[The effect of ketoconazole and some other inhibitors of steroidogenesis on P-450 11 beta-catalyzed reactions].
Ketoconazole (Nizoral), an orally active antimycotic agent with a broad spectrum, has been reported to interfere with steroidogenesis both in patient and in vivo rat studies. It has also been shown that the same drug inhibits some P-450--catalyzed reactions in adrenal cortex mitochondria. In the present work, we studied the inhibitory effect of Ketoconazole, along with some other known inhibitors of steroidogenesis, on the reconstituted steroid monooxygenase system, which consists of adrenodoxin, its reductase and P-450 11 beta as the protein components being purified from bovine adrenal cortex mitochondria. The results indicated that; Ketoconazole completely inhibited hydroxylation of deoxycorticosterone at the 11 beta-position to form corticosterone and at the 18-position to form 18-hydroxydeoxycorticosterone. The Ki value for Ketoconazole, calculated either from the 11 beta-hydroxylase reaction or the 18-hydroxylase reaction, was 0.56 microM, which was comparable to the value obtained for metyrapone in the same system. Ketoconazole also inhibited 18-hydroxylation of corticosterone to form 18-hydroxycorticosterone, with 50% inhibitory concentration of less than 0.03 microgram/ml. The corresponding value for this inhibitor in the deoxycorticosterone 18-hydroxylase reaction was found to be 0.3 microgram/ml. The contrast between these values for the two substrates is striking. Thus, in a series of reaction steps, the inhibitory effect of corticosterone to 18-hydroxycorticosterone was more potent than deoxycorticosterone to 18-hydroxycorticosterone reaction. Both trilostane and o, p'-DDD over the wide concentration range failed to inhibit any of the reconstituted P-450 11 beta system similar to those applied to the Ketoconazole study.(ABSTRACT TRUNCATED AT 250 WORDS)
D015069:18-Hydroxycorticosterone / Q000096:biosynthesis; D015070:18-Hydroxydesoxycorticosterone / Q000096:biosynthesis; D000302:Adrenal Cortex / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002384:Catalysis; D003345:Corticosterone / Q000096:biosynthesis* / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003900:Desoxycorticosterone / Q000378:metabolism; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism
D015070:18-Hydroxydesoxycorticosterone; D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D013196:Dihydrotestosterone; D003900:Desoxycorticosterone; D015069:18-Hydroxycorticosterone; C009954:trilostane; D007654:Ketoconazole; D003345:Corticosterone