Structure-dependent induction of CYP2B1/2 by 3-methylsulfonyl metabolites of polychlorinated biphenyl congeners in rats

Abstract

The effects of eleven 3-methylsulfonyl (3-MeSO 2)-metabolites of polychlorinated biphenyl (PCB) congeners (which were reported to remain in Swedish mother's milk and Japanese Yusho patient's tissues) and their two structurally similar 3-MeSO 2-PCBs on the hepatic drug-metabolizing enzyme activities were compared with those of phenobarbital (PB) and 3-methylcholanthrene (3-MC).The induction profile of the drug-metabolizing enzymes, CYP2B1 and CYP2B2 in the hepatic microsomes of rats treated with nine 3-MeSO 2 derivatives, namely 3-MeSO 2-2,4′,5-trichlorobiphenyl, 3-MeSO 2-2,2′,4′,5-tetrachlorobiphenyl (3-MeSO 2-2,2′,4′,5-tetraCB), 3-MeSO 2-2,2′,5,5′-tetraCB, 3-MeSO 2-2,3′,4′,5-tetraCB, 3-MeSO 2-2,2′,3′,4′,5-pentachlorobiphenyl (3-MeSO 2-2,2′,3′,4′,5-pentaCB), 3-MeSO 2-2,2′,4′,5,5′-pentaCB, 3-MeSO 2-2,2′,3′,4′,5,5′-hexachlorobiphenyl (3-MeSO 2-2,2′,3′,4′,5,5′-hexaCB), 3-MeSO 2-2,2′,3′,4′,5,6-hexaCB and 3-MeSO 2-2,2′,4′,5,5′,6-hexaCB, was similar to that of rats treated with PB, but was different from that of rats treated with 3-MC. These findings indicate that 3-MeSO 2 metabolites derived from nine PCBs are PB-type inducers of microsomal drug-metabolizing enzymes. The relative inducing potencies of 3-MeSO 2 derivatives on the hepatic drug-metabolizing enzyme activities differed with the extent of chlorination and the positions of chlorine substituent on the phenyl rings. The results of present study show that the structure-CYP2B1/2 induction relationship exists for the 3-MeSO 2 derivatives studied. The inducing abilities of 3-MeSO 2-2,2′,4′,5-tetraCB and 3-MeSO 2-2,2′,4′,5,5′-pentaCB (2 μmol/kg) on the content of cytochrome P450 were higher than those of 2,3′,4,4′,5-pentaCB ( mono- ortho-substituted PCB) (80 μmol/kg), 3,3′,4,4′-tetraCB (coplanar PCB) (80 μmol/kg) and 3,3′,4,4′,5-pentaCB (coplanar PCB) (0.5 μmol/kg). The inducing effects of the administration of 3-MeSO 2-2,2′,4′,5-tetraCB and 3-MeSO 2-2,2′,4′,5,5′-pentaCB at 2 μmol/kg on the contents of total cytochrome P450, CYP2B1 and CYP2B2 corresponded to those of PB at 431 μmol/kg twice at a 24 h interval. It is noticeable that 3-MeSO 2-2,2′,4′,5-tetraCB and 3-MeSO 2-2,2′,4′,5,5′-pentaCB have highly potent PB-type inducing activity on drug-metabolizing enzyme systems.