Companion Animals: Vitamin E

Vitamin E has been shown to be essential for integrity and optimum function of reproductive, muscular, circulatory, nervous, and immune systems (Hoekstra, 1975; Sheffy and Schultz, 1979; Bendich, 1987; McDowell, 2000). It is well established that some functions of vitamin E, however, can be fulfilled in part or entirely by traces of selenium or by certain synthetic antioxidants. Even sulfur-bearing amino acids, cystine and methionine, affect certain vitamin E functions. Considerable evidence indicates there may be undiscovered metabolic roles for vitamin E, which may be paralleled biologically by roles of selenium and possible other substances. The most widely accepted functions of vitamin E are discussed in this section.

Vitamin E has several different but related functions. One of the most important functions is its role as an intercellular and intracellular antioxidant (Figure 1). Vitamin E is part of the body's intracellular defense against the adverse effects of reactive oxygen and free radicals that initiate oxidation of unsaturated phospholipids (Chow, 1979) and critical sulfhydryl groups (Brownlee et al., 1977). Vitamin E functions as a quenching agent for free radical molecules with single, highly reactive electrons in their outer shells. Free radicals attract a hydrogen atom, along with its electron, away from the chain structure, satisfying the electron needs of the original free radical, but leaving the PUFA short one electron. Thus, a fatty acid free radical is formed that joins with molecular oxygen to form a peroxyl radical that steals a hydrogen-electron unit from yet another PUFA. This reaction can continue in a chain, resulting in the destruction of thousands of PUFA molecules (Gardner, 1989; Herdt and Stowe, 1991). Free radicals can be extremely damaging to biological systems (Padh, 1991).

Highly reactive oxygen species such as superoxide anion radical (O2-), hydroxyl radical (·OH), hydrogen peroxide (H2O2) and singlet oxygen (O2·) are continuously produced in the course of normal aerobic cellular metabolism. Also, phagocytic granulocytes undergo respiratory burst to produce oxygen radicals to destroy the intracellular pathogens. However, these oxidative products can, in turn, damage healthy cells if they are not eliminated. Antioxidants serve to stabilize these highly reactive free radicals, thereby maintaining the structural and functional integrity of cells (Chew, 1995). Therefore, antioxidants are very important to immune defense and health of humans and animals.

The antioxidant function of vitamin E is closely related to and synergistic with the role of selenium. Selenium has been shown to act in aqueous cell media (cytosol and mitochondrial matrix) by destroying hydrogen peroxide and hydroperoxides via the enzyme glutathione peroxidase (GSHpx), of which it is a co-factor. In this capacity, it prevents oxidation of unsaturated lipid materials within cells, thus protecting fats within the cell membrane from breaking down. It is the oxidation of vitamin E that prevents oxidation of other lipid materials to free radicals and peroxides within cells, thus protecting the cell membrane from damage (Drouchner, 1976). If lipid hydroperoxides are allowed to form in the absence of adequate tocopherols, direct cellular tissue damage can result, in which peroxidation of lipids destroys structural integrity of the cell and causes metabolic derangement.

Vitamin E reacts or functions as a chain-breaking antioxidant, thereby neutralizing free radicals and preventing oxidation of lipids within membranes. Free radicals may damage not only their cell of origin but migrate and damage adjacent cells in which more free radicals are produced in a chain reaction leading to tissue destruction (Nockels, 1991). At least one important function of vitamin E is to interrupt production of free radicals at the initial stage.

Myodystrophic tissue is common in cases of vitamin E-selenium deficiency, with leakage of cellular compounds such as creatinine and various transaminases through affected membranes into plasma. The more active the cell (e.g., the cells of skeletal and involuntary muscles), the greater is the inflow of lipids for energy supply and the greater is the risk of tissue damage if vitamin E is limiting. This antioxidant property also ensures erythrocyte stability and maintenance of capillary blood vessel integrity.

Interruption of fat peroxidation by tocopherol explains the well-established observation that dietary tocopherols protect or spare body supplies of such oxidizable materials as vitamin A, vitamin C and the carotenes. Certain deficiency signs of vitamin E (i.e., muscular dystrophy) can be prevented by diet supplementation with other antioxidant nutrients, which helps validate the antioxidant role of tocopherols. Semen quality of boars was improved with selenium and vitamin E supplementation, in which vitamin E helped maintain sperm integrity in combination with selenium (Marin-Guzman et al., 1989). Chemical antioxidants are stored at very low levels, and thus are not as effective as tocopherol. It is clear that highly unsaturated fatty acids in the diet increase vitamin E requirements (McDowell, 2000). When acting as an antioxidant, vitamin E supplies become depleted, which explains the frequent observation that the presence of dietary unsaturated fats (susceptible to peroxidation) increases or precipitates a vitamin E deficiency.

Alpha-tocopherol may be involved in the formation of structural components of biological membranes, thus exerting a unique influence on architecture of membrane phospholipids (Ullrey, 1981). It is reported that alpha-tocopherol stimulated the incorporation of 14C from linoleic acid into arachidonic acid in fibroblast phospholipids. Also, it was found that alpha-tocopherol exerted a pronounced stimulatory influence on formation of prostaglandin E from arachidonic acid, while a chemical antioxidant had no effect.

Vitamin E is an inhibitor of platelet aggregation in pigs (McIntosh et al., 1985), and may play a role by inhibiting peroxidation of arachidonic acid, which is required for formation of prostaglandins involved in platelet aggregation (Panganamala and Cornwell, 1982; Machlin, 1991).

Considerable attention is presently being directed to the roles that vitamin E and selenium play in protecting leukocytes and macrophages during phagocytosis, the mechanism whereby animals immunologically kill invading bacteria. Both vitamin E and selenium may help these cells to survive the toxic products that are produced in order to effectively kill ingested bacteria (Badwey and Karnovsky, 1980). Macrophages and neutrophils from vitamin E-deficient animals have decreased phagocytic activity (Burkholder and Swecker, 1990).

Since vitamin E acts as a tissue antioxidant and aids in quenching free radicals produced in the body, any infection or other stress factors may exacerbate depletion of the limited vitamin E stores from various tissues. With respect to immunocompetency, dietary requirements may be adequate for normal growth and production; however, higher levels have been shown to influence positively both cellular and humoral immune status of ruminant species. The former two responses are generally used as criteria for determining the requirement of a nutrient. During stress and disease, there is an increase in production of glucocorticoids, epinephrine, eicosanoids, and phagocytic activity. Eicosanoid and corticoid synthesis and phagocytic respiratory bursts are prominent producers of free radicals, which challenge the animal’s antioxidant systems. Vitamin E has been implicated in stimulation of serum antibody synthesis, particularly IgG antibodies (Tengerdy, 1980). The protective effects of vitamin E on animal health may be involved with its role in reduction of glucocorticoids, which are known to be immunosuppressive (Golub and Gershwin, 1985). In rats an in vivo inflammatory challenge decreased vitamin E blood and liver concentrations (Fritsche and McGuire, 1996). Vitamin E also most likely has an immunoenhancing effect by virtue of altering arachidonic acid metabolism and subsequent synthesis of prostaglandin, thromboxanes and leukotrienes. Under stress conditions increased, levels of these compounds by endogenous synthesis or exogenous entry may adversely affect immune cell function (Hadden, 1987).

The effects of vitamin E and selenium supplementation on protection against infection by several types of pathogenic organisms, as well as antibody titers and phagocytosis of the pathogens, have been reported for calves (Cipriano et al., 1982; Reddy et al., 1985; 1987b) and lambs (Reffett et al., 1988; Finch and Turner, 1989; Turner and Finch, 1990). As an example, calves receiving 125 IU of vitamin E daily were able to maximize their immune responses compared to calves receiving low dietary vitamin E (Reddy et al., 1987a). In sows, vitamin E restriction depressed lymphocytes and polymorphonuclear cells for immune function (Wuryastuti et al., 1993). Dogs with vitamin E deficiency had a depressed proliferative lymphocyte responsiveness (Langweiler et al., 1983).

Antioxidants, including vitamin E, play a role in resistance to viral infection. Vitamin E deficiency allows a normally benign virus to cause disease (Beck et al., 1994). In mice, enhanced virulence of a virus resulted in myocardial injury that was prevented with vitamin E adequacy. A selenium or vitamin E deficiency leads to a change in viral phenotype, such that an avirulent strain of a virus becomes virulent and a virulent strain becomes more virulent (Beck, 1997).

Vitamin E and selenium appear to enhance host defenses against infections by improving phagocytic cell function.

Both vitamin E and GSHpx are antioxidants that protect phagocytic cells and surrounding tissues from oxidative attack by free radicals produced by the respiratory burst of neutrophils and macrophages during phagocytosis (Baboir, 1984; Baker and Cohen, 1983). Hogan et al. (1990, 1992) reported that vitamin E supplementation of diets increased intracellular kill of Staphylococcus aureus and Esherichia coli by neutrophils.

There is limited evidence that vitamin E is involved in biological oxidation-reduction reactions (Hoffmann-La Roche, 1972). Vitamin E also appears to regulate the biosynthesis of DNA within cells.

Both vitamin E and selenium provide protection against toxicity of various heavy metals (Whanger, 1981). Vitamin E is highly effective in reducing toxicity of metals such as silver, arsenic and lead, and shows slight effects against cadmium and mercury toxicity.

Vitamin E can be effective against other toxic substances. For example, treatment with vitamin E gave protection to weanling pigs against monensin-induced skeletal muscle damage (Van Vleet et al., 1987). Recent research has shown a beneficial response for vitamin E supplementation on male reproduction for bulls fed high concentrations of gossypol. Velasquez-Pereira et al. (1998) reported that bulls which received 14 mg free gossypol per kg body weight had a lower (P < 0.05) percentage of normal sperm than those which also received supplemental vitamin E, 30% versus 55%, respectively (Table 1). Likewise, sperm production per gram of parenchyma and total daily sperm production were higher (P < 0.05) when gossypol-treated animals also received vitamin E. Bulls receiving gossypol exhibited more sexual inactivity (P < 0.05) than bulls in other treatments (Table 2). Vitamin E supplementation to bulls receiving gossypol improved number of mounts in the first test and time of first service in the second test. The final conclusion of the Florida data is that vitamin E is effective in reducing or eliminating important gossypol toxicity effects for male cattle.

There is a close working relationship between vitamin E and selenium within tissues. Selenium has a sparing effect on vitamin E and delays onset of deficiency signs. Likewise, vitamin E and sulfur amino acids partially protect against or delay onset of several forms of selenium deficiency syndromes. Tissue breakdown occurs in most species receiving diets deficient in both vitamin E and selenium, mainly through peroxidation. Peroxides and hydroperoxides are highly destructive to tissue integrity and lead to disease development. It now appears that vitamin E in cellular and subcellular membranes is the first line of defense against peroxidation of vital phospholipids (Figure 1), but even with adequate vitamin E, some peroxides are formed. Selenium, as part of the enzyme GSHpx, is a second line of defense that destroys these peroxides before they have an opportunity to cause damage to membranes. Therefore, selenium, vitamin E and sulfur-containing amino acids, through different biochemical mechanisms, are capable of preventing some of the same nutritional diseases. Vitamin E prevents fatty acid hydroperoxide formation, sulfur amino acids are precursors of GSHpx, and selenium is a component of GSHpx (Smith et al., 1974).

Additional functions of vitamin E that have been reported (Scott et al., 1982) include (1) normal phosphorylation reactions, especially of high-energy phosphate compounds, such as creatine phosphate and adenosine triphosphate (ATP); (2) a role in synthesis of vitamin C (ascorbic acid); (3) a role in synthesis of ubiquinone; and (4) a role in sulfur amino acid metabolism. Pappu et al. (1978) have reported vitamin E to play a role in vitamin B12 metabolism. A deficiency of vitamin E interfered with conversion of vitamin B12 to its coenzyme 5' deoxyadenosylcobalamin and concomitantly, metabolism of methylmalonyl-CoA to succinyl-CoA. For humans, Turley and Brewster (1993) suggest that cellular deficiency of adenosylcobalamin may be one mechanism by which vitamin E deficiency leads to neurologic injury.

In rats, vitamin E deficiency has been reported to inhibit vitamin D metabolism in the liver and kidneys with the formation of active metabolites and decreases in the concentration of the hormone-receptor complexes in the target tissue. Liver vitamin D hydroxylase activity decreased by 39%, 25-OHD3 1-alpha hydroxylase activity in the kidneys decreased by 22% and 24-hydroxylase activity by 52% (Sergeev et al., 1990).

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