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Hair Loss Study Abstract: Hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol by rat prostate microsomes: potent inhibition by imidazole-type antimycotic drugs and lack of inhibition by steroid 5 alpha-reductase inhibitors.
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Title
Hydroxylation of 5 alpha-androstane-3 beta,17 beta-diol by rat prostate microsomes:
potent inhibition by imidazole-type antimycotic drugs and lack of inhibition by steroid 5
alpha-reductase inhibitors. Author
Gemzik B, Parkinson A Address
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical
Center, Kansas City 66160-7417.
Source
Arch Biochem Biophys, 296: 2, 1992 Aug 1, 366-73
Abstract
5 alpha-Dihydrotestosterone, the principal androgen mediating prostate growth and
function in the rat, is formed from testosterone by steroid 5 alpha-reductase. The
inactivation of 5 alpha-dihydrotestosterone involves reversible reduction to 5
alpha-androstane-3 beta,17 beta-diol by 3 beta-hydroxysteroid oxidoreductase followed by 6
alpha-, 7 alpha-, or 7 beta-hydroxylation. 5 alpha-Androstane-3 beta,17 beta-diol
hydroxylation represents the ultimate inactivation step of dihydrotestosterone in rat
prostate and is apparently catalyzed by a single, high-affinity (Km approximately 0.5
microM) microsomal cytochrome P450 enzyme. The present studies were designed to determine
if 5 alpha-androstane-3 beta,17 beta-diol hydroxylation by rat prostate microsomes is
inhibited by agents that are known inhibitors of androgen-metabolizing enzymes. Inhibitors
of steroid 5 alpha-reductase (4-azasteroid analogs; 10 microM) or inhibitors of 3
beta-hydroxysteroid oxidoreductase (trilostane, azastene, and cyanoketone; 10 microM) had
no appreciable effect on the 6 alpha-, 7 alpha-, or 7 beta-hydroxylation of 5
alpha-androstane-3 beta,17 beta-diol (10 microM) by rat prostate microsomes.
Imidazole-type antimycotic drugs (ketoconazole, clotrimazole, and miconazole; 0.1-10
microM) all markedly inhibited 5 alpha-androstane-3 beta,17 beta-diol hydroxylation in a
concentration-dependent manner, whereas triazole-type antimycotic drugs (fluconazole and
itraconazole; 0.1-10 microM) had no inhibitory effect. The rank order of inhibitory
potency of the imidazole-type antimycotic drugs was miconazole greater than clotrimazole
greater than ketoconazole. In the case of clotrimazole, the inhibition was shown to be
competitive in nature, with a Ki of 0.03 microM. The imidazole-type antimycotic drugs
inhibited all three pathways of 5 alpha-androstane-3 beta,17 beta-diol hydroxylation to
the same extent, which provides further evidence that, in rat prostate microsomes, a
single cytochrome P450 enzyme catalyzes the 6 alpha-, 7 alpha-, and 7 beta-hydroxylation
of 5 alpha-androstane-3 beta,17 beta-diol. These studies demonstrate that certain
imidazole-type compounds are potent, competitive inhibitors of 5 alpha-androstane-3
beta,17 beta-diol hydroxylation by rat prostate microsomes, which is consistent with the
effect of these antimycotic drugs on cytochrome P450 enzymes involved in the metabolism of
other androgens and steroids.
Language of Publication English
Unique Identifier 92337396
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