The role of 3-methylsulfonyl-2,2 ',4 ',5,5 '-pentachlorobiphenyl, a metabolite of 2,2 ',4,5,5 '-pentachlorobiphenyl, in the induction of hepatic microsomal drug-metabolizing enzymes by 2,2 ',4,5,5 '-pentachlorobiphenyl in rats

After the administration of 2,2',4,5,5'-pentachlorobiphenyl (2,2',4,5,5'-pe ntaCB) to intact rats, the concentration of 2,2',4,5,5'-pentaCB in liver gr adually decreased, whereas 3-methylsulfonyl (3-MeSO2)-2,2',4',5,5'-pentaCB appeared in liver and remained detectable in liver for 6 weeks. A single in jection of 2,2',4,5,5'-pentaCB (342 mu mol/kg) or 3-MeSO2-2,2',4',5,5'-pent aCB (0.5 mu mol/kg) caused a significant increase both in the contents of c ytochromes P450 and b(5) and in the activities of aminopyrine N-demethylase and benzo[a]pyrene hydroxylase, and the increased enzyme contents and acti vities continued for 6 weeks after the administration. The extent of both t he hepatic accumulation of 3-MeSO2-2,2',4',5,5'-pentaCB and the induction o f the enzymes for 6 weeks after the administration of 2,2',4,5,5'-pentaCB w as similar to that after the administration of 3-MeSO2-2,2',4',5,5'-pentaCB . 3-MeSO2-2,2',4',5,5'-pentaCB was considered to play a principal role in t he induction of microsomal drug-metabolizing enzymes by 2,2',4,5,5'-pentaCB . When 2,2',4,5,5'-pentaCB was injected i.p. into bile duct-cannulated rats , 3- and 4-MeSO2-2,2',4',5,5'-pentaCBs were not detected in liver. In antib iotic-treated rats dosed with 2,2',4,5,5'-pentaCB, the concentrations of 3- and 4-MeSO2-2,2',4',5,5'-pentaCBs in liver were markedly reduced. These fi ndings suggest that the process in which 3- and 4-MeSO2 metabolites of 2,2' ,4,5,5'-pentaCB are formed involves the biliary secretion of some precursor s which will be subjected to metabolism by intestinal microflora. The incre asing effects of 2,2',4,5,5'-pentaCB both on the content of cytochrome P450 and on the activity of aminopyrine metabolizing enzyme in hepatic microsom es were not observed in the bile duct-cannulated rats, in which the phenoba rbital treatment enabled the drug-metabolizing enzymes to he induced. In an tibiotic-treated rats, the increases both in the cytochrome P450 content an d in the aminopyrine N-demethylase activity after the administration of 2,2 ',4,5,5'-pentaCB were smaller than those observed in the intact rats. These findings provide the evidence that the induction of some drug-metabolizing enzymes by 2,2',4,5,5'-pentaCB is due not to the action of 2,2',4,5,5'-pen taCB itself but to its 3-methylsulfonyl metabolite, 3-MeSO2-2,2',4',5, 5'-p entaCB. (C) 1999 Elsevier Science B.V. All rights reserved.