Review

Biomedical Science

Journalof

I J Biomed Sci 2004;11:295-302 DOI: 10.1159/000077097

III IIIIIII IIIII Received:November 19, 2003 Accepted: November 19, 2003

Biological Functions and Metabolic Fate of V i t a m i n E Revisited

Ching Kuang Chow
Graduate Center for Nutrition Sciences and Kentucky Agricultural Experiment Station, University of Kentucky, Lexington, Ky., USA

Key Words Vitamin E Biological function, vitamin E Metabolism/fate, vitamin E

vitamin E not only protects against oxidative damage, but also modulates the expression and/or activation of redox-sensitive biological response modifiers that regulate important cellular events.
Copyright 2004 National ScienceCouncil, ROCand S. KargerAG, Basel

Abstract Information accumulated lately has confirmed the essentiality of vitamin E for humans and provided a better understanding of its biological function and metabolic fate. The discovery of a-tocopherol transfer protein, which preferentially binds to RRR-a-tocopherol, not only provides conclusive evidence of the essentiality of vitamin E for humans, but also sheds light on the superiority of RRR-a-tocopherol biologically over other isomers. The presence of tocopherol regeneration systems and multiple interdependent antioxidant systems is largely responsible for the lack of a widespread deficiency in humans and the difficulty to deplete vitamin E in the adult. The bulk of excess tocopherols consumed is excreted to feces unchanged or to urine with the side chain shortened but the chroman ring intact. The ability of dietary vitamin E to mediate mitochondrial superoxide generation affords a possible mode of action of vitamin E at the tissue levels. By decreasing the generation and/or the levels of reactive oxygen/nitrogen species, dietary

Introduction

Vitamin E is the term referring to all tocol and tocotrienol derivatives qualitatively exhibiting the biological activity of RRR-a-tocopherol. The term 'tocopherols' is the generic description for all mono-, di- and trimethyl tocols and tocotrienols and is not synonymous with 'vitamin E'. There are four tocopherols (tocos) and four tocotrienols that occur naturally, differing in the number and position of methyl groups on the chroman ring. All eight naturally occurring tocopherol compounds isolated from plant sources have a 6-chromanol ring (head) and a phytyl side chain (tail) [4, t 5, 40]. Tocotrienols have a similar structure to that of their corresponding tocopherols, except that the side chain contains three double bonds at the 3', 7", and 11" positions. In addition to the naturally occurring isomers, several types of synthetic vitamin E, either in free or ester forms,

K A R G ER
F a x + 4 t 61 306 12 34 E-Mail karger@karger, ch unvw.kargcr.com

2004 Nationat Science Council, ROC S. Karger AG, Basel 1021-7770/04/0113-0295521.00/0 Accessible online at: w~v.karger.com/jbs

Dr. Ching Kuang Chow Graduate Center for Nutritional Sciences, University of Kentucky 308 Funldaouder Building Lexington, KY 40506-0054 (USA) TeI. +1 859 257 7783, E-Mail ckchow@uky.edu

are available commercially. As the ester form, such as atocopheryl acetate, is less susceptible to oxidation, it is more suitable for food and pharmaceutical applications than the free form. The naturally occurring a-tocopherol, formerly known as d-a-tocopherol, is now designated as RRR-a-tocopherol. The synthetic a-tocopherol, which consists of eight stereoisomers [2D,4'D,8'D (RRR), 2L,4'D,8'D (SRR), 2D,4'D,8'L (RRS), 2L,4'D'8~L (SRS), 2D,4'L,8"D (RSR), 2L,4"L,8'D (SSR), 2D,4"L,8'L (RSS), and 2L,4'L,8'L (SSS)] [40], previously known as d/-a-tocopherol or 2DL,4'DL,8'DL-tocopherol, is now called allrac-a-tocopherol. Vitamin E was discovered over 80 years ago [24]. However, due to the lack of a definite clinical syndrome attributable to its deficiency, the need or use of vitamin E for humans had been questioned. Lately, with the recognition of a role of free radicals in the pathogenesis of degenerative diseases, and possible prevention of these diseases by antioxidants, there has been a renewed and expanded interest in vitamin E. The large amount of information accumulated to date has confirmed the essentiality of vitamin E tbr humans and provided a better understanding of its role in cellular functions. This article focuses on the biological functions and metabolic fate of vitamin E with specific reference to several long-puzzling questions of its role in human nutrition.

Is Vitamin E Indeed Essential for Humans?

patients with a variety of fat malabsorption conditions, such as abetalipoproteinemia, chronic cholestatic hepatobiliaD disorder, and cystic fibrosis. Conclusive evidence of the essentiality of vitamin E for humans was obtained from studies of patients with familiar isolated vitamin E deficiency or atoxia with isolated vitamin E deficiency in the 1990s. These patients, who have no malabsorption syndrome, have neurological dysfunctions and extremely tow serum vitamin E levels [43, 73]. Subsequent studies demonstrated that the very low vitamin E status of these patients is attributable to their absence of a-tocopherol transfer protein (a-TTP). a-TTP, which is a cytosolic protein with high affinity to RRRa-tocopherol, is required for the secretion of tocopherol into lipoproteins and facilitates its return to the liver, aTTP is the major intracellular transport protein for vitamin E which mediates a-tocopherol secretion into the plasma via a non-Golgi-dependent pathway, while other binding proteins seem to play a less important role [38]. The human a-TTP gene is located at chromosome 8q13 [ 1], and mutations of the gene impair secretion of tocopherol into hepatic lipoproteins. Studies of the gene structure and mutations of a-TTP of patients with familial isolated vitamin E deficiency confirm a critical role of cc-TTP in maintaining an appropriate vitamin E state [1, 34, 53, 73]. As high doses of vitamin E can prevent or mitigate the neurological course of the patients, a direct transfer of some tocopherol from chylomicrons to other circulating lipoproteins may occur [28].

Vitamin E was first recognized as a lipid-soluble substance necessary for the prevention of fetal death and resorption in rats that had been fed a rancid lard diet [24]. Also, a number of species-dependent deficiency symptoms of vitamin E, such as liver necrosis in rats and pigs, erythrocyte hemolysis in rats and chicken, and white muscle disease in calves, sheep, mice, and mink, were reported decades ago [59]. However, the need of vitamin E for humans was questioned due to the lack of a definite clinical syndrome attributable to its deficiency, the absence of a widespread deficiency in humans, and the difficulty of inducing a deficiency in healthy adults [32]. In the late 1960s, the need of vitamin E for humans was recognized in connection with studies on premature infants in which hemolytic anemia was associated with an inadequate vitamin E status [3]. Subsequent studies have shown that secondary vitamin E deficiency occurs in patients with neurological abnormalities in association with generalized fat malabsorption syndrome of various etiologies [3, 62]. Low serum vitamin E levels are found in

Why is Vitamin E Deficiency Not Common in Humans?

As stated above, decades after the discovery of vitamin E, its need or use in humans remained uncertain due to the lack of a definite clinical syndrome attributable to its deficiency or absence of a widespread vitamin E deficiency. Additionally, it is difficult to induce a deficiency in healthy adults experimentally [32]. Information accumulated over the past decades shows that the presence of (1) tocopherol regeneration systems and (2) functionally interdependent antioxidant systems is largely responsible for the absence of a widespread vitamin E deficiency and that it is difficult to deplete the vitamin in healthy adults.

TocopherolRegeneration Systems
It has long been recognized that the efficacy of a-tocopherol in vivo can be augmented by ascorbic acid [65]. Subsequent studies have demonstrated that the a-to-

296

J Biomed Sci 2004;11:295-302

Chow

copheryl chromanoxy radical can be reverted to a-tocopherol and that the conversion is facilitated by ascorbic acid and glutathione (GSH) [6, 51, 54]. Also, the reducing state of ascorbic acid is maintained by GSH-dependent dehydroascorbate reductase and NADH-semidehydroascorbate reductase and that of GSH by GSH disulfide reductase [14, 22]. Additionally, dihydrolipoic acid, NADHcytochrome b5, and ubiquinol may be involved in the regeneration of et-tocopherol [ 14, 36].

complements the tocopherol regeneration systems in preserving vitamin E. Among the known GSH peroxidases, phospholipid hydroperoxide GSH peroxidase seems to be the most effective one in preventing peroxidative damage to membrane lipids [37, 75].

Why Is RRR-a-Tocopherol More Superior Biologically than Other Isomers of Tocopherols?

Functionally Interdependent Antioxidant Systems

While the cell is continuously subjected to oxidative stress exerted by a large variety of chemical, biological, and physical agents in the cellular environment, various antioxidant systems in the cell are able to control or prevent the adverse effects of oxygen and its reactive intermediates under normal conditions [12, 14]. When the antioxidant potential is weakened and/or oxidative stress is increased, however, irreversible damage to the cell may occur. The susceptibility of a given organ or organ system to oxidative damage is determined by the overall balance between the extent of oxidative stress and the antioxidant capability [12]. Major cellular antioxidant mechanisms include (1) direct interaction with oxidants or oxidizing agents by ascorbic acid, GSH, and other reducing agents; (2) scavenging of free radicals and singlet oxygen by vitamin E, ascorbic acid, carotenoids, superoxide dismutase, and other scavengers; (3) reduction of hydroperoxides by GSH peroxidases and catalase; (4) binding or removal of transition metals by ferritin, transferrin, ceruloplasmin, albumin, and other chelators; (5) separation or prevention of reactive oxygen species from reaching the specific site of action or reacting with essential cellular components by membrane barriers, and (6) repair of resulting damage by dietary nutrients and metabolic activities [ 14]. Vitamin E functions closely with other antioxidant systems [12, 14]. Ascorbic acid, GSH, lipoic acid, and ubiquinol, for example, are involved in the regeneration or restoration of vitamin E. Also, by reducing the hydroperoxide formed, selenoenzyme GSH peroxidase [61] and its functionally related enzymes, GSH disulfide reductase and glucose-6-phosphate dehydrogenase, augment the function of vitamin E against peroxidative damage to membrane lipids [ 17, 18]. The ability of the GSH peroxidase system to respond to oxidative stress adaptively or compensatively seems to be responsible for the lack of significant accumulation of lipid hydroperoxides in the tissues of vitamin-E-deficient and other oxidatively stressed animals [ 11, 12, 14, 18]. By augmenting the antioxidant functions of vitamin E, the GSH peroxidase system also While all isomers oftocopherols are absorbed efficiently, they differ widely in their biological activities. The biological activity of tocopherols is assessed by their relative ability to prevent deficiency symptoms such as fetal resorption-gestation, erythrocyte hemolysis, and/or myopathy in rats [ 10, 77, 78]. The biological activity of vitamin E is normally expressed as international units relative to that of all-rac-o.-tocopheryl acetate. The relative values (IU/mg) are 1.00 for all-rac-o.-tocopheryl acetate, 1.10 for alt-rac-ct-tocopherol, 1.36 for RRR-a-tocopheryl acetate, 1.49 for RRR-a-tocopherol, 0.89 for all-rac-a-tocopheryt succinate, 1.21 for RRR-ct-tocopheryl succinate, 0.370.75 for RRR-f3-tocopherol, 0.12-0.28 for RRR-y-tocopherol, and 0.01-0.04 for RRR-8-tocopherol according to the resorption-gestation test [77, 78]. RRR-7-tocopherol is the major source of tocopherols in a typical US diet [13]. A higher vitamin E activity of RRR-a-tocopherol than of other isomers suggests that the RRR configuration of the phytyl tail is needed for maximum biopotency, a-TTP recognizes preferentially specific structural features with a fully methylated aromatic ring, a saturated phytyl side chain, and a stereochemical RRR configuration of the methyl groups' branching of the side chain [69, 70]. By incorporating RRR-ct-tocopherol over other tocopherots into very-low-density lipoproteins (VLDL), which are then secreted into the plasma, the process results in the preferential enrichment of low-density lipoprotein and high-density lipoprotein with RRR-a-tocopherol in plasma. a-TTP also facilitates the return of RRR-a-tocopherol to the liver from plasma via high- and low-density lipoproteins. Absence of the transfer protein in patients with familial isolated vitamin E deficiency, which impairs the secretion of tocopherol into hepatic lipoproteins, is responsible for their extremely low vitamin E status [41, 44, 72, 73]. The secretory pathway via nascent VLDL from the liver is critical in maintaining tocopherol concentrations in plasma, and discrimination among the isomers by a-TTP occurs during hepatic secretion of nascent

Biological Functions of Vitamin E

J Biomed Sci 2004; 11:295-302

297

VLDL [69, 70, 72]. Thus, by regulating the transfer/binding of tocopherots, a-TTP plays a key role in determining not only their plasma concentrations, but also their biological activities.

Chroman Ring OpenedProducts

Tocopheryl chromanoxy radicals can also be further oxidized to tocopheryl quinone, a small amount of which is found in the liver [23]. The tocopheryl quinone formed can be converted to tocopheryl hydroquinone, and the reaction is catalyzed by a NADPH-cy~ochrome P-450 reductase [33]. Bound or conjugated c~.-tocopherylhydroquinone can be secreted into the bile and eliminated in the feces [ 19]. Another portion of a-tocopheryl hydroquinone may further be metabolized, by side chain shortening via [3-oxidation, to form a-tocopheronic acid (or tocopheronolactone) which is subsequently conjugated and excreted into urine [19]. A small amount of ct-tocopheronic acid is found in the urine of rabbits and humans after administration of large doses of a-tocopherol [60]. Neither a-tocopheryl quinone nor a-tocopheryl hydroquinone is converted to a-tocopherol in vivo [ 19].

What Happens to the Tocopherols Consumed?

Following absorption, tocopherols taken up by the liver are either stored in the parenchymal cells or secreted into the bloodstream within nascent VLDL. Some tocopherols in the VLDL may end up in low-density lipoprotein by the action of lipoprotein lipase in plasma. The scavenger receptor class B type I receptor, a membranebound protein, is capable of transferring vitamin E into the cell, while the ATP-binding cassette transporter A1 can excrete vitamin E out of the cell [38]. Tocopherols in low-density lipoprotein may again be taken up by the liver via the low-density lipoprotein (apolipoprotein B/E) receptor or by non-receptor-mediated uptake [41, 69]. Some tocopherols in association with chylomicrons and VLDL are transferred to peripheral cells and high-density lipoprotein during lipolysis by lipoprotein lipase. The tocopherols secreted are either rapidly returned from blood to the liver or excreted to feces. Thus, the tocopherols consumed are either stored in parenchymal cells or metabolized/excreted into feces or urine with or without exerting their functions. The fate oftocopherols consumed is summarized below:

Side-Chain-ShortenedProducts without Opening Chroman Ring

Several urinary metabolites of tocopherols with the side chain shortened are formed in the liver directly from a side chain degradation of tocopherols without oxidative splitting of the chroman ring [38]. The side chain oftocopherols is initially hydroxylated via c0-hydroxylation, and the reaction is catalyzed by the cytochrome P-4503A family of enzymes. After hydroxylation, the side chain of tocopherols is shortened via [3-oxidation from 16 carbons to three carbons. It appears that the product, 2,5,7,8-tetramethyl- 1(2'-carboxyethyl)-6-hydroxychroman instead of a-tocopheronic acid, is the major urinary metabolite of a-tocopherol [58]. Since 2,5,7,8-tetramethyl-l(2'-carboxyethyl)-6-hydroxychroman can be oxidized to form a-tocopheronic acid, whether the latter compound is an artifact or an authentic metabolite is uncertain. Similarly, 2,5,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman, 2,7,8- trimethyl-2(2'-carboxyethyl)-6-hydroxychroman,and 2,8-dimethyl-2(2'-carboxyethyl)-6-hydroxychroman have been identified as the principal urinary metabolites for 13-,7- and 8-tocopherols, respectively [8, 38, 76]. The identification of these urinary metabolites provides a better understanding of the metabolic fates of various tocopherols consumed. Information available suggests that the side-chain-shortened products, with the chroman ring intact, are the major urinary metabolites of tocopherols absorbed, especially when a large dose is consumed. Coupled with its preferential bounding to RRRa-tocopherol, a-TTP also sheds lights on the differential biological activities of various isomers of vitamin E which are similarly absorbed.

Unchanged Tocopherols
In addition to unabsorbed tocopherols, a portion of absorbed tocopherols, not returned to the liver or taken up by other organs from the circulation, is excreted via the bile unchanged and then into the feces. The amount of unchanged tocopherols excreted into the feces is normally increased, as the dose increases.

One-Electron Oxidation Products

After exerting its function as a free radical scavenger, tocopherol is first converted to tocopheryl chromanoxy radical. The chromanoxy radical can readily be reverted to tocopherol, and the process is facilitated by such reducing agents as GSH and ascorbic acid in association with enzyme systems (see above). Some tocopheryl chromanoxy radicals may be quenched to form dimers or trimers. A small amount of the dimers and trimers of a-tocopherol is found in the liver [23].

298

J Biomed Sci 2004; 11:295-302

Chow

H o w M a y V i t a m i n E Function at the Tissue Level?

Although the scientific rationale, epidemiological data, and retrospective studies largely support the assumption that an increased intake of vitamin E is associated with a reduced risk of degenerative diseases, prospective, randomized, placebo-controlled trials have failed to verify a consistent benefit [21, 43, 47, 48, 64, 74]. Based on the totality of available scientific evidence, the US Food and Drug Administration did not approve the health claims associated with vitamin E intake and risk of cancer or cardiovascular disease. Similarly, the recent Panel on Dietary Antioxidants of the US Food Nutrition Board did not recommend an increase in its daily allowance. In addition to the inconclusive findings from more recent prospective placebo-controlled trials, a lack of understanding of the mode of action of vitamin E at the tissue level is also responsible. While a number of biochemical abnormalities are associated with vitamin E deficiency, the mechanism by which vitamin E prevents various metabolic and pathological lesions is not yet clear. A mediating role of vitamin E in mitochondrial superoxide generation, however, may explain how the vitamin exerts its action at the tissue level. The mitochondrion, which utilizes over 85% of oxygen, is the major site of superoxide generation, while superoxide plays a central role in the formation of reactive oxygen species, including hydrogen peroxide, hydroxyl radical, and peroxynitrite [63]. Interestingly, the mitochondrion has the highest concentration of vitamin E, and disruption of the mitochondriaI structure is one of the earliest events in the skeletal muscle of vitamin-E-deficient animals [67]. Recently, dietary vitamin E has been shown to reduce the mitochondrial superoxide generation [20, 45]. Dietary vitamin E may also reduce the levels of superoxide by stabilizing mitochondrial membranes and scavenging the superoxide generated. By reducing the generation/levels of superoxide, dietary vitamin E not only attenuates oxidative damage, but may also mediate the expression and/or activation of redox-sensitive biological modifiers vital for important cellular events [ 16].
How M a y Vitamin E Function as an Antioxidant in vivo? Reactive oxygen/nitrogen species may react with cellular components with resultant degradation and/or inactivation of essential cellular constituents [ 12, 27, 31, 80]. Vitamin E can react more rapidly with peroxy radicals several orders of magnitude faster than with acyl lipids

and thus prevents peroxidation tissue damage [40]. Also, vitamin E may exert its antioxidant function by limiting the generation and/or levels of superoxide and related reactive oxygen/nitrogen species [16, 20, 45]. In the presence of transition metal ions, superoxide may be converted to highly reactive hydroxyl radicals [50, 79]. Also, superoxide can react readily with nitric oxide to form peroxynitrite [63]. Peroxynitrite and hydroxyl radicals are the most reactive free radicals that may occur in biological systems. Additionally, superoxide may release iron from its protein complex [29, 42, 49]. The cellular labile iron or free iron associated with low molecule mass has the potential to participate in redox cycling and catalyze the formation of hydroxyl radicals from superoxide/hydrogen peroxide [39, 42, 49]. On the other hand, the state and levels of labile iron can be modified by oxidants or reductants acting on cell iron sources, such as ferritin. It has long been recognized that dietary vitamin E alters the iron metabolism and protects against oxidative damage resulting from iron overload [9, 26, 56]. The protective effect can now be partly attributable to the ability of dietary vitamin E to limit the generation and/or level of superoxide. By reducing the generation and/or levels of superoxide, vitamin E not only reduces the levels of harmful free radicals, but also limits the release of iron from its protein complex. In collaboration with higher rates of mitochondrial superoxide generation, higher levels of labile iron and oxidation products were found in the tissues of rats fed a low vitamin E diet [35]. Additionally, transgenic mice overexpressing manganese superoxide dismutase had lower tissue levels of labile iron and oxidation products, while manganese superoxide knockout mice had higher tissue levels of labile iron and oxidation products [35]. These findings also support the view that superoxide and free iron play a key role in initiating oxidative tissue damage. Thus, vitamin E may prevent oxidative damage or exert its antioxidant function by (1) directly scavenging oxidants/free radicals and (2) downregulating mitochondrial superoxide generation which in turn reduces the formation of peroxynitrite and release of labile iron from its protein complex. By reducing superoxide and available labile iron, the possibility of hydroxyl radical formation is also reduced.
How May Vitamin E Act as a Biological Response Modifier? Since not all the biological effects can be explained based on its antioxidant property, vitamin E may also function as a biological response modifier independent of

Biological Functions of Vitamin E

J Biomed Sci 2004; 11:295-302

299

its antioxidant function [71]. Recent advances in molecular biology and genomic techniques have led to the discovery of novel vitamin-E-sensitive genes and signal transduction pathways [57]. RRR-o~-tocopherol, for example, has been shown to regulate key cell signaling functions, protein kinase C activity, and vascular smooth muscle cell growth by mechanisms unrelated to its antioxidant [66]. Also, RRR-o,-tocopherol modulates the expression of the hepatic collagen ~1 gene, ~-TTP gene, a-tropomysin gene, and collagenase gene and diminishes adhesion molecule, collagenase, and scavenger receptor expression and increases connective tissue growth factor expression [2]. While the mechanism by which vitamin E mediates cell-signaling functions is not yet clear, alteration of oxidative stress or redox homeostasis may be one of the hallmarks of the processes that regulate gene transcription in physiology and pathophysiology [30]. Changes in the pattern ofgene expression through redox-sensitive regulatory transcription factors are crucial components of the machinery that determines cellular responses to oxidative conditions. For example, the transcription factors nuclear factor-kappaB and hypoxia-inducible factor- 1a are directly influenced by reactive species and proinflammatory signals [30]. Major signaling transduction pathways that may be involved in hyperoxia include the mitogen-activated protein kinases, activator protein-l, and nuclear factor-kappaB which converge, ultimately, to the expression of a range of stress response genes, cytokines, and growth factors [46]. Also, oxidative stress or redox state seems to have a dual effect on the activation of nuclear factor-kappaB [5]. Regulation of signal transduction and gene expression is a multifaceted process involving ligands, receptors, and second messengers that trigger cascades of protein kinases and phosphatases and propagate the signal to the nucleus to alter the gene expression. Redox-based regulatory path-

ways provide additional means of gating signal transduction, and redox-based regulation of gene expression emerges as a fundamental regulatory mechanism in living cells [55]. The intracellular production of reactive oxygen/ nitrogen species seems to be of fundamental importance in cell proliferation, differentiation, apoptosis, necrosis, vascular hyperglycemia, platelet adhesion/aggregation, thrombosis, tumor angiogenesis, and other important cellular events [7, 25, 52, 68]. Thus, by reducing the generation and/or levels of superoxide and other reactive oxygen/nitrogen species, dietary vitamin E may modulate the activation and/or expression of redox-sensitive biological response modifiers and may thereby attenuate the cellular events leading to the onset of cardiovascular diseases, cancer, and aging and neurodegenerative diseases [16]. However, whether this mediating role of vitamin E in the cell-signaling events is independent of or secondary to antioxidant function or changes in redox state remains to be elucidated.

Concluding Remarks

While the interest in the role of vitamin E in preventing the pathogenesis of degenerative disease remains high, recent prospective, randomized, placebo-controlled trials have failed to verify a consistent benefit. Information accumulated over the past decades has confirmed the essentiality of vitamin E for humans and provided a better understanding of its biological function and the metabolic fate. The ability of dietary vitamin E to mediate superoxide generation/level affords a possible mode of action of the vitamin at the tissue levels. More studies are needed to determine more precisely the benefits of vitamin E in human health and its mode of action at the tissue levels.

References
1 Arita M, Sato, Y, Miyata A, Tababe T, Takahashi E, Kayden It J, Arai H, Inoue K. Human a-tocopherol transfer protein: Gene structure and chromosomal localization. Biochem J 305: 437-443; 1995. 2 Azzi A, Ricciarelli R, Zingg JM. Non-antioxidant molecular functions of alpha-tocopberol (vitamin E). FEBS Lett 519:8-10;2002. 3 Bieri JG, Farrell PM. Vitamin E. Vitam Horm 34:31-75; 1976. 4 Burton GW, Traber MG. Vitamin E: Antioxidant activity, biokinetics, and bioavailability. Annu Rev Nutr 10:357-380; 1990. 5 Byun MS, Jeon KI, Choi JW, Shim JY, Jue DM. Dual effect of oxidative stress on NF-kappakB activation in HeLa cells. Exp Mol Med 34:332-339;2002. 6 Chart AC, Tran K, Raynor T, Ganz PR, Chow CK. Regeneration of vitamin E in human platelets. J Biol Chem 266:17290-17295; 1991. 7 Chiarugi P. Reactive oxygen species as mediators of cell adhesion. Ital J Biochem 52:28-32; 2003. 8 Chiku S, Hamamura K, Nakamura T. Novel urinary metabolite of ~5-tocopherol in rats. J Lipid Res 25:40-48; 1984. 9 Chou AC, Broun GO, Fitch CD Jr. Abnormalities of iron metabolism and erythropoieses in vitamin E-deficient rabbits. Blood 52:18%195; 1978.

300

J Biomed Sci 2004;i 1:295-302

Chow

l0 Chow CK. Increased activity of pyruvate kinase in plasma of vitamin E-deficient rats. J Nutr 105:1221-1224;1975. 11 Chow CK. Biochemical responses in the lungs of ozone-tolerant rats. Nature 260:721-722; 1976. 12 Chow CK. Nutritional influence in cellular antioxidant defense systems. Am J Clin Nutr 32: 1066-1081;1979. 13 Chow CK. Vitamin E and blood. World Rev Nutr Diet 45:133-166; 1985. 14 Chow CK. Vitamin E and oxidative stress. Free Radic Biol Med 11:215-232; 1991. 15 Chow CK. Vitamin E. In: Rucker RB, Suttie JW, McCormick DB, Machlin LJ, eds. Handbook of Vitamins, ed 3. New York, Marcel Dekker, 165-197; 2001. 16 Chow CK. Vitamin E regulation of mitochondrial superoxide. Biol Signals Recept 10:112124;2001. 17 Chow CK, Tappel AL. An enzymatic protective mechanism against lipid peroxidation damage to lungs of ozone-exposed rats. Lipids 7:518-524;I972. 18 Chow CK, Reddy K, Tappel AL. Eft~ct of dietary vitamin E on the activities of glutathione peroxidase system in rat tissue. J Nutr 103:618-624;1973. 19 Chow CK, Draper HH, Csallany AS, Chiu M. The metabolism of 14C-u-tocopheryl quinone and 14C-ct-tocopherylhydroquinone. Lipids 2: 390-396; 1967. 20 Chow CK, Ibrahim W, Wei Z, Chan AC. Vitamin E regulates mitochondrial hydrogen peroxide generation. Free Radic Biol Med 27:580587;1999. 21 Clarke R, Armitage J. Antioxidant vitamins and risk of cardiovascular disease: Review of large-scale randomised trials. Cardiovasc Drugs Ther 16:411-415;2002. 22 Diliberto E Jr, Dean G, Carter C, Allen PL. Tissue, subceilular, and submitochondriaI distributions of semidehydroascorbate reductase: Possible role of semidehydroascorbate reductase in cofactor regeneration. J Neurochem 39: 563-568;1982. 23 Draper HH, CsaIlany A. Metabolism and flanction of vitamin E. Fed Proc 28:1690-1695; 1969. 24 Evans HM, Bishop KS. On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science 56:650-651; 1922. 25 Finkel T. Oxidant signals and oxidative stress. Curr Opin Cell Biol 5:247-254;2003. 26 Fraga CG, Oteiza PI. Iron toxicity and antioxidant nutrients. Toxicology 180:23-32;2002. 27 Freeman BA, Crapo JD. Biology of disease: Free radicals and tissue injury. Lab Invest 47: 412-426;1982. 28 Gabsi S, Gouider-Khouja N, Belal S, Fki M, Kefi M, Turki I, Ben-Hamida M, Kayden H, Mebazaa R, Hentati F. Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. Enr J Neurol 8:477-481; 2001. 29 Gutteridge JM. Iron promoters of the Fenton reaction and lipid peroxidation can be released from hemoglobin by peroxide. FEBS Lett 201: 291-295; 1986.

30 Haddad JJ. Antioxidant and prooxidant mechanisms in the regulation of redox(y)-sensitive transcription factors. Cell Signal 14:879-897; 2002. 31 Halliwell B. Oxidants and human disease: Some new concepts. FASEB J I:358-364; 1987. 32 Harmon EM, Witting LA, Horwitt MK. Relative rates of depletion of alpha-tocopherol and tinoleic acid after feeding polyunsaturated fats. Am J Clin Nutr 18:243-248; 1966. 33 Hayashi T, Kanetoshi A, Nakamura M, Tamura M, Shirahama H. Reduction of alpha-tocopherolquinone to alpha-tocopherolhydroquinone in rat hepatocytes. Biochem Pharmacol 44:489-493;1992. 34 Hentati A, Deng HX, Hung WY, Nayer M, Ahmed MG, He X, Tim R, Stumpf DA, Siddique T. Human alpha-tocopherol transfer protein: Gene structure and mutations in familial vitamin E deficiency. Ann Neurol 39:295-300; 1996. 35 Ibrahim W, Chow CK. Unpublished results. 36 Ibrahim WH, Bhagavan HN, Chopra RK, Chow CK. Dietary coenzyme Q 10 and vitamin E alter the status of these compounds in rat tissues and mitochondria. J Nutr 130:2343-2348; 2000. 37 Imai H, Nakagawa Y. Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Free Radic Biol Med 34:145-169;2003. 38 Jialal I, Traber M, Devaraj S. Is there a vitamin E paradox? Curr Opin Lipidol 12:49-53;2001. 39 Kakhlon O, Ioav Cabantchik Z. The labile iron pool: Characterization, measurement, and participation in cellular processes. Free Radic Biol Med 33:I037-1046;2002. 40 Kamal-Eldin A, Appetqvist LA. The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids 31:671-701; 1996. 41 Kayden HJ, Traber MG. Absorption, lipoprotein transport, and regulation of plasma concentrations of vitamin E in humans. J Lipid Res 34:343-358;1993. 42 Keyer K, Imlay JA. Superoxide accelerates DNA damage by elevating free iron Ievels. Proc Natt Acad Sci USA 93:13635-t 3640; 1996. 43 Kline K, Lawson KA, Yu W, Sanders BG. Vitamin E and breast cancer prevention: Current status and future potential. J Mammary Gland Biol Neoplasia 8:91- 102;2003. 44 Kohlschiitter A, Hiibner C, Jansen W, Lindner SG. A treatable familial neuromyopathy with vitamin E deficiency, normal absorption, and evidence of increased consumption of vitamin E. J Inherit Metab Dis 11: 149-152; 1988. 45 Lass A, Sohal RS. Effect of coenzyme Q(10) and alpha-tocopherol content of mitochondria on the production of superoxide anion radicals. FASEB J 14:87-94;2000. 46 Lee PJ, Choi AM. Pathways of cell signaling in hyperoxia. Free Radic Biol Med 35:341-350; 2003. 47 Manson JE, Bassnk SS, Stampfer MJ. Does vitamin E supplementation prevent cardiovascular events? J Womens Health (Larchmt) i2: 123-136;2003.

48 Meagher EA. Treatment of atherosclerosis in the new millennium: Is there a role for vitamin E? Prey CardioI 6:85-90;2003. 49 Minotti G. Sources and role of iron in lipid peroxidation. Chem Res Toxicol 6:134-146; 1993. 50 Minotti G, Aust SD. The requirement for iron (III) in the initiation of lipid peroxidation by iron (II) and hydrogen peroxide. J Biol Chem 262:1098-1 i04;I 987. 51 Niki E, Tsuchiya J, Tanimura R, Kamiya Y. Regeneration of vitamin E from alpha-chromanoxy radical by glutathione and vitamin C. Chem Lett 6:789-792;1982. 52 O'Donnell VB. Free radicals and lipid signaling in endothelial cells. Antioxid Redox Signal 5: 195-200;2003. 53 Quahchi K, Arita M, Kayden H J, Hentati F, Hamida MB, Sokol R, Arai H, Inoue IG Mandel IL, Koenig M. Ataxia with isolated vitamin E deficiency is caused by mutation in the ntocopherol transfer protein. Nat Genet 9:141145;I995. 54 Packer JE, Slater TF, Wilson RL. Direct observation of a free radical interaction between vitamin E and vitamin C. Nature 278:737738;1979. 55 Pfeilschifter J, Eberhardt W, Huwiler A. Nitric oxide and mechanisms of redox signaling. J Am Soc NephroI 14(8 suppl 3):S237-$240; 2003. 56 Poli G, Albano E, Biasi F, Cecchini G, Carini R, Bellomo G, Dianzani MU. Lipid peroxidation stimulated by carbon tetrachloride or iron and hepato%e death: Protective effect of vitamin E. Eur J Biochem 59:449-455;1975. 57 Rimbach G, Minihane AM, Majewicz J, Fischer A, Pallauf J, Virgli F, Weinberg PD. Regulation of cell signalling by vitamin E. Proc Nutr Soc 61:415-425;2002. 58 Schultz M, Leist M, Petrzika M, Gassmann B, Brigelius-Flohe R. Novel urinary metabolite of c~-tocopherol, 2,5,7,8- tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman, as an indicator of an adequate vitamin E supply? Am J Clin Nutr 62(6 Suppl):1527S- 1534S; 1995. 59 Scott ML. Studies on vitamin E and related factors in nutrition and metabolism. In: DeLuca HF, Suttie JW, eds. The Fat-Soluble Vitamins. Madison, University of Wisconsin Press, 355368; 1969. 60 Simon EJ, Eisengart A, Sundheim L, Milhorat AT. The metabolism of vitamin E. II. Purification and characterization of urinary metabolites of a-tocopherol. J Biol Chem 221:807817;1956. 61 Smith P, Tappel AL, Chow CK. Glutathione peroxidase activity as a function of dietary selenomethionine. Nature 247:392-393;1974. 62 Sokol RJ. Vitamin E deficiency and neurological disease. Annu Rev Nutr 8:351-373; 1988. 63 Squadrito GL, Pryor WA. Oxidative chemistry of nitric oxide: The roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med 25:392-403;1998. 64 Sung L, Greenberg ML, Koren G, Tomlinson GA, Tong A, Malkin D, Feldman BM. Vitamin E: The evidence for multiple roles in cancer. Nntr Cancer 46:1-14;2003.

Biological Functions o f Vitamin E

J Biomed Sci 2004;11:295-302

301

65 Tappel AL. Will antioxidant nutrients slow aging process? Geriatrics 23:97-105; 1968. 66 Tasinato A, Boscoboinik D, Bartoli GM, Maroni P, Azzi A. d-Alpha-tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its antioxidant properties. Proc Natl Acad Sci USA 92:12190-12194;1995. 67 Thomas PK, Cooper JM, King RH, Workman JM, Schapira AH, Sampson MA, Muller DP: Myopathy in vitamin E deficient rats: Muscle fiber necrosis associated with disturbances of mitochondrial function. J Anat 183:451-461; 1993. 68 Touyz RM. Recent advances in intracellular signalling in hypertension. Curr Opin Nephrol Hypertens 12:165-174;2003. 69 Traber MG. Determinations of plasma vitamin E concentrations. Free Radic Biol Med 16: 229-239; 1994. 70 Traber MG, Kayden HJ. Preferential incorporation of a-tocopherot vs. 7-tocopheml in human lipoproteins. Am J Clin Nutr 49:517-526; 1989.

71 Traber MG, Packer L. Vitamin E: Beyond antioxidant function. Am J Clin Nutr 62(6 Suppl): 1501 S- 1509S; 1995. 72 Traber MG, Bin-ton GW, Ingold KU, Kayden tIJ. RRR- and SRR-a-tocopherols are secreted without discrimination in human chylomicrons, but RRR-a-tocopherol is preferentially secreted in very low density lipoproteins. J Lipid Res 31:675-685;1990. 73 Traber MG, Sokol RJ, Kohlschtitter A, Kayden H J. Impaired discrimination between stereoisomers of a-tocopherol in patients with familial isolated vitamin E deficiency. J Lipid Res 34:201-210;1993~ 74 Upston JM, Kritharides L, Stocker R. The role of vitamin E in atherosclerosis. Prog Lipid Res 42:405-422;2003. 75 Ursini F, Maiorino M, Gregolin C. 't-he selenoenzyme phospholipid hydroperoxide glutathione peroxidase. Biochim Biophys Acta 839: 62-70;1985.

76 Wechter WJ, Kantoci D, Murry ED Jr, D'Amico DC, Jung ME, Wang Wt-I. A new endogenous natriuretic factor: LLU-a. Proc Natl Acad Sci USA 93:6002-6007; 1996. 77 Weiser H, Vecchi M. Stereoisomers of e.-tocopheryl acetate. II. Biopotencies of all eight stereoisomers, individually or in mixtures, as determined by rat resorption-gestation tests. Int J Vitam Nutr Res 52:351-370;1982. 78 Weiser H, Vecehi M, Schlachter M. Stereoisomers of alpha-tocopheryl acetate. IV. USP units and alpha-tocopherol equivalents of allrac-, 2-ambo- and RRR-alpha-tocopherol evaluated by simultaneous determination of resorption-gestation, myopathy and liver storage capacity in rats. Int J Vitam Nutr Res 56:4556;1986. 79 Welch KD, Davis TZ, Van Eden ME, Aust SD. Deleterious iron-mediated oxidation ofbiomolecules. Free Radic Biol Med 32:577-583; 2002. 80 Yu BP. Cellular defense against damage from reactive oxygen species. Physiol Rev 74:139162; 1994~

302

J Biomed Sci 2004;11:295-302

Chow