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Biodiscrimination of the Eight -Tocopherol Stereoisomers Results in Preferential Accumulation of the Four 2R Forms in Tissues and Plasma of Rats^1,2,3,

F. Hoffmann-La Roche Ltd, Vitamins and Fine Chemicals, Research and Technology Development, 4002 Basel, Switzerland

According to the USP, 2R,4'R,8'R--tocopheryl acetate (RRR--TAc) is 1.36 times more active than all-rac--tocopheryl acetate (all-rac--TAc). The all-rac form contains 12.5% each of the stereoisomers RRR, RRS, RSR, RSS, SSS, SSR, SRS and SRR, which display different biopotencies. In the present study, female rats fed a vitamin E-deficient diet were administered 0.82 mg of all-rac--TAc or 0.60 mg of RRR--TAc daily for up to 90 d. -Tocopherol concentrations in liver, brain, adipose tissue and plasma were not significantly different among groups on treatment d 64 and 90. Thus, equipotent dosages of all-rac--TAc or RRR--TAc resulted in equimolar -tocopherol plasma and tissue concentrations. A comparison with rats administered tocopherol-free placebo showed that plasma and tissue -tocopherol of -TAc-treated rats represented -tocopherol uptake during the repletion period. The eight individual -tocopherol stereoisomers in tissues and plasma were determined by chiral HPLC and capillary gas chromatography. Rats treated with all-rac--TAc preferentially accumulated the four 2R -tocopherol stereoisomers (15–22% each, sum of all 2R = 70–86%) in tissues and plasma. The remaining 14–30% were 2S stereoisomers with a predominance of the SRS form. In conclusion, all-rac--TAc administration led to the presence of all eight -tocopherol stereoisomers in rat liver, brain, adipose tissue and plasma. The four 2R stereoisomers including RRR--tocopherol were equally and significantly enriched. This confirmed that the configuration at C-2 of the -tocopherol molecule has a major impact on stereoisomer biodiscrimination. Furthermore, the results are in agreement with the hypothesis that for -tocopherol stereoisomers, biopotency differences are related to corresponding differences of -tocopherol concentrations.

KEY WORDS: • vitamin E • all-rac--tocopheryl acetate • -tocopherol stereoisomers • biodiscrimination • activity ratio (biopotency) • rats

¹ Some of these data were presented as posters at the symposia "Vitamins and Biofactors in Life Science" and "International Symposium on Vitamin E", September 16–24, 1991, Kobe and Kawashima Japan [Weiser, H., Vecchi, M., Riss, G. & Kormann, A. W. Long-term biopotencies and biodiscrimination of -tocopheryl acetate stereoisomers in rats], and at the symposium "Beyond Deficiency; New Views on the Function and Health Effects of Vitamins", February 10–12, 1992, Arlington, NY (Weiser et al. 1992).

² Paul Jordan: Estimating the ratio of group means in a Bayesiar context. A detailed description of this statistical method has been deposited with NAPS as an auxiliary publication. See NAPS document no. 04949 for four pages of supplementary material. Order from NAPS, c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163-3513. Remit with your order, not under separate cover, $7.75 (U.S. funds on a U.S. Bank only) for photocopies or $4.00 for microfiche. Outside the U.S. and some parts of Canada, add postage of $4.50 for photocopies, $1.75 for microfiche. Institutions and organizations may order by purchase order; however, there is a billing and handling charge for this service of $15, plus any applicable postage.

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Manuscript received 26 February 1996. Revision accepted 11 June 1996.