Ch3

h3c ho

Figure 4.2. Stereochemistry of «-tocopherol.

Figure 4.2. Stereochemistry of «-tocopherol.

0.4 x mg p-tocopherol + 0.3 x mg y-tocopherol + 0.01 x mg ¿-tocopherol + 0.3 x mg a-tocotrienol + 0.05 x mg p-tocotrienol + 0.01 x mg y-tocotrienol (Holland etal., 1991).

As shown in Figure 4.2, the tocopherols have three asymmetric centers. The naturally occurring compound is D-a-tocopherol, in which all three asymmetric centers have the R-configuration [2R,4'R,8'R, or all-R (RRR)-a -tocopherol]. Chemical synthesis yields a mixture of the eight possible stereoisomers (all-rac-a-tocopherol); as shown in Table 4.1, the stereoisomers all have different biological activity in the rat biological assay, and the all- rac mixture has a relative biological activity of 0.74 x the activity of RRR-a-tocopherol. Conventionally, this factor of 0.74 has been used to calculate the nutritional contribution of synthetic all-rac-a-tocopherol. The most important determinant of biological activity is the chirality of C-2; the four isomers with the 2R configuration are all more active than the corresponding 2S isomers. Indeed, the 2S isomers are not maintained in plasma and do not bind to the a-tocopherol transfer protein in liver (Section 4.2).

The U.S./Canadian Dietary Reference intakes report (Institute of Medicine, 2000) departed from tradition by considering only the contribution of the 2R isomers to vitamin E intake, and proposed an equivalence of 0.45 iu per mg for synthetic all-rac-a-tocopherol, although in consideration of upper tolerable levels of intake (Section 4.6.1), they considered the contribution of all isomers equally. However, although the 2S isomers have a shorter half-life than RRR-a-tocopherol in the circulation, and hence a lower apparent biological availability, they are active in animal biological assays (Hoppe and Krennrich, 2000).

Tocopherols and tocotrienols are important constituents of chloroplast membranes in green plants, and are also found in large amounts in seeds. The aromatic ring arises from homogentisic acid, which is both a precursor of aromatic amino acids and also an intermediate in the catabolism of tyrosine. The side chain is formed by the addition of geranyl-geranyl pyrophosphate to yield initially <5-tocotrienol. Successive methylation of the ring results in the formation of y-, f-, and a-tocotrienols; the tocopherols are formed by reduction of the side chain. Tocotrienols can be considered to be end-products of the hydroxymethylglutaryl coenzyme A (HMG CoA) reductase pathway that also leads to the synthesis of cholesterol, and they down-regulate HMG CoA reductase and cholesterol synthesis.

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