Effect of Cytochrome P450 Inducers on Liver Microsomal Metabolism of Tetrachlorobiphenyls in Rats, Guinea Pigs and Hamsters.

Abstract

Effect of cytochrome P450 (P450) inducers on liver microsomal metabolism of 3,4,3',4'-, 3,5,3',5'- and 2,5,2', 5'-tetrachlorobiphenyl (TCB) was studied using male Wistar rats, male Hartley guinea pigs and male Golden syrian hamsters. In metabolism of 3,4,3'4'- and 3,5,3',5'-TCB, liver microsomes from 3-methylcholanthrene (MC)- or 3,4,5,3',4'-pentachlorobiphenyl (PenCB)-treated hamsters showed hydroxylase activities for both TCB isomers, although the activities were much less than those of rats. In contrast, liver microsomes form untreated and phenobarbital (PB)-, MC- or PenCB-treated guinea pigs showed no hydroxylase activity. In 2,5,2',5'-TCB metabolism, 3-hydroxylase activity was observed in untreated guinea pigs and hamsters, but not in untreated rats. The activity pigs was induced by PB treatment in all three species, at rates of 324, 19 and 20 pmol/min/mg protein in rats, guinea and hamsters, respectively. This activity was not enhanced by treatment with either MC or PenCB. Only in hamsters was 4-hydroxylated metabolite formed in all microsomes used in addition to the 3-hydroxylated one, and the formation was accelerated 2.0-, 2.7- and 4.8-fold by treatment with PB, MC and PenCB, respectively. These results suggest that different P450 isoforms in hamster liver microsomes are involved in 3- and 4-hydroxylation of 2,5,2',5'-TCB. Thus, there are species differences in the basal ability to hydroxylate TCB isomers, and in the extent of effect of P450 inducers on the metabolism of these isomers among the three species.