In vitro inhibition by ketoconazole of human testicular steroid oxidoreductases.
An oral antimycotic agent, ketoconazole has been demonstrated to be an inhibitor of cytochrome P-450-dependent monooxygenases. To investigate its effect on steroid oxidoreductases, in vitro studies were carried out using subcellular fractions of human testes. Ketoconazole competitively inhibited activities of 3 beta-hydroxy-5-ene-steroid oxidoreductase/isomerase and NADH-linked 20 alpha-hydroxysteroid oxidoreductase for steroid substrate and the Ki values were 2.9 and 0.9 microM, respectively. In contrast, ketoconazole inhibited neither 17 beta-hydroxysteroid oxidoreductase nor NADPH-linked 20 alpha-hydroxysteroid oxidoreductase, indicating that the two 20 alpha-hydroxysteroid oxidoreductases are distinct. Further, ketoconazole inhibited non-competitively the above enzyme activities for the corresponding cofactors of NAD and NADH. From the binding mode of ketoconazole to cytochrome P-450 and the present findings, it appears likely that the agent binds to a site which is different from that of steroids or pyridine nucleotides.
Higashi
Y
Y
Department of Urology, Tokyo Medical and Dental University School of Medicine, Japan.
Yoshida
K
K
Oshima
H
H
D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D001667:Binding, Competitive; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D009243:NAD / Q000037:antagonists & inhibitors; D009249:NADP / Q000378:metabolism; D013251:Steroid Isomerases / Q000032:analysis; D013737:Testis / Q000201:enzymology*
D009243:NAD; D009249:NADP; D015096:3-Hydroxysteroid Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; D013251:Steroid Isomerases; D007654:Ketoconazole