Clotrimazole induction of cytochrome P-450: dose-differentiated isozyme induction.
Treatment of male rats for 3 days with the N-substituted imidazole, clotrimazole, produced up to a 4-fold induction of hepatic microsomal cytochrome P-450. The monooxygenase activities induced varied with the dose administered. At low doses (less than 25 mg/kg), p-nitroanisole demethylase and aniline hydroxylase activities were induced. Only at higher doses were other monooxygenase activities (erythromycin and ethylmorphine demethylases and cytochrome P-450 metabolic-intermediate complex formation from troleandomycin) induced. Microsomal UDP-glucuronosyltransferase activity toward morphine was induced at low doses in a manner similar to that of p-nitroanisole demethylase. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of microsomes indicated that low doses of clotrimazole caused the intensification of a 48,000 molecular weight protein band, whereas at high doses, there was a marked intensification of an additional 50,500 molecular weight protein, the same molecular weight band as was intensified in phenobarbital- and dexamethasone-induced microsomes. The observations suggest a phenomenon of "dose-differentiated" isozyme induction for cytochrome P-450.
D000815:Aniline Hydroxylase / Q000096:biosynthesis; D000818:Animals; D003022:Clotrimazole / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D004917:Erythromycin / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D010090:Oxidoreductases, O-Demethylating / Q000096:biosynthesis; D051381:Rats; D014217:Troleandomycin / Q000378:metabolism
D007093:Imidazoles; D004917:Erythromycin; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; C026048:4-nitroanisole O-demethylase; D006899:Mixed Function Oxygenases; D010090:Oxidoreductases, O-Demethylating; D000815:Aniline Hydroxylase; D014453:Glucuronosyltransferase; D003022:Clotrimazole