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Vitamin E and its Role in the Prevention of Atherosclerosis and Carcinogenesis: A Review

The Royal College of Surgeons in Ireland, Dublin, IRELAND (A.D.), Baltimore, Maryland
Division of Gastroenterology, Sinai Hospital of Baltimore and University of Maryland School of Medicine, Baltimore, Maryland (S.D.)

Address reprint requests to: Sudhir Dutta, M.D., Suite 51, Hoffeberger Prof. Center, 2435 W. Belvedere Avenue, Baltimore, MD 21215. E-mail: sudhirdutta{at}lifebridgehealth.org

	ABSTRACT

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
Epidemiological and experimental studies suggest that antioxidants like vitamin E (-tocopherol) may play an important role in prevention of chronic disease. Several observational surveys have linked populations with a large intake of vitamin E with reduced incidence of heart disease. These observations have been strengthened by the demonstration of strong antioxidant activity by vitamin E in cellular, molecular and animal experiments. These results have highlighted a potential role for vitamin E supplementation in the prevention of chronic disease in humans. Interestingly however, large-scale clinical trials of vitamin E and other antioxidants in preventing specific disease processes (e.g., coronary artery disease) have generated conflicting and mixed outcomes. In this review, the role of vitamin E in the prevention of atherosclerosis and carcinogenesis has been carefully examined with particular emphasis on salient human studies (clinical trials) and their limitations. In addition, pertinent biochemical, physiological and metabolic features of vitamin E have also been incorporated. A list of common natural food sources of vitamin E has been provided. Important in vitro and animal studies related to the antiatherosclerotic and anticarcinogenic actions of vitamin E have been discussed in detail. Finally, the direction of future investigations in primary and secondary prevention of chronic diseases by vitamin E supplementation has been outlined.

Key words: vitamin E, atherosclerosis, tocopherol, lipid peroxidation, carcinogenesis, heart disease

Key teaching points:

• Vitamin E is a fat soluble vitamin which is absorbed from the human small intestine (enterocyte) after solubilization in bile salt micelles.

• In human diets, -tocopherol is the principal form of vitamin E, while -tocopherol is the primary form in vitamin E supplements. -tocopherol helps protect cell membranes from the lipid peroxidation by trapping peroxyl radicals and is regenerated by an electron donor like vitamin C.

• Vitamin E is available in abundance in common nuts and seeds such as almonds, peanuts, sunflower seeds, filbert and vegetable oils. Currently, the RDA of vitamin E for an average size person is 15 mg -tocopherol per day.

• Vitamin E is transported in plasma with lipoproteins in the plasma (i.e., HDL and LDL) and protects against free radical peroxidation of the carrier protein.

• Protective action of vitamin E against atherosclerosis (i.e., coronary and coratid artery disease) is most likely related to its preventive action against lipid peroxidation. The ability of vitamin E to induce apoptosis in tumor cells and modulate oncogenes may be essential for its anticarcinogenic effect.

• While a large body of cellular, animal and epidemiological studies has demonstrated effectiveness of vitamin E in reducing the progression of atherosclerosis and reducing frequency of certain cancers, the results of large scale clinical trials with vitamin E have failed to show its beneficial effect in a consistent manner.

• Long term (>5 years) longitudinal studies are needed in patients with well defined coronary and carotid artery disease with precise endpoints in response to an optimal dose of vitamin E supplement either alone or in combination with other antioxidants to establish its clinical efficacy in prevention of atherosclerosis.

	Biochemistry

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
In nature, vitamin E exists in at least eight naturally occurring compounds, including -, ß-, - and -tocopherol and -, ß-, - and -tocotrienol. The tocotrienols are similar to tocopherols in molecular structure except that they contain three double bonds in the isoprenoid side chain. Within the vitamin E family of compounds, -tocopherol is the most biologically active and occurs naturally as one isomer. -Tocopherol is the predominant form of vitamin E found in human diets, while -tocopherol acetate and synthetic isomers of -tocopherol are the primary forms of vitamin E supplements. Both free tocopherol and its acetate ester are water-insoluble, and factors necessary for their intestinal absorption are also necessary for the absorption of dietary lipids [1]. Vitamin E uptake by the intestinal epithelium involves proper emulsification, solubilization within bile salt micelles, uptake by enterocytes, packaging within chylomicrons and secretion into the circulation via the lymphatic system.

Vitamin E’s function as an antioxidant is dependent upon its ability to break radical-propagated chain reactions. As a result, the formation of the tocopheroxyl radical, the odd-electron derivative of vitamin E, is an inherent part of any vitamin E based, antioxidative reaction [2]. As the principle, lipid-soluble antioxidant in biological membranes, -tocopherol reacts with many oxidant molecules. In turn, -tocopherol helps protect cell membranes from lipid peroxidation by trapping peroxyl radicals [3]. It involves the abstraction of a hydrogen atom from the OH group of the tocopherol by a peroxyl (oxidant) molecule. Upon the formation of the tocopheroxyl radical from a reaction between -tocopherol and an oxidant molecule, -Toc• is now free to interact with another peroxyl radical [-Toc• + LOO• LOO-Toc] [3]. The reaction [LOO• + -TocH LOOH + -Toc•] produces a stable tocopheroxyl radical, which does not propagate radical chains and lipid hydroperoxides. Since the rate constant for this reaction is several orders of magnitude greater than the reaction for peroxyl radical propagation, -tocopherol is able to efficiently protect cellular membranes at levels as low as 1 -tocopherol per 1000 phospholipids [4]. Furthermore, -tocopherol can be regenerated from the tocopheroxyl radical by an electron donor, like ascorbic acid, and is thereby able to maintain cellular antioxidant protection over a period of time. Thus, vitamin C (AsH₂), a weak antioxidant by itself, can enhance the antioxidant activity of vitamin E by regenerating the protonated -tocopherol from the -tocopheroxyl radical [AsH₂ + -Toc• AsH• + -TocH]. In fact, this synergistic reaction between vitamin C and -tocopherol has led researchers to investigate the possibility of enhancing vitamin E antioxidant function by incorporating the use of vitamin C. Although it has been well documented that at high concentrations -tocopherol can act as a prooxidant during the autooxidation of polyunsaturated fatty acids, the regenerating effect of vitamin C on tocopherol is a potentially beneficial reaction that needs to be furthered characterized in human and animal models.

	Availability in Food Products

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
While tocopherols and tocotrienols are two groups of compounds found in plants that have vitamin E biological activity, it is now well-recognized that the 2R-stereoisomers of -tocopherol are the only forms considered essential in meeting human dietary requirements. Succinate and acetate derivatives of vitamin E also retain basic tocopherol biological activity and are used predominantly in supplements because of their increased stability at ambient temperature in the environment [5]. In the 1987–1988 Nationwide Food Consumption Survey conducted by the U.S. Department of Agriculture, data showed that significant sources of vitamin E included margarine, mayonnaise, salad dressings, vitamin E fortified breakfast cereals, vegetable shortening, peanut butter, potato chips, cooking oils and tomato products [6]. Tocotrienols, in turn, are widely distributed in such cereals as wheat, barley, rye and rice and also in palm oil and rice bran oil [7].

Vegetables have little - and -tocopherol, evidenced by the fact that, with the exception of frozen spinach, no other vegetable exceeds a ratio of 1 mg -tocopherol per 100 g edible portion. Similarly, the majority of fruits are poor dietary sources of vitamin E. An exception, however, is dried apricots which have 6.2 mg of -tocopherol per 100 g edible portion. Among legumes, lima beans and peas are good sources of -tocopherol containing 7.2 and 6.4 mg per 100 g of edible portion, respectively. Although most fruits and vegetables have a low vitamin E content, common nuts and seeds are rich sources of vitamin E. Almonds, brazil nuts, filberts, peanuts and sunflower seeds are all contain high amounts of vitamin E. The Food and Nutrition Board of the National Research Council has indicated that two tablespoons of almonds, filberts or sunflower seeds will provide 40% or more of the recommended dietary allowance (RDA) for vitamin E. It is noteworthy that as many as two tablespoons of brazil nuts or peanuts provide 10% to 24% of the U.S. RDA for vitamin E.

While the data on vitamin E content of unprocessed vegetables, fruits, nuts, seeds and oils is predictable, variations on this data result due to the processing and refining of these foods. Changes in vitamin E content can result depending on whether foods are consumed cooked or raw. It is well recognized that tocopherol degradation in food is accelerated by exposure to heat, light and air. Interestingly however, added -tocopheryl acetate has been reported to remain completely stable in many fortified foods [8]. Potato chips and tomato products contain vitamin E mostly from the vegetable oils that are used as part of their processing. Currently, the recommended daily allowance (RDA) of vitamin E for an average size adult is 15 mg of -tocopherol [8].

	Absorption and Transport of Vitamin E

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
In a study by Traber et al. [9], a 10% fecal recovery of radiolabeled vitamin E was observed after its administration with 2 mg -tocopheryl acetate by gastric intubation in rats. This observation suggests near 90% absorption of vitamin E at the dose given. In humans, approximately 70% absorption of radiolabeled vitamin E has been reported [9]. After its intestinal absorption, 65% of -tocopherol appeared in the lymph of rats following a slow infusion (0.12 mg/hour) of vitamin E into the duodenum [9]. Furthermore, it was noted that as the amount of -tocopherol infusion increased, the efficiency of its intestinal absorption decreased. The efficiency of tocopherol absorption is related to the method of tocopherol administration, the amount of tocopherol given and the length of time allowed for absorption. In addition, dietary lipids also appear to alter the efficiency of tocopherol absorption in vivo. While medium-chain triglycerides appear to enhance the absorption of vitamin E, long-chain polyunsaturated fatty acids (PUFAs) and retinoic acid may reduce its absorption [9]. However, studies by Tijburg et al. [10] and Iuliano et al. [11] have demonstrated that dietary PUFAs do not inhibit the absorption of vitamin E and may in fact enhance its uptake.

It is noteworthy that prior to the intestinal absorption of dietary vitamin E across the epithelial cell (enterocyte) lining, dietary vitamin E must also be appropriately emulsified and solubilized. The process of emulsification begins in the upper gastrointestinal tract where mechanical forces break up lipids into smaller and smaller globules and mix them with bile salts to form micelles. These "mixed" micelles contain a mixture of bile salts along with the lipolytic products of triglycerides, created by the action of pancreatic lipase. These micelles, with radii of 15–50 Å, solubilize hydrophobic molecules such as tocopherol and transport solubilized tocopherol across an unstirred water layer present at the brush border membrane of enterocytes [9]. At this point, the uptake of tocopherol by the enterocyte occurs entirely by passive diffusion. Once within the enterocyte, tocopherol is packaged into chylomicrons and secreted into the lymphatic system that drains it into the bloodstream.

Once vitamin E reaches the systemic circulation via chylomicrons, it is transported by plasma lipoproteins and erythrocytes [9]. In humans, the usual range for plasma vitamin E concentration is 11 to 37 µmol/L or 5 to 16 mg/L. While all varieties of lipoproteins contain -tocopherol, the concentration of vitamin E in each type of lipoprotein is very different. In fact, the distribution of -tocopherol in lipoproteins mirrors the concentration of lipids within the lipoproteins. The presence of tocopherols in lipoproteins provides protection against free radical peroxidation. In humans, HDL and LDL are the major carriers of tocopherols, with males having more of their vitamin E concentrated in LDL and women having more of their vitamin E concentrated in HDL [12]. Despite this difference, the average total plasma concentration of vitamin E in both men and women is the same.

The importance of the various steps involved in the intestinal absorption of tocopherol is demonstrated in clinical disorders where one of these aforementioned processes is dysfunctional. For example, very low serum concentrations of tocopherol have been consistently reported in patients with both chronic liver disease and cholestasis [13]. In these patients, intestinal bile salt concentrations are presumably insufficient for the formation of mixed micelles, and, subsequently, the solubilization of vitamin E and its absorption by enterocytes is insufficient. Oral administration of bile salts with vitamin E supplementation allows these patients to once again absorb tocopherol in the small intestine. In patients with pancreatic insufficiency, e.g., patients with cystic fibrosis, marked reduction in pancreatic enzyme secretion results in insufficient lipid digestion and mixed micelle formation. These patients usually demonstrate low serum tocopherol levels as a result of the inability of enterocytes to absorb vitamin E from the small intestine. In such individuals, pancreatic enzyme replacement therapy and supplementation of -tocopheryl acetate (10 mg/kg/day) can overcome the serum tocopherol depletion [13].

	Distribution of Vitamin E in Various Tissues

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
A variety of mechanisms facilitate transport of vitamin E from the lipoproteins in the bloodstream to the tissues. First, in vitro experiments have demonstrated that lipoprotein lipase, an enzyme present on the capillary endothelial surface, is capable of promoting the transfer of tocopherol from chylomicrons to fibroblasts in blood vessels or intestinal walls [14]. Muscles and adipose tissues also express lipoprotein lipase and presumably transport tocopherol via a similar mechanism. Second, LDL has also been shown to deliver vitamin E to fibroblast tissue cultures via a high-affinity receptor mediated pathway. This particular method of vitamin E transport has been corroborated by molecular studies in LDL receptor-negative fibroblasts obtained from patients with familial hypercholesterolemia. These studies have shown that the uptake of -tocopherol is greatly reduced in the absence of LDL receptors. Similarly, when LDL was modified by methylation, which reduced its binding with its cell surface receptor, the uptake of (³H)-tocopherol was greatly diminished along with (¹²⁵I) labeled LDL uptake [15]. Third, HDL also facilitates vitamin E transport in plasma although the specific mechanism regarding its transport in tissues has not been defined. It has been suggested that, in addition to its normal function of transporting cholesterol from peripheral tissues to the liver, HDL also assists in delivering tocopherol to the liver and other tissues such as the central nervous system. In porcine brain it has been demonstrated that HDL plays a major role in transporting -tocopherol to capillary endothelial cells. In a study by Goti et al. [16], a porcine analogue of human and rodent scavenger receptor promoted the uptake of HDL-associated -tocopherol into cells constituting the blood brain barrier. This mechanism presumably facilitates entry of -tocopherol into cerebrospinal fluid (CSF). In fact, -tocopherol has been detected in human CSF at a concentration of 29.2 ± 9.5 nmol/L [17]. Fourth, in addition to the lipoproteins that transport bound -tocopherol in plasma, cytosolic -tocopherol transport proteins are essential for the intra-cellular transfer of vitamin E in hepatocytes and its secretion into lipoproteins. Along with triglycerides, phospholipids, cholesterol and apolipoproteins, -tocopherol is incorporated into chylomicrons within intestinal epithelial cells and delivered to the liver within chylomicron remnants that are formed by the intravascular degradation of chylomicra by endothelial lipoprotein lipase [18]. This process of chylomicron remnant formation is essential for hepatic uptake of vitamin E. In turn, once within the liver parenchyma, -tocopherol is transferred specifically by the -tocopherol transfer protein (-TTP) into VLDL and re-secreted into plasma. Furthermore, the phospholipid transfer protein (PLTP) specific for the transfer of -tocopherol between lipoproteins and the tocopherol-associated protein (TAP), a cytosolic tocopherol binding protein with broad tissue distribution, are two additional proteins that have been found to be specific for intracellular transport of vitamin E [18].

	Cellular and Molecular Studies on the Potential Preventative Action of -Tocopherol in Coronary Artery Disease and Carcinogenesis

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
In cell and molecular studies, it has been consistently reported that the oxidant-quenching action of vitamin E provides its beneficial effect by protecting cells from peroxyl radical induced oxidative damage. Several lines of evidence suggest that lipid peroxidation plays a critical role in the development of atherosclerosis in coronary arteries in humans.

In the development of atherosclerosis, LDL particles accumulate within the arterial sub-endothelial space. These resident LDL particles then undergo chemical alteration, like oxidation (oxLDL), resulting in the formation of a modified LDL that is capable of inducing local vascular cells to stimulate monocyte recruitment and their differentiation into macrophages [19]. These accumulating cells further oxidize resident LDL particles. As the protein component of LDL (apoprotein B-100) becomes more negatively charged, the LDL particles are recognized by scavenger receptors on macrophages that, in turn, internalize these LDL particles resulting in the formation of foam cells [20]. As additional monocytes are recruited to the sub-endothelial space, the already present macrophages and foam cells remain trapped within the vasculature, unable to escape due to their internal build-up of oxLDL. Adjacent endothelial cells, respond to the cytotoxic buildup of oxLDL by releasing lipids and lysosomal enzymes that further enhance the progression of atherosclerotic lesions [21].

While lipid peroxidation is critical to the progression of the atherosclerotic process in blood vessels, vitamin E, as a potent antioxidant, has the potential to limit this process and slowdown the inevitable formation of arterial lesions in important blood vessels including the coronary arteries. Both in vitro and in vivo studies have demonstrated that -tocopherol inhibits LDL oxidation and decreases the release of reactive oxygen species [22]. Furthermore, it also has been shown to reduce the release of pro-inflammatory cytokines, and inhibit monocyte-endothelial cell adhesion [23]. In a recent study by van Tits et al. [24], -tocopherol significantly inhibited superoxide production by polymorphonuclear leukocytes induced by phorbol ester. Similarly, Deveraj et al. [22] showed that -tocopherol supplementation (1200 IU/day for three months) resulted in a 90% inhibition of interleukin-1ß (IL-1ß) release from LPS-activated monocytes. IL-1ß is a molecule that promotes monocyte-endothelial adhesion and promotes cholesterol esterification in macrophages. In addition to these functions, it has been demonstrated in cellular studies that U937 monocytic cells exposed to -tocopherol (50 or 100 µmol/L) are not able to adhere to endothelial cells because of -tocopherol mediated inhibition of monocyte receptors CD11b and VLA-4 and transcription factor NFB [25]. These compounds are essential for proper adhesion between monocytes and endothelial cells and their decreased expression secondary to -tocopherol reduces monocyte-endothelial adhesion and presumably slows the process of atherogenesis.

However, it is noteworthy that several clinical studies have failed to demonstrate antiatherogenic effects of vitamin E. In a study by Terentis et al. [26], the concentrations of oxidized lipids, -tocopherol, and its oxidation products (i.e., -tocopherylquinone (TQ), 5,6-epoxy--tocopherylquinone (TQE1) and 2,3-epoxy--tocopherylquinone (TQE2)) were measured in human atherosclerotic lesions by gas chromotography-mass spectrometry analysis. While oxidized lipid content increased with increasing disease severity, it was noted that TQ, the major oxidation product independent of disease stage, represented less than 20% of the total -tocopherol compounds measured. Furthermore, the relative extent of -tocopherol oxidation was maximal in early stage carotid lesions where it exceeded lipid oxidation. These results indicate that lipid oxidation can increase substantially throughout the course of disease, whereas the extent of arterial wall -tocopherol oxidation remains limited. It seems that in human atherosclerotic lesions most of the endogenous -tocopherol remains intact and only a limited amount of antioxidant activity is detected early in the atherogenic process. These data seem to suggest that vitamin E supplementation may be of little benefit in preventing LDL lipid oxidation in arterial walls in humans.

In addition to tocopherol’s function as an antioxidant, its role as an enhancer of the immune system, regulator of cell growth and inducer of apoptosis may be crucial in its ability to inhibit carcinogenesis. There are several proposed mechanisms by which vitamin E may demonstrate anticarcinogenic effects. First, as an antioxidant, vitamin E quenches reactive oxidant species and thereby decreases the number of oxidative and potentially harmful events that can occur at the cellular and molecular level. For example, studies have demonstrated that tocopherol, when applied topically to mouse skin cells, greatly inhibits the formation of cyclobutane pyrimidine photoproducts induced by UVB radiation [27]. Second, Shklar et al. [28], reported that vitamin E was capable of stimulating the migration of macrophages and lymphocytes to a tumor site. These macrophages and lymphocytes both contained large quantities of tumor necrosis factor- and tumor necrosis factor-ß, respectively, which were released at the site of tumor formation. Furthermore, vitamin E also demonstrates strong anticarcinogenic activity by modulating the function of oncogenes such as p53. It enhances the expression of wild-type p53 gene product (tumor suppressor gene), and reduces the expression of mutant p53 and other oncogenes [29].

One of the most promising anticarcinogenic properties of vitamin E is its ability to induce apoptosis in tumor cells. In a study by Turley et al. [30], it was shown that vitamin E succinate induced apoptosis of human B lymphoma cells in culture. Additional studies have revealed that vitamin E succinate induces apoptosis in a wide range of isolated, cultured tumor cells derived from cancers originating in breast, cervical, endometrial, colon, prostate and lymphoid tissue. These malignancies account for over 90% of all human malignancies [5]. In a study by Neuzil et al. [31], it was found that -tocopheryl succinate can induce apoptosis in hematopoietic and other cancer cell lines by inhibiting protein kinase C (PKC) activity. PKC activity inhibits apoptosis through several mechanisms, which include: a.) the modulation of Fas ligand expression, b.) promotion of phosphorylation, c.) enhancement of bcl-2, an antiapoptotic protein and d.) by activating protein phosphatase 2A which hyperphosphorylates, and inactivates, PKC [32,33]. Interestingly, however, vitamin E succinate does not induce apoptosis in normal human epithelial cells present in mammary and prostatic glands [34]. Vitamin E has also been demonstrated to exert cytolytic activity upon a variety human cancer cell lines in vitro [35]. At both 70 and 300 µM, vitamin E decreased the viability and proliferation of a squamous cell carcinoma tumor cell line (SK-MES), from lung carcinoma [35]. Another cell line, SCC-25, derived from human oral carcinoma, also responded with a decrease in tumor cell proliferation in response to vitamin E exposure in culture medium. In fact, when a cisplatinum-resistant variant of the same cell line was plated and treated with 70 µM of -tocopherol acid succinate for 2, 5, 12 and 24 hours in culture medium (DMEM + 10% fetal calf serum, FCS, + 10 M hydrocortisone), there was a significant (p < 0.01) reduction in the viability of the cells, as determined by an MTT assay, a sensitive test for the measurement of cell proliferation based upon the reduction of the tetrazolium salt 3,[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide [35].

	Relevant Animal Studies on the Preventive Action of Vitamin E Against Progression of Atherogenesis and Carcinogenesis

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
Studies in animal models have demonstrated a strong inverse relation between the intake of antioxidants and the incidence of atherosclerosis and cancer. By inhibiting lipid peroxidation of LDL, vitamin E can significantly diminish the atherosclerotic process. Furthermore, by promoting immune system enhancement, the induction of tumor cell apoptosis and the activation of the p53 tumor suppressor gene, vitamin E can potentially slow down the process of neoplastic transformation in humans.

It was noted that when Watanabe hereditary hyperlipidemic (WHHL) rabbits were fed probucol, a lipid-soluble, cholesterol-lowering drug with potent antioxidant properties, the formation of atherosclerotic lesions in various blood vessels was inhibited [36]. This result was obtained independently of probucol’s cholesterol-lowering properties and supports the concept that its antioxidant mechanism may be partly responsible for its antiatherogenic effect.

In a study by Ferre et al. [37], apolipoprotein E-deficient mice (n = 80) were placed on high-fat, low-cholesterol diets, and the changes in hepatic lipid peroxidation and hepatic antioxidant functions were measured. All mice were distributed into five groups and were fed regular chow or chow supplemented with coconut, palm, olive or sunflower seed oil. After 10 weeks, the mice were killed and livers removed to measure lipid peroxidation, -tocopherol and enzyme activity. In addition, atherosclerotic aortic lesions were also measured. It was observed that in the mouse diets supplemented with olive, palm or sunflower seed oil, aortic lesions were significantly smaller in size. Olive and sunflower seed oil contain the highest concentration of vitamin E, and in mice fed diets supplemented with these oils, there was no increase in hepatic lipid peroxidation. It is notable that the dietary concentration of vitamin E correlated (r = 0.98, p < 0.05) with the hepatic concentration of vitamin E. The study concludes that the high content of vitamin E in olive and sunflower seed oils may be protective against the high fat diet in the apo-E deficient mice.

In a study utilizing apolipoprotein E -/- (homozygous negative) mice, Thomas et al. [38] showed that vitamin E + coenzyme Q (CoQ) supplementation significantly reduced tissue lipid hydroperoxides in contrast with control mice or mice fed either supplement only. CoQ is reduced to the antioxidant form CoQH2 during intestinal uptake [38]. These mice were fed a high-fat diet without (control) or with 0.2% (wt/wt) vitamin E, 0.5% CoQ, or 0.2% vitamin E + 0.5% CoQ for 24 weeks. Vitamin E + CoQ supplementation limited the progression of atherosclerosis in the aortic root, aortic arch and the descending thoracic aorta. In contrast, this extent of atherosclerotic protection was not seen in the control sample or the mice fed vitamin E or CoQ alone. In apo E -/- mice it seems that vitamin E + CoQ supplements have a stronger antiatherogenic effect than vitamin E or CoQ supplements alone. Furthermore, this inhibition of disease is associated with a decrease in the concentration of aortic lipid hydroperoxides [38].

In addition to the increasing data on vitamin E induced reduction of atherosclerosis, several animal studies have revealed potential anticarcinogenic properties of vitamin E as well. Using the hamster buccal pouch tumor model, in which 0.1% (w/v) 7,12-dimethylbenzanthracene (DMBA) is used for topical application, it was noted that there was a statistically significant inhibition of carcinogenesis (induced by DMBA) by the oral administration of vitamin E [39]. This inhibition was characterized by a delay in the development of dysplastic leukoplakia and by the development of fewer and smaller tumors over a 16-week experimental period. Evidence for squamous cell carcinoma in the oral cavity developed after 21 to 25 weeks rather than the 10 to 12 weeks seen in the control population. Furthermore, vitamin E induced regression in established squamous cell carcinomas of the hamster buccal pouch when -tocopherol was injected into the tumor-bearing pouches in a dose of 250 µg twice weekly for four weeks. After four weeks, the tumor burden in the vitamin E injected animals was significantly lower (10 ± 1.00 mm³) as compared to tumor burden (1467 ± 13.27 mm³) in controls [39].

It has been shown that the topical application of vitamin E can reduce the incidence of ultraviolet (UV)-induced skin cancer in mice [27]. Through a combination of antioxidant and UV absorptive properties, vitamin E provides protection against UV-induced skin photodamage. A dose-dependent decrease in mouse skin, thymine dimer formation has been demonstrated by -tocopherol. Topical application of a 1% -tocopherol dispersion to mouse skin produced an 80% suppression of dimer formation.

In a study by Neuzil et al. [31] examining the induction of cancer cell apoptosis by -tocopherol succinate (-TOS), it was found that, in mice with colon cancer xenografts, -TOS suppressed tumor growth by 80%. HCT116 colorectal cells cancer cells (10⁷ cells in 0.2 mL PBS) were injected subcutaneously between the scapulae of each mouse, and, once tumors were established, animals received an intraperitoneal dose of 50 µL of 200 mM -TOS (100 mg -TOS per kg) in DMSO every third day. Upon euthanizing the mice, it was noted that the tumor volume was reduced by 75% after treatment with -TOS compared with negative controls and, moreover, that these tumors contained substantially more apoptotic cells, as revealed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick labeling (TUNEL) staining.

Finally, in a study by Woutersen et al. [40], azaserine-treated rats maintained on diets high in either ß-carotene, vitamin C or selenium, but not vitamin E, demonstrated fewer pancreatic tumors than controls. In this study, SPF albino Wister rats were injected with 30 mg azaserine/kg body weight at 14 and 21 days of age. One week later their diets were supplemented with either ß-carotene 60 mg/kg diet, vitamin C 10 g/kg diet, -tocopherol acetate 600 mg/kg, selenium 2.5 mg/kg or all four combined. While it is unclear as to why vitamin E alone had a lesser effect on the development of pancreatic neoplasms compared with the other antioxidants, it was determined that the group of rats ingesting all four antioxidants combined displayed the fewest number of pancreatic lesions. All these important studies in animals seem to suggest a potential antiatherogenic and anticarcinogenic effect of vitamin E in humans.

	Human Studies

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
Several epidemiological studies have revealed an inverse relationship between vitamin E intake and the progression of chronic diseases. It is believed that vitamin E’s various actions, including its role as an antioxidant, have both antiatherogenic effects and chemoprotective action.

In the Cambridge Heart Antioxidant Study (CHAOS) [41], researchers tested a hypothesis that treatment with a high dose of -tocopherol would reduce the subsequent risk of myocardial infarction (MI) and cardiovascular death in patients with established ischemic heart disease. 2002 patients with angiographically proven coronary atherosclerosis were enrolled and followed up for a median of 510 days. 1035 patients were assigned either 800 IU or 400 IU capsules of vitamin E. The remaining 967 patients received identical placebo capsules. The findings from this study revealed that vitamin E treatment significantly reduced the risk of cardiovascular death and non-fatal MI (41 vs. 64 events, relative risk 0.53, 95% CI 0.34–0.83, p = 0.005) [41].

Similarly, in a study by Boaz et al. [42], the secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE) trial demonstrated a protective effect of vitamin E against cardiovascular disease endpoints and myocardial infarction in hemodialysis patients with prevalent cardiovascular disease. In these patients, who demonstrate an age-adjusted mortality rate 3.5 to 4 times greater than that of the general population [43], more than 40% of deaths are attributable to cardiovascular disease [44]. This high mortality rate may in part be explained by the increased oxidative stress in hemodialysis patients compared with non-hemodialysis reference groups [45]. In this study, hemodialysis patients with pre-existing cardiovascular disease 40 to 75 years of age were enrolled and randomized to receive 800 IU/day vitamin E or matching placebo. Patients were followed for a median 519 days, and the primary endpoint was a composite variable consisting of myocardial infarction (fatal and non-fatal), ischemic stroke, peripheral vascular disease and unstable angina. The results showed a significant decrease in cardiovascular disease endpoints and myocardial infarction in the patients assigned to vitamin E versus placebo. Only 16% of patients assigned to vitamin E developed a primary endpoint versus 33% of patients assigned to the placebo group. Furthermore, 5% of patients assigned to vitamin E had a myocardial infarction versus 17% of patients on placebo. This study clearly demonstrates a significant trend toward both fatal and non-fatal myocardial infarction risk reduction with vitamin E supplementation in hemodialysis patients with pre-existing cardiovascular disease.

In another study conducted by Salonen et al. [46], it was found that a combined supplementation of both vitamin E and slow-release vitamin C can retard the progression of atherosclerosis in the common carotid artery in men. A randomized sample of 520 smoking and non-smoking men and postmenopausal women (45 to 69 years of age) ingested, twice daily, a special formulation of either 91 mg of d--tocopherol, 250 mg of vitamin C, a combination of vitamin E and vitamin C or placebo for three years. Atherosclerotic progression, defined as the linear regression slope of ultrasonographically assessed common carotid artery mean intima-media thickness (IMT), was calculated over semi-annual assessments. Among men randomized to placebo, vitamin E only or vitamin C only, the average increase of the mean IMT was 0.020 mm/year, 0.018 mm/year and 0.017 mm/year, respectively. Notably, however, the proportion of men with disease progression was reduced by 74% (95% CI 36%–89%, p = 0.003) by supplementation with both vitamins E and C, as compared to the placebo group. In women, no significant reduction in mean IMT was reported. The results from this study show that a combined supplementation of both vitamin E and vitamin C may retard the progression of common carotid atherosclerosis in men only.

In the U.S. Nurses’ Health Study [47], a large prospective cohort study, 87,000 female nurses were followed for an average of eight years. Among the 13% of those women who regularly used vitamin E supplementation (of at least 100 IU/day), there was a significant reduction in relative risk of 31% (95% CI, 3%–51%) for nonfatal myocardial infarction and death from cardiovascular disease compared with women who did not use the supplements. However, despite the positive long term data in the U.S. Nurses’ Health Study, it was noted that the use of vitamin E supplements for less than two years was not associated with a reduced risk for cardiovascular events (RRR, 5%, p > 0.05).

Finally, in a study by Rimm et al. [48], in which 39,000 male health professionals were followed for four years, 17% of the men took vitamin E supplements. Men in the upper quintile (median intake, 419 IU/day) compared with men in the lower quintile of vitamin E intake (6 IU/day) had a 40% relative risk reduction (CI, 19%–56%) for nonfatal myocardial infarction, death from coronary heart disease or coronary revascularization.

Contrary to the two studies demonstrating the beneficial effects of vitamin E supplementation against coronary artery disease, several papers have revealed potential pro-oxidant and pro-atherogenic effects of -tocopherol when administered in certain populations and/or with certain pharmacological agents. Weinberg et al. [49] have shown that in smokers consuming a high polyunsaturated diet, vitamin E may function as a pro-oxidant. In this study, ten subjects who smoked more than one pack of cigarettes per day were fed either a baseline diet with olive oil as the major fat source, a diet with high-linoleic safflower oil as the major fat source or the safflower oil diet plus 800 IU vitamin E per day. LDL oxidation lag time and plasma total F2-isoprostanes were measured as determinants of in vivo, oxygen-derived free radical stress. While the safflower diet alone demonstrated an increase in plasma isoprostanes relative to the baseline diet (116 ± 11.2 minutes vs. 53.0 ± 7.2 minutes), there was no significant change in its effect on the LDL oxidation lag time. In the safflower + vitamin E diet, the lag time increased relative to the baseline diet (79.6 ± 5.4 minutes vs. 60.4 ± 3.1 minutes), and the plasma isoprostane level increased markedly (188.2 ± 10.9 nmol/L vs. 53.0 ± 7.2 nmol/L) as well. These data suggest that under the specific conditions that exist in smokers consuming a high polyunsaturated fatty acid diet, vitamin E can function as a pro-oxidant in vivo. Moreover, these findings clearly suggest that caution should be exercised in the administration of vitamin E as a therapeutic means for reducing the risk of coronary artery disease in smokers.

In a separate study by Cheung et al. [50], the authors compared the effect of niacin plus simvistatin on the plasma levels of HDL cholesterol (HDL-C) in subjects with coronary artery disease (CAD) versus niacin + simvistatin + antioxidants (vitamins E and C, ß-carotene and selenium). Over twelve months, lipoprotein changes were studied in 153 CAD subjects with low HDL-C randomized to take either simvistatin + niacin (S-N), antioxidants alone, S-N + antioxidants (S-N + A) or placebo. Although the S-N and S-N + A groups had comparably significant reductions in plasma cholesterol, triglyceride and LDL-C, the HDL-C level was consistently higher in the S-N group than in the S-N + A group (41 ± 11 mg/dL vs. 37 ± 6.8 mg/dL). Furthermore, the S-N group demonstrated an increase in apolipoprotein A-I particle size, a favorable response, that was also blunted by S-N + A administration. It seems, therefore, that in combination with S-N, antioxidants have the ability to blunt the HDL-C increasing effects of S-N alone in patients with coronary artery disease and low HDL. Similarly, these investigators have reported that, while S-N provided marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL levels, antioxidant vitamins seemed to attenuate the S-N mediated regression of coronary artery stenosis [51]. Due to the study design, it is not possible to identify which particular antioxidant was responsible for the observed effects. However, based on these data, the effect of antioxidants either alone or in various combinations with lipid therapy is questionable and requires additional examination in humans.

Along the same lines, two recent studies, the Italian clinical trial by the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico) [52] and the 1999 Heart Outcomes Prevention Evaluation (HOPE) study [53], have also reported that vitamin E treatment of patients with cardiovascular disease had no significant effect on the frequency of primary endpoints, i.e., nonfatal myocardial infarction, stroke or death from these disorders. However, it is noteworthy that the dietary habits, type and dose of vitamin E supplementation and the lifestyle of the patients may have contributed to the study outcome [54]. In retrospect, the total duration of the HOPE trial may have been too short to observe a beneficial effect of vitamin E. It should also be emphasized that, where positive effects of vitamin E have been noted, the interaction of vitamin E with other micronutrients and vitamins may have contributed to the observed, beneficial results.

In a study by the collaborative Group of the Primary Prevention Project [55] investigating the efficacy of antiplatelets and antioxidants in the primary prevention of cardiovascular events, it was demonstrated that vitamin E supplementation (300 mg/day) had no effect on any prespecified endpoint. Although the trial involving 4,495 participants with one or more major cardiovascular risk factors was stopped prematurely, a mean follow-up of 3.6 years showed that aspirin supplementation (100 mg/day) lowered the frequency of all cardiovascular events from 8.2 to 6.3% (RR = 0.77 [0.62–0.95]) whereas vitamin E had no benefit on any of the prespecified cardiovascular endpoints. Similarly, a study by Keith et al. [56] has shown that vitamin E supplementation in an outpatient population with advanced heart failure (N = 56) failed to affect significantly any marker of in vivo oxidative stress and furthermore did not result in any significant improvements in prognostic or functional indexes of heart failure or in the quality of life of patients.

Hodis et al. [57] have recently reported that -tocopherol supplementation (400 IU/day) significantly raised plasma vitamin E levels (p < 0.0001), reduced circulating oxidized LDL (p = 0.03) and reduced LDL oxidative susceptibility (p < 0.01) compared with placebo. However, in this study of men and women 40 years of age or older with an LDL cholesterol level equal to or greater than 3.37 mmol/L and no clinical signs or symptoms of cardiovascular disease, the investigators also found that over a three-year period vitamin E supplementation did not reduce the progression of intima-media thickness, as measured by ultrasonography, compared with subjects assigned to placebo.

Finally, a recent investigation by the Heart Protection Study Collaborative Group [58] examining 20,536 UK adults with coronary disease, other occlusive arterial disease or diabetes demonstrated that there was no significant effect on cardiovascular primary endpoints in the group randomly allocated vitamin supplementation (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene) versus the group receiving matching placebo. The mean duration of follow-up was five years for all randomised patients.

In examining the effects of vitamin E supplementation on cancer in humans, there have been several reports on the potential chemoprotective properties of -tocopherol. It is believed that many cancers develop as a result of cellular oxidative stress and that antioxidants may be beneficial in suppressing this process. In the Finnish -Tocopherol, ß-Carotene Study [59], 29,000 men were randomized to receive vitamin E and ß-carotene in a 2 x 2 factorial design. At a six-year follow-up, there was a 32% reduction in prostate cancer incidence and a 41% reduction in prostate cancer mortality among the men who received supplementary vitamin E.

Similarly, the nutrition intervention trials in Linxian, China [60] demonstrated that over the course of five years individuals receiving vitamin supplements, particularly vitamin E plus ß-carotene and selenium, had a significant (p = 0.03) decrease in the incidence of gastric cancer versus individuals receiving no vitamin supplementation. Dosing for the vitamin supplementation consistently ranged between one and two times the U.S. RDA, and a total of 29,584 individuals were included in the study. Of the 792 individuals who died of cancer during the five-year follow-up, the group receiving vitamin E + beta-carotene + selenium demonstrated a 9% reduction in overall mortality (RR = 0.91, 95% CI = 0.84–0.99). Cancer mortality was reduced 13% (RR = 0.87, 95% CI = 0.75–1.00) with esophageal/gastric cancer rates being reduced by 10%. Despite these results, it is important to note that this study cannot establish the effect of vitamin E alone on prevention of gastric cancer, because a cocktail of antioxidants was administered to people in an area where there were widespread deficiencies of these nutrients.

Despite these promising data, additional human studies continue to question the benefit of vitamin E supplementation in the prevention of carcinogenesis. In a five-year follow-up of 20,000 UK adults randomly allocated to receive a daily antioxidant vitamin cocktail (600 mg vitamin E, 250 mg vitamin C and 20 mg beta-carotene) versus placebo, the Heart Protection Study Collaborative Group found no significant difference between the groups with respect to the development of new primary cancers (excluding non-melanoma skin cancer). Primary cancer sites across a variety of organ systems occurred in 7.8% of the individuals receiving antioxidant supplementation and 8.0% of the placebo group.

	Conclusion and Future Research

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
While cellular, molecular and animal studies continue to demonstrate the effectiveness of -tocopherol in reducing the progression of atherosclerosis and carcinogenesis, large-scale clinical trials have failed to demonstrate the anticipated beneficial effect in humans. The mixed results obtained from a variety of clinical studies involving vitamin E attest to the complexity of studying the potential protective role of vitamin E against chronic disease processes. In fact, several key issues related to vitamin E supplementation in humans need further investigations. First, long term (>5 year span) longitudinal studies are needed to examine the effect of -tocopherol in reducing the incidence of coronary and/or carotid artery disease (atherosclerosis) as well as various cancers in well defined, healthy populations (primary prevention). Second, similar studies are needed in well defined populations with specific disease process (e.g., coronary artery disease) in reducing the progression and/or recurrence of the underlying disease process. Third, the dose and duration of vitamin E supplementation necessary to achieve clinical endpoints needs further delineation. Four, the effect of various disease states and medications on the absorption and efficacy of vitamin E in patients with chronic disease requires additional clinical investigations. Five, the potential additive or antagonistic effects of other antioxidants (vitamin C, ß-carotene, etc.) administered concomitantly with vitamin E supplementation in disease states and in health need further evaluation. Finally, new methods to assess precisely the oxidative stress status in individuals scheduled to receive vitamin E supplementation in clinical trials would greatly assist in identifying patients who could benefit most from various nutritional interventions.

	ACKNOWLEDGMENTS

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 
The authors would like to acknowledge the contributions of Dr. Jeffery Blumberg, Professor, School of Nutrition Sciences and Policy, Jean Meyer USDA-HNRC on Aging, Tufts University, Boston, Massachusetts. Dr. Blumberg was instrumental in enhancing the quality of this manuscript by his critical suggestions and constructive comments. Moreover, he helped us identify specific areas relevant for future investigations in this field. His encouragement to complete this project is most appreciated.

Received September 12, 2002. Accepted May 13, 2003.

	REFERENCES

TOP ABSTRACT Biochemistry Availability in Food Products Absorption and Transport of... Distribution of Vitamin E... Cellular and Molecular Studies... Relevant Animal Studies on... Human Studies Conclusion and Future Research ACKNOWLEDGMENTS REFERENCES

 

1. Carey M, Small D: The characteristics of mixed micellar solutions with particular references to bile. Am J Med49 :590 –608,1970 .[Medline]
2. Ingold K, Webb A, Witter D, Burton G, Metcalfe T, Muller D: Vitamin E remains the major lipid soluble chain breaking antioxidant in human plasma even in individuals suffering severe vitamin e deficiency. Arch Biochem Biophys259 :224 –225,1987 .[Medline]
3. Burton G, Ingold K: Vitamin E: application of the principles of physical organic chemistry to the exploration of its structure and function. Acc Chem Res19 :194 –201,1896 .
4. Kornbrust D, Mavis R: Relative susceptibility of microsomes from lung, heart, liver, kidney, brain and testes to lipid peroxidation: correlation with vitamin E content. Lipids15 :315 –322,1980 .[Medline]
5. Kline K, Yu W, Sanders B: Vitamin E: mechanisms of action as tumor cell growth inhibitors. J Nutr131 :161S –163S,2001 .[Free Full Text]
6. US Department of Agriculture, Human Nutrition Information Service: "Nationwide Food Consumption Survey, 1987–88. Individual Intakes, 3 Days." Computer Tape PB 90-504044. Springfield, VA: National Technical Information Service,1990 .
7. Ong A: Natural sources of tocotrienols. In Packer L, Fuchs J (eds): "Vitamin E in Health and Disease," 1st ed. New York: Marcel Dekker, pp3 –8,1993 .
8. Machlin L: "Handbook of Vitamins." New York: Marcel Dekker,1984 .
9. Traber M, Kayden H, Green J, Green M: Absorption of water miscible forms of vitamin E in a patient cholestasis and in rats. Am J Clin Nutr44 :914 –923,1986 .[Abstract/Free Full Text]
10. Tijburg LB, Haddeman E, Kivits GA, Westrate JA, Brink EJ: Dietary linoleic acid at high and reduced dietary fat level decreases the faecal excretion of vitamin E in young rats. Br J Nutr77 :327 –336,1997 .[Medline]
11. Iuliano L, Michelatta F, Maranghi M, Frati G, Diczfalusy U, Violi F: Bioavailability of vitamin E as function of food intake in healthy subjects: effects on plasma peroxide-scavenging activity and cholesterol-oxidation products. Arterioscler Thromb Vasc Biol21 :E34 –37,2001 .
12. Behrens WA, Thompson JN, Madere R: Distribution of alpha tocopherol in human plasma lipoproteins. Am J Clin Nutr35 :691 –696,1982 .[Abstract/Free Full Text]
13. Jeffrey G, Muller D, Burroughs A, Matthews S, Kemp C, Epstein O, Metcalfe TA, Southam E, Tazir-Melboucy M, Thomas PK, et al.: Vitamin E deficiency and its clinical significance in adults with primary biliary cirrhosis and other forms of chronic liver disease. J Hepatol4 :307 –317,1987 .[Medline]
14. Traber MG, Olivecrona T, Kayden HJ: Bovine milk lipoprotein lipase transfers tocopherol to human fibroblasts during triglyceride hydrolysis in vitro. J Clin Invest75 :1729 –1734,1985 .
15. Thellman C, Shireman R: In vitro uptake of [³H]--tocopherol from low density lipoprotein by cultured human fibroblasts. J Nutr115 :1673 –1679,1985 .
16. Goti D, Hrzenjak A, Levak-Frank S, Frank S, van der Westhuyzen D, Malle E, Sattler W: Scavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells and contributes to selective uptake of HDL-associated vitamin E. J Neurochem.76 :498 –508,2001 .[Medline]
17. Vatassery G, Nelson M, Maletta G, Kuskowski M: Vitamin E (tocopherols) in human cerebrospinal fluid. Am J Clin Nutr53 :95 –99,1991 .[Abstract/Free Full Text]
18. Stocker A, Azzi A: Tocopherol binding proteins: their function and physiological significance. Antiox Redox Signal2 :397 –404,2000 .[Medline]
19. Diaz M, Frei B, Vita J, Keaney J: Antioxidants and atherosclerotic heart disease. N Eng J Med337 :408 –416,1997 .[Free Full Text]
20. Henriksen T, Mahoney EM, Steinberg D: Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci USA85 :6499 –6503,1981 .
21. Schwartz CJ, Valente AJ, Sprague EA, Kelley JL, Nerem RM: The pathogenesis of atherosclerosis: an overview. Clin Cardiol14(Suppl I) :I1 –I16,1991 .[Medline]
22. Deveraj S, Li D, Jialal I: The effect of alpha-tocopherol supplementation on monocyte function: decreased lipid oxidation, interleukin-1ß secretion and monocyte adhesion to endothelium. J Clin Investig98 :756 –763,1996 .[Medline]
23. Jialal I, Deveraj S, Kaul N: The effect of -tocopherol on monocyte proatherogenic activity. J Nutr131 :389S –394S,2001 .[Abstract/Free Full Text]
24. van Tits L, Demacker P, de Graaf J, Lemmers H, Stalenhoef A: Alpha-tocopherol supplementation decreases production of superoxide and cytokines by leukocytes ex vivo in both normolipidemic and hypertriglyceridemic individuals. Am J Clin Nutr71 :458 –464,2000 .[Abstract/Free Full Text]
25. Islam K, Deveraj S, Jialal I: -Tocopherol enrichment of monocytes decreases agonist-induced adhesion to human endothelial cells. Circulation98 :2255 –2261,1998 .[Abstract/Free Full Text]
26. Terentis A, Thomas S, Burr J, Liebler D, Stocker R: Vitamin E oxidation in human atherosclerotic lesions. Circ Res90 :333 –339,2002 .[Abstract/Free Full Text]
27. Krol E, Kramer-Stickland K, Liebler D: Photoprotective actions of topically applied vitamin E. Drug Metab Revs32 :413 –420,2000 .
28. Shklar G, Schwartz J: Tumor necrosis factor in experimental cancer: regression with alpha tocopherol, beta-carotene, and algae extract. Eur J Cancer Clin Oncol24 :839 –850,1988 .[Medline]
29. Schwartz J, Shklar G, Trickler D: p53 in the anticancer mechanism of vitamin E. Oral Oncol Eur J Cancer29B :313 –318,1993 .
30. Turley J, Funakoshi S, Ruscetti R, Kasper J, Murphy W, Longo D, Birchenall-Roberts M. Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid: role for transforming growth factor beta. Cell Growth Differ6 :655 –663,1995 .[Abstract]
31. Neuzil J, Weber T, Schroder A, Lu M, Ostermann G, Gellert N, Mayne G, Olejnicka B, Negre-Salvayre A, Sticha M, Coffey R, Weber C: Induction of cancer cell apoptosis by -tocopheryl succinate: molecular pathways and structural requirements. FASEB J15 :403 –415,2001 .[Abstract/Free Full Text]
32. Wang R, Zhang L, Yin D, Mufson R, Shi Y: Protein kinase C regulates Fas (CD95/APO-1) expression. J Immunol161 :2201 –2207,1998 .[Abstract/Free Full Text]
33. Ito T, Deng X, Carr B, May W: Bcl-2 phosphorylation required for anti-apoptosis function. J Biol Chem272 :11671 –11673,1997 .[Abstract/Free Full Text]
34. Israel K, Yu W, Sanders B, Kline K: Vitamin E succinate induces apoptosis in human prostate cancer cells: role for Fas in vitamin E succinate-triggered apoptosis. Nutr Cancer36 :90 –100,2000 .[Medline]
35. Shklar G, Schwartz J: Effects of vitamin E on oral carcinogenesis and oral cancer. In Packer L, Fuchs J, (eds): "Vitamin E in Health and Disease," 1st ed. New York: Marcel Dekker, pp497 –511,1993 .
36. Carew T, Schwenke D, Steinberg D: Antiatherogenic effect of probucol unrelated to its hypercholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the watanabe heritable hyperlipidemic rabbit. Proc Natl Acad Sci USA84 :7725 –7729,1987 .[Abstract/Free Full Text]
37. Ferre N, Camps J, Paul A, Cabre M, Calleja L, Osada J, Joven J: Effects of high-fat, low-cholesterol diets on hepatic lipid peroxidation and antioxidants in apolipoprotein E-deficient mice. Mol Cell Biochem218 :165 –169,2001 .[Medline]
38. Thomas S, Leichtweis S, Pettersson K, Croft K, Mori T, Brown A, Stocker R: Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol21 :585 –593,2001 .[Abstract/Free Full Text]
39. Shklar G: Inhibition of oral mucosal carcinogenesis by vitamin E. J Natl Cancer Inst68 :791 –797,1987 .
40. Woutersen RA, Appel MJ, Van Garderen-Hoetmer A: Modulation of pancreatic carcinogenesis by antioxidants. Food Chem Tox37 :981 –984,1999 .
41. Stephens N, Parsons A, Schofield P, Kelly F, Cheeseman K, Mitchinson M, Brown M: Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet347 :781 –786,1996 .[Medline]
42. Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green M: Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet356 :1213 –1218,2000 .[Medline]
43. Harnett J, Kent G, Foley R, Parfrey P: Cardiac function and hematocrit level. Am J Kidney Dis25(Suppl 1) :S3 –S7,1995 .[Medline]
44. Parfrey P: Cardiac and cerebrovascular disease in chronic uremia. Am J Kidney Dis21 :77 –80,1993 .[Medline]
45. Toborek M, Wasik T, Drodz M, Klin M, Magner-Wrobel K, Kopieczna-Grzebieniak E: Effect of hemodialysis in lipid peroxidation and antioxidant systems in patients with chronic renal failure. Metabolism41 :1229 –1232,1992 .[Medline]
46. Salonen J, Nyyssonen K, Salonen R, Lakka H, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Lakka TA, Rissanen T, Leskinen L, Tuomainen TP, Valkonen VP, Ristonmaa U, Poulsen HE: Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis. J Int Med248 :377 –386,2000 .[Medline]
47. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC: Vitamin E consumption and the risk of coronary disease in women. N Eng J Med328 :1444 –1449,1993 .[Abstract/Free Full Text]
48. 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 Eng J Med328 :1450 –1456,1993 .[Abstract/Free Full Text]
49. Weinberg R, VanderWerken B, Anderson R, Stegner J, Thomas M: Pro-oxidant effect of Vitamin E in cigarette smokers consuming a high polyunsaturated fat diet. Arterioscler Thromb Vasc Biol21 :1029 –1033,2001 .[Abstract/Free Full Text]
50. Cheung M, Zhao X-Q, Chait A, Albers J, Brown G: Antioxidant supplements block the response of HDL to simvistatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Thromb Vasc Biol21 :1320 –1326,2001 .[Abstract/Free Full Text]
51. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ: Simvistatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med345 :1583 –1592,2001 .[Abstract/Free Full Text]
52. 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. Lancet354 :447 –455,1999 .[Medline]
53. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med342 :145 –153,2000 .[Abstract/Free Full Text]
54. Meydani M: Vitamin E and atherosclerosis: beyond prevention of LDL oxidation. J Nutr131 :366S –368S,2001 .[Abstract/Free Full Text]
55. de Gaetano G: Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet357 :89 –95,2001 .[Medline]
56. Keith ME, Keith ME, Jeejeebhoy KN, Langer A, Kurian R, Barr A, O’Kelly B, Sole MJ: A controlled clinical trial of vitamin E supplementation in patients with congestive heart failure. Am J Clin Nutr73 :219 –224,2001 .[Abstract/Free Full Text]
57. Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR, Liu CH, Hwang J, Selzer RH, Azen SP: Alpha-tocopherol supplementation in healthy individuals reduced low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation106 :1453 –1459,2002 .[Abstract/Free Full Text]
58. Heart Protection Study Collaborative Group: MRC/BHF Heart protection study of antioxidant vitamin supplementation in 20,536 high risk individuals: a randomised placebo-controlled trial. Lancet360 :23 –33,2002 .[Medline]
59. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group: The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Eng J Med330 :1029 –1035,1994 .[Abstract/Free Full Text]
60. Blot W, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, Yang CS, Zheng SF, Gail M, Li GY, et al.: Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease specific mortality in the general population. J Natl Cancer Inst85 :1483 –1492,1993 .[Abstract/Free Full Text]

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