Acute and subacute effects of miconazole nitrate on hepatic styrene oxide hydrolase and cytochrome P-450-dependent monooxygenase activities in male and female AKR/J mice.
The imidazole-containing anti-fungal drug, miconazole nitrate, was shown to enhance hepatic microsomal styrene oxide hydrolase and inhibit several cytochrome P-450-dependent monooxygenase activities in the AKR/J mouse. Miconazole was a more potent inhibitor of cytochrome P-450-dependent monooxygenase activities in microsomes from male than female mice, and inhibitory potency also varied with substrate. When administered in vivo miconazole nitrate stimulated epoxide hydrolase activity, but had a substrate-dependent biphasic effect on cytochrome P-450-dependent monooxygenase activities. Monooxygenase activities with benzo[a]pyrene and benzphetamine were inhibited to varying degrees in liver homogenate and hepatic microsomes from mice sacrificed 45 min after miconazole administration. After repeated administration of miconazole, liver weight, microsomal protein yield and cytochrome P-450 were increased, as were specific monooxygenase activities with ethoxycoumarin and ethoxyresorufin, but benzphetamine N-demethylase activity was decreased. These results suggested that a metabolite of miconazole was responsible for the inhibition of benzphetamine N-demethylase. It was of special interest that ethoxyresorufin O-deethylase activity was induced in the AKR/J mouse by miconazole, since the AKR/J mouse is not responsive to induction by aromatic hydrocarbons.
James
M O
MO
Department of Medicinal Chemistry, University of Florida, Gainesville 32610.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000096:biosynthesis*; D005260:Female; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008825:Miconazole / Q000494:pharmacology*; D010105:Oxygenases / Q000037:antagonists & inhibitors*; D004364:Pharmaceutical Preparations / Q000378:metabolism; D012737:Sex Factors
D004364:Pharmaceutical Preparations; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D004851:Epoxide Hydrolases; C022686:styrene oxide hydratase