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Theoretical kinetics of sequential metabolism in vitro. Study of the formation of 16 alpha-hydroxyandrostenedione from testosterone by purified rat P450 2C11

K Sugiyama, K Nagata, JR Gillette and JF Darbyshire

Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

P450 2C11 from rat liver is known to metabolize testosterone to 2 alpha- , 16 alpha-, and 6 beta-hydroxytestosterone, and to androstenedione and 16 alpha-hydroxyandrostenedione. Because Waxman (J. Biol. Chem. 259, 15481-15490) has reported that the enzyme converts androstenedione to 16 alpha-hydroxyandrostenedione, it seemed likely that the metabolite was formed from testosterone by way of androstenedione. Indeed, we have found that P450 2C11 does not convert 16 alpha-hydroxytestosterone to 16 alpha-hydroxyandrostenedione to any significant extent and, therefore, that the metabolite is formed from testosterone almost solely by way of androstenedione. To determine whether some of the 16 alpha-hydroxyandrostenedione might be formed directly from the androstenedione-enzyme complex, we developed an approach by which it is possible to calculate the amount of the androstenedione, released into the medium, relative to the amount of the androstenedione-enzyme complex that is converted directly to 16 alpha-hydroxyandrostenedione under initial conditions when the concentration of released androstenedione will be negligible. The approach uses two factors: factor A is the androstenedione/(androstenedione + 16 alpha- hydroxyandrostenedione) present at the end of the incubation, and factor B corrects for the amount of released androstenedione that recombines with the enzyme and is converted to 16 alpha- hydroxyandrostenedione. Although the values of both factors A and B will vary with the concentrations of testosterone and preformed androstenedione present in the incubation mixtures and with the duration of incubation, the value of A*B will be independent of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 22, Issue 4, pp. 584-591, 07/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics




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