Inhibition of bovine adrenocortical mitochondrial cytochrome P-450(11)beta-mediated reactions by imidazole derivatives and mineralocorticoid analogs.
The effects of several imidazole antimycotic agents, an imidazole and several mineralocorticoid analogs on the cytochrome P-450(11)beta-catalyzed 11 beta-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 11 beta-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 11 beta-hydroxylation. Spironolactone and other newly synthesized mineralocorticoid analogs were also found to inhibit the cytochrome P-450(11)beta-mediated reactions. The ID50 values of these drugs for inhibition of the 11 beta-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(11)beta-mediated reactions.
Wada
A
A
Department of Biochemistry, Osaka University Medical School, Japan.
Ohnishi
T
T
Nonaka
Y
Y
Okamoto
M
M
D000302:Adrenal Cortex / Q000201:enzymology* / Q000648:ultrastructure; D000450:Aldosterone / Q000096:biosynthesis; D000818:Animals; D002417:Cattle; D003022:Clotrimazole / Q000494:pharmacology; D003345:Corticosterone / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000096:biosynthesis; D005045:Etomidate / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology; D008825:Miconazole / Q000494:pharmacology; D008901:Mineralocorticoids / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology
D007093:Imidazoles; D008901:Mineralocorticoids; D003900:Desoxycorticosterone; D000450:Aldosterone; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D003022:Clotrimazole; D007654:Ketoconazole; D003345:Corticosterone; D005045:Etomidate