Cytochrome P450 catalyzed oxidation of monochlorobenzene, 1,2- and 1,4-dichlorobenzene in rat, mouse, and human liver microsomes

We studied metabolism of monochlorobenzene (MCB), 1,2-dichlorobenzene (1,2- DCB) and 1,4-DCB in liver microsomes from untreated male and female Wistar rats and B6C3F1 mice or in those after the induction of CYP3A or 2E1 as wel l as in human male liver microsomes. MCB and 1,2-DCB were oxidised mainly b y rat and human CYP2E1. It was found that 1,4-DCB was oxidised by rat and h uman CYP2E1 at a several-fold lower rate than 1,2-DCB, but a greater part t o covalently binding products. In contrast to previous studies showing rat CYP3A1 as the main CYP form oxidising both DCBs, our experiments indicate o nly a certain role of rat and human CYP3A in MCB, 1,2-DCB and 1,4-DCB oxida tion to covalently bound products. The relative roles of human liver CYP2E1 and 3A4 in the metabolism of 1,4-DCB seem to be individually different. Me tabolic rates of MCB, 1,2-DCB and 1,4-DCB correlated with CYP2E1 immunochem ical level in microsomes from 11 different human livers and with metabolic rates of CYP2E1 substrates. These rates in different human livers were up t o 10-fold different and were generally several-fold higher than those in un treated rats or mice. Metabolic activation of MCB and 1,2-DCB to products b inding covalently to microsomal proteins and to calf-thymus DNA, respective ly, mostly corresponded to production of water-soluble metabolites. Signifi cant species and sex differences in the oxidation of MCB, 1,2-DCB and 1,4-D CB were reflected in a markedly higher oxidation in male mice than male rat s and higher oxidation in male than female mice. The formation of covalentl y bound products generally corresponded to production of soluble metabolite s, but female rats formed significantly less covalently bound products of 1 ,4-DCB (and also of 1,2-DCB and MCB) than male rats and mice of both sexes, in possible reflection of the fact that 1,4-DCB is not carcinogenic in fem ale rats despite its carcinogenicity for male rats and both sexes of mice. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.