months. A slight improvement in several psychological tests was observed in the antioxidant-supplemented subjects (124). In another study of nursing home patients in Finland, there was a marked improvement in general condition after 2 months in the vitamin E- and selenium-supplemented subjects, which continued throughout the 1-year study (125). As research continues on the protective role of the antioxidants in the aging process, study results suggest that free radicals have a signicant inuence on aging, that free radical-mediated damage can be controlled with adequate antioxidant defenses, and that optimal antioxidant intake can lead to a longer, healthier life.
VIII.
CATARACTS
Age is considered a major risk factor in cataract development. It is unclear whether cataract development is the result of cumulative insults of a lifetime or whether decreased resistance or repair capacity of the lensor the aging process itselfincreases susceptibility to cataract formation (126128). The lens of the eye is very susceptible to light-induced lipid peroxidation, and oxidation is believed to be an early and signicant event in development of the majority of cases of senile cataract (126,129).
Results of animal research have shown that vitamin E can arrest and reverse cataract development to some extent, suggesting that lipid peroxidation is involved in the process. In isolated animal lenses and in a number of animal models, vitamin E delayed or minimized cataract development induced by experimental oxidative stress (Table 3; 130139). Recent epidemiological research has also suggested an association between risk of cataract and antioxidant status. In a comparison of self-reported vitamin supplementation by 175 subjects with cataracts and 175 individually matched cataract-free subject, signicantly more supplementary vitamins C and E were taken by the cataract-free group than the group with cataracts. In the group who took only vitamin E supplements, cataract risk was 56% lower than in the group who did not take vitamin E. There was a 70% decrease in cataract risk in subjects using vitamin C supplements alone compared with subjects who did not take vitamin C (129). Results of a study of the correlation between antioxidant status and senile cataract in 112 subjects 4070 years of age suggest that high plasma levels of at least two of the three antioxidant vitamins (vitamins E and C and carotenoids) were associated with a signicantly reduced risk of cataract development, compared with low plasma levels of at least one of these vitamins. The odds ratio for senile cataract (controlled for age, race, sex, and diabetes) was 0.2 for subjects with a high serum antioxidant status. The researchers noted that the study results
Table 3 Effects of Vitamin E on Induced Cataract Development Study Isolated rat lenses exposed to glucose Irradiated isolated rat lenses Isolated rat lenses exposed to heat Isolated rat lenses exposed to galactose Streptozocin-induced diabetic rats Isolated rat lenses exposed to corticosteroids Rats fed 50% galactose diet Results Vitamin E protected lenses from extensive swelling and degenerative changes Vitamin E reduced the degree and extent of cataract development Vitamin E prevented cataract development Vitamin E partially prevented degeneration typical of mature cataracts Vitamin E-supplemented animals had only slight lens changes compared with extensive cataractous degeneration in unsupplemented rats Vitamin E decreased the incidence of cataract development Vitamin E supplementation had no signicant effect on cataract incidence, but there appeared to be less lens damage Vitamin E supplementation reduced rate of cataract formation and delayed appearance of various cataract stages Vitamin E-supplemented animals had substantially lower incidence of lens opacities Vitamin E supplementation arrested cataract progression in 50% of animals Vitamin E pretreatment decreased cataractogenic damage to lenses induced by irradiation Ref. 130 131 132 133 134
135 133
Rats fed 30% galactose diet
136
Cataract-prone mice Oxidant-treated rabbits Rats exposed to single brief doses of neutron or gamma irradiation
137 138 139
appear to support the hypothesis that the lens antioxidant defense may be a factor in cataract development (140). In a casecontrol study in Finland that evaluated the association between serum levels of vitamin E, -carotene, and selenium and subsequent risk of senile cataract over a 15-year period, low serum vitamin E and -carotene levels predicted an increased risk of senile cataract. The odds ratio for cataract risk was 2.6 for patients with serum vitamin E and -carotene levels in the lowest third (141). In another study in Finland of 410 male subjects, aged 4463 years at baseline, there was an inverse association between plasma vitamin E levels and progression of cortical lens opacities. Plasma vitamin E concentrations in the lowest quartile were associated with a 3.7-fold increased risk of progression of early cortical lens opacities compared with the highest quartile (142). Results of the longitudinal study of cataract in the United States, which included 764 participants, showed that the risk of nuclear opacication was decreased by 57% in subjects who regularly used vitamin E supplements (143). In the Beaver Dam Eye Study in the United States, the relation between serum vitamin E and carotenoid levels and cataract incidence was evaluated in 252 subjects 5086 years of age. Subjects with serum vitamin E levels in the highest tertile had a 60% decrease in cataract risk. Although serum carotenoid levels were not signicantly inversely related to cataract risk, there were marginal inverse correlations between serum cryptoxanthin and lutein levels and cataract risk in individuals 65 years of age and older (144). Although most research evidence suggests a benecial effect of vitamin E and other antioxidants against cataract development, controlled clinical trials are recommended to more precisely dene the protective role of antioxidants in prevention of cataracts.
IX.
AIR POLLUTION
Ozone and nitrogen dioxide are present in very high concentrations in polluted environments and can initiate free radical reactions that lead to lung damage. Cigarette smoke contains numerous substances known to be oxidants or free radicals; smoking also initiates a signicant increase in lung inammatory cells (potent producers of free radicals) (145). A protective role for vitamin E against the damaging effects of smoke and smog has been demonstrated in a number of studies in animals (146149). Studies in humans have also shown protective effects of vitamin E against pollution damage. In a study of the effects of daily vitamin E supplementation (600 mg) on red blood cell susceptibility to ozone-related free radical damage in 12 adults, vitamin E signicantly protected red blood cells at the highest levels of hydrogen peroxide-induced stress, but not at lower levels (150). In other studies of Los Angeles residents exposed to photochemical smog, vitamin E supplementation was not protective against biological responses to short-term exposure to ozone. However, the researchers noted that their results do not rule out the possibility that vitamin E supplementation may have a protective effect on human lung tissue, where free radical levels may be higher than in the blood (151,152). Because smokers inhale high levels of free radicals in the gaseous and tar phases of tobacco use, an increased antioxidant intake may be benecial (153). A study of young adult smokers demonstrated that the lower respiratory tract uid of smokers was decient in vitamin E compared with nonsmokers. Vitamin E supplementation (2400 IU/day for 3 weeks) resulted in increased vitamin E concentrations in lower than baseline levels of nonsmokers, providing clear evidence that vitamin E utilization may be increased in lung cells of smokers. As noted by the researchers, vitamin E may be an important antioxidant in the lungs defense against free radical damage by cigarette smoke (145).
In another study, red blood cells of smokers showed increased peroxidation when incubated with hydrogen peroxide compared with nonsmokers. This effect was inhibited in smokers supplemented with vitamin E (1000 IU/day for 2 weeks). Levels of free radical products in plasma were much higher in unsupplemented smokers than in vitamin E-supplemented smokers or nonsmokers. According to the researchers, their results suggest that smoking leads to changes in antioxidant status (153). Initial breath pentane output, which may provide an index of lipid peroxidation in vivo, was signicantly higher in a group of smokers than in healthy nonsmokers, although plasma vitamin E concentrations were similar in both groups. When smokers were supplemented with 800 mg vitamin E per day for 2 weeks, breath pentane excretion decreased signicantly, but remained signicantly higher than in nonsmokers. It was concluded that a normal plasma vitamin E concentration does not prevent the increased peroxidation observed in smokers but that vitamin E supplementation will signicantly reduce lipid peroxidation and that the recommended daily allowance for vitamin E may be insufcient for individuals exposed to cigarette smoke (154). Until the causative agents of air pollution are completely eliminated, it is likely that vitamin E can help protect the lungs from damage and disease.
X.
STRENUOUS EXERCISE
There is increased uptake and utilization of oxygen during exercise, and two- to threefold higher free radical levels are observed in muscle and liver of exercise-exhausted animals (155). During exhaustive exercise, muscle damage occurs even in highly trained athletes. In a study of marathon runners, men had signicantly greater skeletal muscle damage (estimated by analysis of serum concentrations of the intramuscular enzyme creatine kinase) than women after a 42km race, with or without correction for body surface area. Although creatine kinase release from skeletal muscle results from muscle cell injury, it is yet to be determined if it is related to reversible or irreversible damage (156). As exercise is associated with free radical-mediated tissue damage, there should be a greater demand for antioxidants during exercise. Results of animal studies suggest an increased vitamin E requirement during endurance training (157,158). In a study of male college students, exhaustive exercise led to a signicant rise in serum lipid peroxide levels immediately following exercise. Leakage of enzymes from tissues to the blood increased signicantly with exercise and was considered to be indicative of exerciseinduced, free radical-mediated tissue damage. When the students were supplemented with vitamin E (300 mg/day for 4 weeks), serum MDA levels signicantly decreased immediately after exhaustive exercise and the increase in serum enzyme activities was lower. It was concluded by the investigators that lipid peroxidation associated with strenuous exercise can be inhibited by vitamin E supplementation (159). Another study of young, healthy males investigated the effects of antioxidant supplementation (vitamin C, vitamin E, and -carotene) on breath pentane output and serum MDA levels before and after exercise (treadmill running). Antioxidant supplementation resulted in signicantly lower resting and postexercise concentrations of expired pentane and serum MDA, but did not prevent the exercise-induced rise in indices of lipid peroxidation (160). Another study evaluated the modulating effects of daily antioxidant supplementation (100 mg vitamin E and 500 mg vitamin C for 15 weeks) or placebo on the short-term effects of ozone in 38 Dutch cyclists. Relatively low ozone concentrations were associated with a decrease in two lung function parameters (FEUI and FUC) after cycling. Ozone had a signicant effect on these parameters of lung function during exercise in the placebo group, but not in the antioxidant-supplemented group (161).
In a study of male volunteers in two age groups (2229 and 5574 years), subjects were randomized to receive 800 IU vitamin E per day for 48 days or placebo before eccentric exercise (running downhill on an inclined treadmill). All vitamin E-supplemented subjects excreted fewer urinary TBA adducts after an intense bout of eccentric exercise than subjects who received placebo at 12 days postexercise. Muscle lipid-conjugated dienes tended to increase after exercise in the young group of subjects taking placebo, but the vitamin E-supplemented group showed no change in this index of lipid peroxidation. The researchers noted that study results are consistent with the concept that vitamin E provides protection against exerciseinduced oxidative injury (162). In two studies evaluating the effects of vitamin E on performance of trained swimmers, swimming speed did not differ signicantly between vitamin E-supplemented swimmers and those receiving placebo (163,164). Effects of vitamin E on physical performance and tissue damage were also evaluated in a group of mountain climbers. In unsupplemented mountain climbers, prolonged exposure to physical exertion at high altitudes while climbing resulted in signicantly increased breath pentane output and decreased physical performance, as demonstrated by a signicant decrease in anaerobic threshold. In contrast, vitamin E supplementation (400 IU/day) prevented the increase in breath pentane exhalation and the decrease in anaerobic threshold. The researchers concluded that vitamin E has a benecial effect on cell protection and physical performance, at least at high altitude (165). As research continues on the protective role of vitamin E in exercise, study results have shown an increased requirement for vitamin E to prevent lipid peroxidation associated with strenuous exercise.
XI.
SUMMARY
Increasing evidence implicates free radical-mediated cell damage in the development of various degenerative diseases and conditions. Susceptibility of the body to free radical stress and peroxidative damage is related to the balance between the free radical load and the adequacy of antioxidant defenses. Levels of antioxidants shown to be protective against free radical damage are substantially higher than intakes readily obtainable from normal diets. As studies continue on the benecial effects of vitamin E and other antioxidants in counteracting peroxidative damage in the body, increased intakes of vitamin E and other antioxidant nutrients can provide protection from the increasingly high free radical loads deriving from environmental sources and associated with current lifestyle habits.
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Efcacy of Vitamin E in Human Health and Disease

Copyright 2002 by Taylor & Francis Group, LLC

CLINICAL DEFICIENCY STATES

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a Proportional to number of double bonds in muscle

lipids, except for monounsaturated fatty acids.

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Country Finland Finland Finland

313 females 129 males

All sites Lung Bladder, gastrointestinal tract Nine primary sites

United States United States

111 284 males

Copyright 2002 by Taylor & Francis Group, LLC

Breast All sites Lung Lung Lung Lung

England India United States United States Japan Finland

39 females 101 99 59 37 117 males

Lung Lung Lung Lung Cervix Cervix Cervix Ovaries

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Colon Stomach Thyroid Leukemia, lymphoma Prostate

United States Korea Italy India Uruguay

212 59 399 NA 175 males

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Rats fed 30% galactose diet

137 138 139

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Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

Copyright 2002 by Taylor & Francis Group, LLC

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