Effect of ketoconazole (an imidazole antimycotic agent) and other inhibitors of steroidogenesis on cytochrome P450-catalyzed reactions.
The effects of Ketoconazole, an orally active imidazole antimycotic agent, and other known inhibitors of steroidogenesis were examined in the reconstituted steroid monooxygenase system which consists of adrenodoxin, its reductase and purified P450. We found that: Ketoconazole completely inhibits the hydroxylation of deoxycorticosterone (DOC) at the 11 beta and 18-positions; Ketoconazole also inhibits the 18-hydroxylation reaction that converts corticosterone to form 18-hydroxycorticosterone; both Trilostane (4,5-epoxy-17-hydroxy-3-oxoandrostane-2-carbonitrile) and o,p'-DDD do not inhibit either the 11 beta or 18-hydroxylase activities of the reconstituted P450(11 beta) system (NADPH-adrenodoxin reductase activity is also not inhibited by either drug); Ketoconazole inhibits the conversion of cholesterol to pregnenolone in a dose-dependent fashion, and is a more potent inhibitor than metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone) in the P450scc-catalyzed reaction system; other inhibitors fail to show any inhibitory effects in this system.
Nagai
K
K
Miyamori
I
I
Ikeda
M
M
Koshida
H
H
Takeda
R
R
Suhara
K
K
Katagiri
M
M
D015069:18-Hydroxycorticosterone / Q000378:metabolism; D000302:Adrenal Cortex / Q000201:enzymology; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism; D003345:Corticosterone / Q000096:biosynthesis; D065607:Cytochrome P-450 Enzyme Inhibitors; D003900:Desoxycorticosterone / Q000031:analogs & derivatives / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000494:pharmacology*; D008928:Mitochondria / Q000201:enzymology; D011284:Pregnenolone / Q000096:biosynthesis; D013256:Steroids / Q000096:biosynthesis*
D065607:Cytochrome P-450 Enzyme Inhibitors; D013256:Steroids; D000616:Aminoglutethimide; C042509:18-hydroxydeoxycorticosterone; D003900:Desoxycorticosterone; D015069:18-Hydroxycorticosterone; D011284:Pregnenolone; D002784:Cholesterol; D007654:Ketoconazole; D003345:Corticosterone