The effects of enzyme induction on the generation of cytotoxic metabolites from phenytoin, mianserin, imipramine, desipramine and amitriptyline by mouse liver microsomes has been investigated and then compared with the bioactivation mediated by human hepatic microsomes. Cytotoxicity was assessed by co-incubation of drug and microsomes with human mononuclear leucocytes which served as target cells. Enzyme induction was assessed by measurement of hepatic cytochrome P-450 content, and determination of alkoxycoumarin O-dealkylase activity. None of the compounds investigated were metabolized to cytotoxic metabolites in the presence of control mouse microsomes. However, significant bioactivation could be observed for each drug when incubated with microsomes prepared from mice pretreated with either phenobarbitone (60 mg/kg) or β-naphthoflavone (75 mg/kg). The rank order for metabolism-dependent cytotoxircity with phenobarbitone-induced mouse microsomes (expressed as % cell death) was phenytoin (14.6%) > desipramine (10.5%) > imipramine (7.5%) > mianserin (3.4%) > amitriptyline (3.1%). Expression of cytotoxidty with phenytoin required pre-exposure of the target cells to trichloropropane oxide, an epoxide hydrolase inhibitor. Only mianserin and desipramine were activated to cytotoxic metabolites by human liver microsomes. Analysis of stable metabolites revealed that mianserin underwent extensive (>80%) metabolism by both control and induced mouse microsomes and that the principal metabolites, 8-hydroxymianserin, desmethylmianserin and mianserin N-oxide, were the same as those produced by human liver microsomes. These data suggest that mianserin is activated to a cytotoxic metabolite selectively by a constitutive form of human cytochrome P-450, whereas phenytoin, amitriptyline and imipramine are selectively activated by forms of mouse cytochrome P-450 which are induced by either phenobarbitone or β-naphthoflavone. © 1990.
