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

Abstract

After the administration of 2,2′,4,5,5′-pentachlorobiphenyl (2,2′,4,5,5′-pentaCB) to intact rats, the concentration of 2,2′,4,5,5′-pentaCB in liver gradually decreased, whereas 3-methylsulfonyl (3-MeSO 2)-2,2′,4′,5,5′-pentaCB appeared in liver and remained detectable in liver for 6 weeks. A single injection of 2,2′,4,5,5′-pentaCB (342 μmol/kg) or 3-MeSO 2-2,2′,4′,5,5′-pentaCB (0.5 μmol/kg) caused a significant increase both in the contents of cytochromes P450 and b 5 and in the activities of aminopyrine N-demethylase and benzo[ a]pyrene hydroxylase, and the increased enzyme contents and activities continued for 6 weeks after the administration. The extent of both the hepatic accumulation of 3-MeSO 2-2,2′,4′,5,5′-pentaCB and the induction of the enzymes for 6 weeks after the administration of 2,2′,4,5,5′-pentaCB was similar to that after the administration of 3-MeSO 2-2,2′,4′,5,5′-pentaCB. 3-MeSO 2-2,2′,4′,5,5′-pentaCB was considered to play a principal role in the 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-MeSO 2-2,2′,4′,5,5′-pentaCBs were not detected in liver. In antibiotic-treated rats dosed with 2,2′,4,5,5′-pentaCB, the concentrations of 3- and 4-MeSO 2-2,2′,4′,5,5′-pentaCBs in liver were markedly reduced. These findings suggest that the process in which 3- and 4-MeSO 2 metabolites of 2,2′,4,5,5′-pentaCB are formed involves the biliary secretion of some precursors which will be subjected to metabolism by intestinal microflora. The increasing 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 microsomes were not observed in the bile duct-cannulated rats, in which the phenobarbital treatment enabled the drug-metabolizing enzymes to be induced. In antibiotic-treated rats, the increases both in the cytochrome P450 content and 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′-pentaCB itself but to its 3-methylsulfonyl metabolite, 3-MeSO 2-2,2′,4′,5,5′-pentaCB.