Elsevier

Biochemical Pharmacology

Volume 35, Issue 3, 1 February 1986, Pages 487-491
Biochemical Pharmacology

Inhibition of rat liver microsomal cytochrome P-450 steroid hydroxylase reactions by imidazole antimycotic agents

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Abstract

The imidazole antimycotic agents ketoconazole, miconazole and clotrimazole were tested for their abilities to inhibit the reactions involved in the oxidative metabolism of androst-4-ene-3,17-dione by rat liver microsomal cytochromes P-450. All three compounds were found to function as potent inhibitors of steroid hydroxylase reactions, producing 50% inhibition of 6β-, 16β-, and 16α-hydroxylase activities at concentrations between 10−7 and K−5M. The antimycotic agents, when added to liver microsomes, bound to cytochrome P-450 with high affinity to produce a “type II” spectral complex. These agents showed differential inhibition of the various steroid hydroxylases and were found not to affect the activities of the liver microsomal steroid 5α-reductase or the androst-4-ene-3,17-dione 17-oxidoreductase. The results presented demonstrate an interaction of these imidazole antimycotic agents with the various cytochromes P-450 of liver microsomes, resulting in selective inhibition of monooxygenase activity.

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    Supported, in part, by Grants NIGMS 16488 and CA-30253 from the National Institutes of Health, USPHS. J.J.S. was supported, in part, by a USPHS National Research Service Award (1-F32-HD-06596-01) and a Post-doctoral Fellowship from the Chilton Foundation.

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