Studies on the structure-activity relationships for the metabolism of polybrominated biphenyls by rat liver microsomes.
The in vitro metabolism of polybrominated biphenyl (PBB) congeners by cytochrome P-450-dependent monooxygenases was investigated using hepatic microsomes isolated from immature male rats pretreated with 3-methylcholanthrene (MC) or phenobarbital (PB). MC pretreatment increased the NADPH-dependent microsomal metabolism of pure PBB congeners which possessed adjacent nonhalogenated ortho and meta carbons on at least one ring. 4,4'-Dibromobiphenyl (-DBB) was metabolized at the fastest rate, followed by 3,4,4'-tribromobiphenyl, 3,4,3',4'-tetrabromobiphenyl (-TBB), 2,3,3',4'-TBB, 2,5,3',4'-TBB, and 2,4,2',5'-TBB in decreasing order. It appeared that further bromination prevented metabolism since 2,4,5,3',4'-pentabromobiphenyl (-PBB), 2,3,4,2',4',5'-hexabromobiphenyl (-HBB), and 2,3,4,5,3'.4'-HBB were not metabolized although they possess adjacent nonhalogenated ortho and meta carbons. PB pretreatment increased in vitro rat hepatic microsomal metabolism of PBB congeners which possessed adjacent nonhalogenated meta and para carbons on at least one ring. 2,2'-DBB was metabolized at the fastest rate, followed by 2,4,2',5'-TBB, 2,5,2',5'-TBB, 2,3,3',4'-TBB, 2,5,3',4'-TBB, and 2,4,5,2',5'-PBB in decreasing order. The results suggest that the rates of metabolism of PBB congeners are dependent upon the positions of bromine and the form of cytochrome P-450 induced. In vitro rates of metabolism of 3,4,3',4'-TBB using hepatic microsomes isolated from rats pretreated with either 3,4,5,3',4',5'-HBB or 3,4,3',4'-TBB were also investigated. There was good correlation between the rates of 3,4,3',4'-TBB metabolism, induction of microsomal ethoxyresorufin-O-deethylase activity, and specific content of MC-inducible cytochrome P-450 (P-450 beta NF-B). The results suggest that the isozyme P-450 beta NF-B is responsible for the metabolism of 3,4,3',4'-TBB.
D000818:Animals; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D010088:Oxidoreductases / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology; D011075:Polybrominated Biphenyls / Q000378:metabolism* / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D007527:Isoenzymes; D011075:Polybrominated Biphenyls; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C032790:3,3',4,4',5,5'-hexabromobiphenyl; C036685:3,3',4,4'-tetrabromobiphenyl; D010634:Phenobarbital