title: Modification of benzo(a)pyrene metabolism in hepatic microsomes from untreated and induced rats by imidazole derivatives which inhibit monooxygenase activity and enhance epoxide hydrolase activity.
abstract: We have determined how four simple imidazole derivatives, namely 4(5)-phenylimidazole, 1-phenylimidazole, benzimidazole, and naphthimidazole, affect positional metabolism of benzo(a)pyrene (BaP) by hepatic microsomes from untreated, phenobarbital (PB)-induced and 3-methylcholanthrene (3MC)-induced male Wistar rats, and epoxide hydrolase activity with styrene oxide and BaP 4,5-oxide as substrates. The imidazole derivatives were potent inhibitors of total BaP metabolism in microsomes from control and PB-induced rats (I50 approximately 10(-5) M) but did not affect the proportions of BaP metabolites formed. In microsomes from 3MC-induced rats, only naphthimidazole inhibited metabolism at a concentration of 5 X 10(-4) M, but all four imidazole derivatives increased the proportion of BaP 9,10-dihydrodiol formed. Addition of purified epoxide hydrolase enzyme to assays had the same effect on metabolite profile in 3MC-induced rats as addition of imidazole derivatives. The imidazole derivatives enhanced epoxide hydrolase activity with styrene oxide, but not with BaP 4,5-oxide as substrate. This study shows that the dominant effect of imidazole derivatives on BaP metabolism varies with rat pretreatment. In hepatic microsomes from control and PB-induced rats, overall inhibition of oxidative metabolism is the dominant effect, whereas in microsomes from 3MC-induced rats, the effect on epoxide hydrolase is dominant. This study also shows that epoxide hydrolase activity limits the rate of formation of BaP 9,10-dihydrodiol by hepatic microsomes from 3MC-induced rats, but not by hepatic microsomes from control or PB-induced rats.
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene; D001580:Benzopyrenes / Q000378:metabolism*; D004347:Drug Interactions; D004851:Epoxide Hydrolases / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D001580:Benzopyrenes; D007093:Imidazoles; D001564:Benzo(a)pyrene; D008748:Methylcholanthrene; D006899:Mixed Function Oxygenases; D004851:Epoxide Hydrolases; D010634:Phenobarbital