Inhibition of bovine adrenocortical mitochondrial cytochrome P-450 11β-mediated reactions by imidazole derivatives and mineralocorticoid analogs

Abstract

The effects of several imidazole antimycotic agents, an imidazole anesthetic and several mineralocorticoid analogs on the cytochrome P-450 11β catalyzed 11β-hydroxylation of 11-deoxycorticosterone and aldosterone synthesis were examined. Ketoconazole, clotrimazole, miconazole and etomidate were found to be potent inhibitors of the reactions, causing 50% inhibition of the 11β-hydroxylase activity at concentrations between 10 −8 and 10 −7 M. The potency of etomidate as to the inhibition of aldosterone- and 18-hydroxycorticosterone-production was found to be almost equal to that in the case of 11β-hydroxylation. Spironolactone and other newly synthesized mineralocorticoid analogs were also found to inhibit the cytochrome P-450 11β-mediated reactions. The ID 50 values of these drugs for inhibition of the 11β-hydroxylase activity were almost equal to those in the case of the aldosterone- and 18-hydroxycorticosterone-biosynthetic activities. The results of kinetical studies indicated that one of the mineralocorticoid analogs, Compound 23–0586, acts as a competitive inhibitor for the cytochrome P-450 11β mediated reactions.