STRUCTURE-DEPENDENT INDUCTION OF CYP2B1 2 BY 3-METHYLSULFONYL METABOLITES OF POLYCHLORINATED BIPHENYL CONGENERS IN RATS/

The effects of eleven 3-methylsulfonyl (3-MeSO2)-metabolites of polych lorinated biphenyl (PCB) congeners (which were reported to remain in S wedish mother's milk and Japanese Yusho patient's tissues) and their t wo structurally similar 3-MeSO2-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-metaboli zing enzymes, CYP2B1 and CYP2B2 in the hepatic microsomes of rats trea ted with nine 3-MeSO2 derivatives, namely 3-MeSO2-2,4', 5-trichlorobip henyl, 3-MeSO2-2,2',4', 5-tetrachlorobiphenyl (3-MeSO2-2,2',4',5-tetra CB), 3-MeSO2 2,2',5,5'-tetraCB, 3-MeSO2-2,3',4',5-tetraCB, 3-MeSO2-2,2 ',3',4', 5-pentachlorobiphenyl (3-MeSO2-2,2',3',4',5-pentaCB), 3-MeSO2 -2,2',4',5,5'-pentaCB, 3-MeSO2-2,2',3',4',5,5'-hexachlorobiphenyl (3-M eSO2-2,2',3',4',5,5'-hexaCB), 3-MeSO2-2,2',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-MeSO2 metabolites derived from nine PCBs are PB-type i nducers of microsomal drug-metabolizing enzymes. The relative inducing potencies of 3-MeSO2 derivatives on the hepatic drug-metabolizing enz yme activities differed with the extent of chlorination and the positi ons of chlorine substituent on the phenyl rings. The results of presen t study show that the structure-CYP2B1/2 induction relationship exists for the 3-MeSO2 derivatives studied. The inducing abilities of 3-MeSO 2-2,2',4',5-tetraCB and 3-MeSO2-2,2',4',5,5'-pentaCB (2 mu mol/kg) on the content of cytochrome P450 were higher than those of 2,3',4,4',5-p entaCB (mono-ortho-substituted PCB) (80 mu mol/kg), 3,3',4,4'-tetraCB (coplanar PCB) (80 mu mol/kg) and 3,3',4,4',5-pentaCB (coplanar PCB) ( 0.5 mu mol/kg). The inducing effects of the administration of 3-MeSO2- 2,2',4',5-tetraCB and 3-MeSO2-2,2',4',5,5'-pentaCB at 2 mu mol/kg on t he contents of total cytochrome P450, CYP2B1 and CYP2B2 corresponded t o those of PB at 431 mu mol/kg twice at a 24 h interval. It is noticea ble that 3-MeSO2-2,2',4',5-tetraCB and 3-MeSO2-2,2',4',5,5'-pentaCB ha ve highly potent PB-type inducing activity on drug-metabolizing enzyme systems. (C) 1997 Elsevier Science B.V.