Characterization of hepatic microsomal cytochrome P-450 from rats treated with methylsulphonyl metabolites of polychlorinated biphenyl congeners

Abstract

The inducing potency of 3-methylsulphonyl(MeSO 2)-2,2′,4′,5,5′-pentachlorobiphenyl (pentaCB), which was one of the major MeSO 2 metabolites of polychlorinated biphenyls (PCBs) present in seal blubber[1], on the hepatic drug metabolizing enzyme activities was examined in comparison with that of the parent compound and phenobarbital (PB). The inducing fashion of the above enzymes and changes in the contents of PB-inducible P-450 forms by 2,3′,4′,5-tetrachlorobiphenyl (tetraCB) (IU-70), 2,2′,3′,4′,5-pentaCB (IU-87), 2,2′,4′,5,5′-pentaCB (IU-101) and 2,2′,3′,4′,5,5′-hexachlorobiphenyl (hexaCB) (IU-141), and their MeSO 2 metabolites were investigated in rats. Administration at various doses (0.2-1.0 μmol/kg) of 3-MeSO 2-2,2′,4′,5,5′-pentaCB produced nearly dose-related increases in the hepatic concentration of this methyl sulphone, in the contents of cytochromes P-450 and b 5, and in activities of aminopyrine N-demethylase, 7-ethoxycoumarin O-deethylase and benzo[ a]pyrene hydroxylase of liver microsomes. Major PB-inducible forms, CYP2B1, CYP2B2, CYP3A2 and CYP2C6 were induced with four PCBs (342 μmol/kg) and their 3-MeSO 2 metabolites (0.5–10 μmol/kg), indicating that 3-MeSO 2 metabolites were strong PB-type inducers of hepatic drug-metabolizing enzymes. 3-MeSO 2-2,2′,4′,5,5′-pentaCB was an especially strong inducer. On the other hand, four PB-inducible forms of cytochrome P-450 were not induced with the 4-MeSO 2 isomers. The relation between liver concentrations of the corresponding 3-MeSO 2 derivatives and induction of four PB-inducible forms of cytochrome P-450 after administration of four PCBs and their 3-MeSO 2 derivatives further confirmed that the 3-MeSO 2 metabolites played an important role in the induction which parent PCB congeners caused on the hepatic drug-metabolizing enzyme system.