Inhibition of human hepatic and placental xenobiotic monooxygenases by imidazole antimycotics

Abstract

Three imidazole antimycotic drugs, ketoconazole, clotrimazole and miconazole, were studied to characterize the inhibition of aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECDE) and 7-ethoxyresorufin O-deethylase (ERDE) activities in human liver and placenta in vitro in comparison with liver enzymes from control, phenobarbital (PB) and 3-methylcholanthrene (MC) pretreated rats. All three compounds inhibited rat liver enzymes, although MC pretreatment seemed to lead to a resistance of inhibition relative to PB-treated and control animals. There were large differences in the extent of inhibition of human hepatic and placental activities. Furthermore, while the type of inhibition of the hepatic ERDE was competitive or mixed, that of the placental enzyme cannot be described in ordinary terms of inhibition kinetics. Ketoconazole and clotrimazole were relatively potent inhibitors of maternal cigarette smoking-induced placental ECDE activities (IC50 values from 0.5 microM to 5 microM), whereas much less inhibition of the placental AHH activity was obtained with ketoconazole and miconazole (IC50 values from 50 microM to 500 microM). In most cases, hepatic enzymes were less sensitive to antimycotics than placental activities. This was in contrast with results from rat enzyme studies, in which MC pretreatment seemed to decrease the inhibitory response.