highest relative potency, it is common to assay only for this isomer rather than to perform the more difficult separation and measurement of all eight natural compounds.
The principal commercially available forms of vitamin E are acetate and hydrogen succinate esters of RRR-α-tocopherol (formerly d-α-tocopherol) and of all-rac-α -tocopherol (formerly d,l-α-tocopherol). RRR-α-tocopherol is usually concentrated from natural sources, but it can be synthesized. All-rac-α-tocopherol is a condensation product of trimethylhydroquinone and racemic isophytol; the process results in a totally synthetic mixture of four 2R-stereoisomers (RRR-, RSR-, RRS-, and RSS-α-tocopherol) and four 2S-stereoisomers (SRR-, SSR-, SRS-, and SSS-α-tocopherol). It is sometimes confused with 2-ambo-α-tocopherol (also labeled d,l-α-tocopherol), a partially synthetic condensation product of trimethylhydroquinone and natural phytol that, as the acetate, served as the vitamin E standard for the international unit (IU) until its distribution was discontinued in 1956 (WHO, 1963). The confusion was of concern to Ames (1979) who claimed that the two synthetic forms differed in their relative potency, on the basis of retrospective examination of fetal-resorption bioassays over the previous 21 years. However, Weiser and Vecchi (1981) concluded from more recent research that the previously established biopotency ratios of 1:1 for all-rac-α-tocopheryl acetate to 2-ambo-α-tocopheryl acetate and 1.36:1 for RRR-α-tocopheryl acetate to 2-ambo-α-tocopheryl acetate were still valid. The US Pharmacopeia and National Formulary (1985) accepted those relationships, although relative plasma concentrations in humans after oral administration of RRR-α-tocopheryl acetate and all-rac-α-tocopheryl acetate suggested that RRR-α-tocopheryl acetate can have 2-3 times the bioavailability of the synthetic form per unit of weight (Acuff et al., 1994; Kiyose et al., 1995, 1997). Nevertheless, use of the traditionally defined IU persists: 1 IU = 1 USP unit = 1 mg of all-rac-α-tocopheryl acetate = 0.74 mg RRR-α-tocopheryl acetate = 0.67 mg RRR-α-tocopherol.
Alternatively, α-tocopherol equivalents (α-TEs) have been used to characterize vitamin E activity in human and animal diets; 1 α-TE was defined as the activity of 1 mg of RRR-α-tocopherol. Other natural compounds that once were thought to provide substantial vitamin E activity are β-tocopherol, γ-tocopherol, α-tocotrienol, and β-tocotrienol. When present and assayed, their contributions to dietary α-TEs were estimated by multiplying their concentrations in milligrams by 0.5, 0.1, 0.3, and 0.05, respectively (National Research Council, 1989). However, these other naturally occurring forms of vitamin E appear not to contribute toward meeting the vitamin E requirements of humans because, although absorbed, they are not converted to α-tocopherol and are recognized poorly by the α-tocopherol transfer protein in the liver. Because the 2S-stereoisomers of synthetic α-tocopherol are not maintained in human plasma or tissues, the relative vitamin E activity of 1 mg of all-rac-α-tocopherol has been set at 50% that of 1 mg of RRR-α-tocopherol (Institute of Medicine, 2000). Whether these quantitative relationships apply to nonhuman primates has not been established.
Absorption of tocopherols from the small intestine depends upon bile and pancreatic secretions, as involved in the typical processes of fat digestion (Traber, 1999). Pancreatic esterases are required for release of free fatty acids from dietary triglycerides and for hydrolytic cleavage of tocopheryl esters. Bile acids, monoglycerides, and free fatty acids form mixed micelles in the gut, in which the tocopherols dissolve. Chylomicrons—incorporating triglycerides, free and esterified cholesterol, phospholipids, and apolipoproteins—are synthesized in intestinal mucosal cells. Tocopherols enter the mucosal cells by an unknown mechanism and are incorporated into the chylomicrons, which are secreted into the mesenteric lymphatics and later enter the blood.
Although the efficiency of vitamin E absorption is relatively low in humans (about 15-45%) (Blomstrand and Forsgren, 1968), there appears to be no discrimination against different forms of vitamin E in the gut. During later chylomicron catabolism in the circulation, some of the absorbed forms of vitamin E are transferred to plasma lipoproteins, but much appears to remain with the chylomicron remnants taken up by the liver parenchyma. During catabolism of chylomicron remnants in the liver, RRR-α-tocopherol can be preferentially transferred (compared with other isomers) by α-tocopherol transfer protein in the hepatocytic cytosol to very-low-density lipoproteins (VLDLs) (Hosomi et al., 1997). VLDLs are later secreted by the liver into the plasma. In the circulation, VLDL-bound tocopherols are transferred nonspecifically to various plasma lipoproteins. Traber et al. (1990) demonstrated the preferential association of RRR-α-tocopherol with VLDLs in the livers of cynomolgus monkeys by feeding various deuterated tocopherols and finding that RRR-α-tocopherol was about 80% of the VLDL-bound tocopherol in hepatic perfusate. After secretion of VLDLs into plasma, lipolysis by lipoprotein lipase and hepatic tryglyceride lipase results in transfer and preferential enrichment of plasma lipoproteins with RRR-α-tocopherol. That is consistent with observations that RRR-α-tocopherol is the primary form of vitamin E circulating in plasma in the species that have been studied.
Tocopherols circulate in the body as components of several plasma lipoproteins, and no specific vitamin E-transport protein has been identified in the plasma. In the plasma of African green monkeys (Carr et al., 1993), the molar ratio of α-tocopherol to high-density lipoprotein