SPECIES AND STRAIN DIFFERENCES IN THE HEPATIC CYTOCHROME P450-MEDIATED BIOTRANSFORMATION OF 1,4-DICHLOROBENZENE

Our goal was to characterize possible species and strain differences i n the hepatic microsomal biotransformation of 1,4-dichlorobenzene (1,4 -DCB). Experiments compared extent of labeled 1,4-DCB conversion to ox idized metabolites, glutathione conjugates, and covalently bound metab olites by hepatic microsomes from humans, from male B6C3F1 mice, and f rom males of three rat strains (Fischer 344, Sprague-Dawley (SD), and Wistar). These rodents were selected for comparison because of their d issimilar responses to 1,4-DCB, notably, hepatocarcinogenicity in the B6C3F1 mouse but not the Wistar or Fischer rat, and nephrotoxicity and carcinogenicity in the Fischer rat. The species rank order for total in vitro conversion of I,4-DCB was mouse > rat much greater than human . Conversion by microsomes from Fischer and Wistar rats was similar, w hereas SD rats showed less biotransformation than the other two strain s. Microsomes from the mouse produced most of the reactive metabolites as indicated by covalent binding to macromolecules (>20% of total met abolites formed). This covalent binding by mouse microsomes was extens ively inhibited by ascorbic acid (AA), with a concomitant increase in hydroquinone formation, indicating an important role for benzoquinones as reactive metabolites. Phenobarbital pretreatment of rats enhanced the in vitro conversion of 1,4-DCB and the amount of covalent binding. Covalent binding for all rat microsomes was partly (33-79%) inhibited by AA. Addition of glutathione (GSH) plus AA further diminished the c ovalent binding with concomitant increased formation of the GSH-conjug ated epoxide. Human microsomes produced the least reactive metabolites , with the majority (>70%) of this covalent binding prevented by GSH a ddition. The observed species differences, notably the more pronounced biotransformation of 1,4-DCB to reactive species including benzoquino nes, could be factors in this compound's liver carcinogenicity in B6C3 F1 mice but not other rodent species. (C) 1997 Academic Press.