Inhibition mechanism of reconstituted cytochrome P-450scc-linked monooxygenase system by antimycotic reagents and other inhibitors.
The effects of various antimycotic reagents and some other reagents on a cytochrome P-450-linked monooxygenase system were investigated with respect to the activities of NADPH-ferricyanide reductase. NADPH-cytochrome c reductase of NADPH-adreno-ferredoxin reductase from NADPH to cytochrome c via adreno-ferredoxin, NADPH-cytochrome P-450-phenylisocyanide complex reductase, and the cholesterol side chain cleavage of the cytochrome P-450scc-linked monooxygenase system. No reagents inhibited the NADPH-ferricyanide reductase activity. Only cloconazole inhibited about 50% of NADPH-cytochrome c reductase activity. Cloconazole, econazole, clotrimazole, etomidate and ketoconazole inhibited both NADPH-cytochrome P-450-phenylisocyanide complex reductase and the side chain cleavage activity of cholesterol of the cytochrome P-450scc-linked monooxygenase system. Cloconazole, econazole, etomidate and ketoconazole behaved like non-competitive inhibitors for NADPH-cytochrome P-450-phenylisocyanide reductase activities and their Ki values were 10(-4)-10(-6) M. Cloconazole was a non-competitive inhibitor of NADPH-cytochrome c reductase and its Ki value was 8.3 x 10(-4) M. Cloconazole, clotrimazole, econazole, etomidate, ketoconazole and mitotane completely inhibited the side chain cleavage activity of cholesterol.
Kurokohchi
K
K
Department of Biochemistry, Kagawa Medical School, Japan.
Nishioka
M
M
Ichikawa
Y
Y
D000302:Adrenal Cortex / Q000201:enzymology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002417:Cattle; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors*; D004579:Electron Transport; D005045:Etomidate / Q000494:pharmacology; D066298:In Vitro Techniques; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000378:metabolism
D000935:Antifungal Agents; D009570:Nitriles; C019519:phenylisocyanide; D006899:Mixed Function Oxygenases; D002786:Cholesterol Side-Chain Cleavage Enzyme; D009251:NADPH-Ferrihemoprotein Reductase; D005045:Etomidate