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A. Chemistry and Synthesis of Vitamin E Compounds
Vitamin E activity in plants is derived from eight naturally occurring plant compounds, the tocopherols and tocotrienols. In 1922 Evans and Bishop at the University of California, Berkeley first recognized the presence of a nutritional factor in vegetable oils essential for reproduction in the rat (Scott et al., 1982). In 1936 Evans et al. isolated and named the compound alpha-tocopherol, deriving the name from the Greek "tokos-pherein," meaning "offspring-to bear" and adding the -ol suffix to denote the presence of an alcohol group (Scott et al., 1982).
According to the International Union of Pure and Applied Chemistry-International Union of Biochemistry (IUPAC-IUB) Commission on Biochemical Nomenclature, vitamin E is used as a generic descriptor for all tocol and tocotrienol derivatives which qualitatively exhibit the biologic activity of alpha-tocopherol (IUPAC-IUB, 1973). Both the tocopherols (tocols) and tocotrienols consist of a hydroquinone nucleus and an isoprenoid side chain (Scherf et al., 1996; Machlin, 1991). Characteristically, tocopherols have a saturated side chain, while the tocotrienols have an unsaturated side chain containing three double bonds. There are four principal compounds of each of these two sources of vitamin E activity (alpha, beta, gamma, delta), differentiated by the presence of methyl (-CH3) groups at positions 5, 7 or 8 of the chroman ring (Figure 1). Alpha-tocopherol, the most biologically active of these compounds, is the predominant active form of vitamin E in feedstuffs and the form used commercially for supplementation of animal diets (Scherf et al., 1996). The biological activity of the other tocols and the tocotrienols is limited, ranging from 0% to 30% of the activity by weight of alpha-tocopherol (Table 1).
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The tocopherol molecule contains three asymmetric (chiral) carbon atoms located at the 2', 4' and 8' positions (Figure 1). In the d- form of alpha-tocopherol, the methyl groups at all three of the asymmetric carbon atoms have identical spatial arrangement, facing below the plane of the tocopherol molecule. This is designated as the RRR form and is the form of alpha-tocopherol found in plants (Scherf et al., 1996). The dl- form of alpha-tocopherol consists of an equal proportion of the R and S configurations at each of the three chiral carbons, which results in an equimolar mixture (12.5% each) of the eight possible stereoisomers of alpha-tocopherol (Weiser et al., 1992). This is designated the all-racemic or the "all-rac" form of alpha-tocopherol, in addition to being called dl-alpha-tocopherol.
Despite claims to the contrary, there is no truly "natural" vitamin E commercially available (Scherf et al., 1996). Natural vegetable oils contain varying mixtures of tocopherols and tocotrienols, each occurring in the alpha, beta, gamma and delta forms. These oils must be processed by vacuum distillation and chemically methylated in order to produce d-alpha-tocopherol specifically and in quantity. Thus, d-alpha-tocopherol is only obtained from natural sources after several chemical processing steps, and the product should be referred to as "natural-derived" and not "natural" vitamin E. More importantly, the International Unit (IU) remains the recognized standard for measuring and comparing the vitamin E activity of various sources. One IU of vitamin E is defined as 1.0 mg of dl-alpha-tocopheryl acetate. One IU of vitamin E activity is equivalent to another, regardless of source. In most cases, natural-derived vitamin E is esterified to acetate forming the more stable dl-alpha-tocopheryl acetate ester. The mixed tocopherols derived as a secondary product of dl-alpha-tocopherol production are used as natural-source antioxidants in the feed and food industries.
All-rac-alpha-tocopheryl acetate is the most common form of vitamin E form used in animal feeds and supplements. This form of vitamin E is manufactured by chemical synthesis, condensing trimethyl hydroquinone and isophytol and conducting ultra-vacuum molecular distillation, producing a highly purified form of alpha-tocopherol. This material is then acetylated for stability. As discussed previously, all-rac-alpha-tocopherol is an equimolar mixture of eight stereoisomers (four enantiomeric, R,S, pairs) of alpha-tocopherol acetate. The enantiomeric pairs, called racemates, have been shown to be present in equimolar proportions (Cohen et al., 1981; Weiser and Vecchi, 1981, 1982: Scott et al., 1982).
Alpha-tocopherol is a viscous, yellow oil, insoluble in water but soluble in most organic solvents (Illus. 1). Tocopherols are extremely heat resistant but are readily oxidized. Naturally occurring tocopherols and tocotrienols are subject to oxidative destruction, which is accelerated by heat, moisture, rancid fats, copper and iron. As a result, native tocopherols and tocotrienols are excellent antioxidants that can protect carotenes, retinol, biotin and other oxidizable substrates in feed. However, the tocopherols and tocotrienols are, in the process of acting as antioxidants, rendered biologically inactive as a source of vitamin E. For this reason, the acetylated form of alpha-tocopherol, tocopheryl acetate, is used as a source of dietary vitamin E. In some applications, the alcohol form of tocopherol or mixed tocopherols are used specifically as antioxidants.
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Vitamin E absorption takes place in concert with fat digestion and absorption, requiring bile salts and pancreatic lipase and esterase enzymes (Sitrin et al., 1987). Most vitamin E is absorbed in the upper two-thirds of the small intestine (Bjorneboe et al., 1990). Whether presented as free alcohol or as esters, most vitamin E is absorbed as the alcohol, and unlike vitamin A, is not re-esterified during absorption. Tocopherol esters are largely hydrolyzed in the intestinal lumen. Intestinal cells (enterocytes) absorb vitamin E in association with mixed lipid micelles. Within the enterocytes, vitamin E is incorporated into chylomicrons, which are then absorbed into the lymphatic system. Chylomicrons are in turn partially hydrolyzed and absorbed by the tissues, primarily the liver.
All body tissues and organs accumulate vitamin E, but the largest accumulation is in adipose tissue, skeletal muscle and liver (Bjorneboe et al., 1990). Immune cells (neutrophils, macrophages and lymphocytes) contain very high concentrations of vitamin E, as do erythrocytes. The liver accumulates vitamin E, although not to the extent of vitamin A, and exports vitamin E in combination with very low density lipoproteins (VLDL) for use by other tissues. In general, vitamin E is disseminated to body tissues by mass action and in proportion to intake. A continuous intake of vitamin E is required in order to maintain vitamin E concentrations in cellular membranes throughout the body.
In ruminants, there is little or no pre-intestinal absorption of dietary tocopherol. Rumen microbial destruction of tocopherol has been reported (McMurray and Rice, 1982; Weiss, 1998). However, the most recent studies, using the stabilized form of vitamin E (dl-alpha-tocopheryl acetate), have reported little if any degradation of vitamin E in the rumen (Weiss, 1998).
In most species, including ruminants, vitamin E absorption is proportional to the vitamin E status and requirement of the animal (Scherf et al., 1996; Traber and Sies, 1996; Hidiroglou et al., 1992b). Vitamin E absorption ranges from 50% to 75% of intake in deficient animals, from 20% to 30% in animals with adequate vitamin E status, and from 1% to 5% in animals fed large excesses of vitamin E. However, this may not always be the case. Hidiroglou et al. (1988b) reported no correlation between vitamin E status and tocopherol absorption.
Other dietary and animal factors—in particular fat intake, digestion and liver function—affect absorption of vitamin E and the other fat-soluble vitamins. Vitamin E absorption can be impaired by a variety of disorders associated with fat malabsorption (Combs, 1991). Either a deficiency (Kim et al., 1998) or an excess of dietary zinc (Lu and Combs, 1988) impairs absorption of vitamin E. Earlier studies with poultry reported that vitamin E accumulation in plasma and liver was proportional to the log of vitamin E intake (Hidiroglou et al., 1992b). An interesting contrast noted in that work was that vitamin E accumulated in liver more slowly and persisted longer than the synthetic antioxidant ethoxyquin, which declined rapidly beginning 30 minutes after an oral dose. This indicates a specific cellular role of tocopherol, which was concentrated in sites of free-radical generation, the mitochondria and microsomes, of liver cells.
Mammals and birds preferentially absorb tocopherol versus other tocols. Rates and amounts of absorption of the various tocopherols and tocotrienols are in the same general order of magnitude as their biological potencies. Alpha-tocopherol is absorbed most efficiently. Gamma-tocopherol is absorbed less efficiently and more rapidly excreted than the alpha form. In general, it can be assumed that most vitamin E activity in plasma, erythrocytes and other tissues is alpha-tocopherol (Ullrey, 1981; McDowell, 2000).
Vitamin E is transported in plasma by lipoproteins, and is delivered to tissues in association with lipids. Red blood cells contain significant amounts of vitamin E, which protects the erythrocytes from hemolysis. In ruminants, Vitamin E does not cross the placenta in any appreciable amounts, with levels in the fetus generally lower than in the dam (Malone, 1975), making the neonate highly susceptible to vitamin E deficiency (Hidiroglou et al., 1969; Van Saun et al., 1989). Placental vitamin E transfer may decrease as gestation proceeds, possibly a dilution effect resulting from rapid fetal growth or a decrease in maternal vitamin E supply. Neonatal calves, lambs and kids are dependent on colostrum as a source of vitamin E. Less than 1% of the dam's tocopherol intake is secreted in milk (Millar and Dawe, 1973). However, vitamin E concentration in colostrum is high (Table 2), and is directly affected by maternal vitamin E intake during gestation (Whitting and Loosli, 1948; Quigley and Drewry, 1998).
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Relatively little storage of vitamin E occurs in the body. The liver is not a true storage organ for vitamin E. It contains only a small fraction of total body vitamin E stores, in contrast to vitamin A, for which about 95% of the body reserves are contained in the liver. Unlike vitamin A, there is no known plasma transport protein for vitamin E, which is transported to and absorbed by tissues in association with lipoproteins. Small amounts of vitamin E will persist tenaciously in the body during deficiency, in particular in neural tissues (Bjorneboe et al., 1990). However, tissue stores are exhausted rapidly by polyunsaturated fatty acids (PUFA), the rate of disappearance being proportional to the intake of PUFA. Other sources of oxidative stress, including disease and inflammation -deplete vitamin E.
The major excretory route of absorbed vitamin E is bile, in which tocopherol appears mostly in the free alcohol form. Several oxidation products of vitamin E are also excreted in bile and urine, with tocopheryl quinone being the primary catabolite (Traber and Sies, 1996).
et al., 1976).
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