Metabolite of 2,2?,4?,5-tetrabromobiphenyl, 3-methylsulphonyl-2,2?,4?,5-tetrabromobiphenyl, a potent inducer of CYP2B1/2 in rat

Abstract

1. 3-Methylsulphonyl- and 4-methylsulphonyl-2,2',4',5-tetrabromobiphenyls (3-MeSO₂- and 4-MeSO₂-TetraBrBs) were detected in the liver, lung, kidney, adipose tissue and faeces of the 2,2',4',5-tetrabromobiphenyl (TetraBrB)-dosed rat. 2. The administration of 0.05-2.0 µmol kg⁻¹ doses of 3-MeSO₂-TetraBrB produced corrresponding increases in the hepatic concentration of the methyl sulphone metabolite, corresponding increases in the content of total cytochrome P450, and corresponding increases in the activities of 7-benzyloxy-, 7-ethoxy- and 7-pentoxyresorufin O-dealkylases. The inducing effects of the 3-MeSO₂-TetraBrB (0.2 µmol kg⁻¹), both on the content of total P450 and on the activities of the three alkoxyresorufin O-dealkylases, were higher than that of the parent TetraBrB (342 µmol kg⁻¹). 3. The major phenobarbital (PB)-inducible forms of P450, CYP2B1, CYP2B2, CYP3A2 and CYP2C6, were substantially induced by 3-MeSO₂-TetraBrB, but CYP1A1 and CYP1A2 were not. On the other hand, the activities of drug-metabolizing enzymes and the four PB-inducible forms of P450 were unchanged by 4-MeSO₂-TetraBrB treatment. 4. The induction profiles of these enzymes and P450 forms in rat treated with 3-MeSO₂-TetraBrB were similar to those treated with PB. 5. The inducing ability of 3-MeSO₂-TetraBrB (0.5 µmol kg⁻¹) both on the activities of the three alkoxyresorufin O-dealkylases and on the contents of four PB-inducible forms of P450 was roughly equal to that of PB (431 µmol kg⁻¹ twice at a 24-h interval) or 3-MeSO₂-2,2',4',5-tetrachlorobiphenyl (1 µmol kg⁻¹). It is noteworthy that the effects of 3-MeSO₂-TetraBrB on the drug-metabolizing enzymes CYP2B1 and CYP2B2 were several thousand-fold higher than those of parent TetraBrB, while the effect of its isomeric 4-MeSO₂-TetraBrB were not. 6. The extent of hepatic accumulation of the 3-MeSO₂ metabolite after the administration of TetraBrB (342 µmol kg⁻¹) was almost the same as that after the administration of 3-MeSO₂-TetraBrB (0.1-0.2 µmol kg⁻¹). The relationship between the hepatic concentration of the 3-MeSO₂ metabolite and the extent of enzyme induction after the administration of TetraBrB or 3-MeSO₂-TetraBrB suggests that 3-MeSO₂-TetraBrB plays an important role in the induction of microsomal drug-metabolizing enzymes by TetraBrB.