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.

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.