title: Clotrimazole as an inhibitor of benzo[a]pyrene metabolite-DNA adduct formation in vitro and of microsomal mono-oxygenase activity.
abstract: The fungistatic drug clotrimazole (1-[(o-chlorophenyl)diphenylmethyl]imidazole) in concentrations of 5 or 50 microM completely prevented the formation of benzo[a]pyrene metabolite-DNA adducts in vitro catalyzed by liver microsomes from phenobarbital-or 3-methylcholanthrene-treated rats, respectively. Microsomal 7-ethoxycoumarin de-ethylase and aryl hydrocarbon hydroxylase were effectively inhibited by clotrimazole and three clotrimazole derivatives in all induction states tested, with I50 values down to 7 x 10(-8) M. The mechanism of inhibition was noncompetitive in phenobarbital-stimulated microsomes. Microsomal epoxide hydratase in vitro was enhanced up to 450% by clotrimazole and one of the analogues in concentrations between 5 and 500 microM. Clotrimazole spectrally interacted with reduced cytochrome P-450, exhibiting a double-banded Soret region with peaks at 427 and 446 nm, and partially prevented cytochrome P-450-CO complex formation. When administered in vivo, clotrimazole effectively induced cytochrome P-450 content, mono-oxygenase activity and epoxide hydratase activity in rat liver microsomes. The induction pattern was similar to that obtained with phenobarbital. The analogues were less potent inducers.
mesh_terms: D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism*; D003022:Clotrimazole / Q000031:analogs & derivatives / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
chemical_list: D001580:Benzopyrenes; D007093:Imidazoles; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D003022:Clotrimazole; D010634:Phenobarbital