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.Drug Metab Dispos. 1983 Jul-Aug; 11(4):350-4.DM
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.