Polybrominated biphenyls as aryl hydrocarbon hydroxylase inducers: structure-activity correlations.
The synthesis of all possible laterally-substituted polybrominated biphenyl (PBB) congeners containing two para bromines is described. Using enzymic, electrophoretic and ligand-binding assays that distinguish between phenobarbitone(PB)- and 3-methylcholanthrene(MC)-type inducers, the synthetic PBBs were evaluated as inducers of liver microsomal drug-metabolizing enzymes in the immature male Wistar rat. 4,4'-Dibromobiphenyl resembled PB in its mode of induction whereas all the meta-brominated derivatives of 4,4'-dibromobiphenyl, namely 3,4,4'-tri, 3,4,4',5-tetra-, 3,3', 4,4'-tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexabromobiphenyl, resembled MC in their mode of induction. The results obtained with 3,4,4'-tribromobiphenyl demonstrate that, in contrast to the polychlorinated biphenyls (PCBs), a single meta halogen substituent is sufficient to abolish the PB-type characteristics of 4,4'-dibromobiphenyl and convert it to a strictly MC-type inducer. PBBs which induce AHH activity must be substituted at both para positions and at one, two, three or four meta positions. Ortho-substitution of PBBs which contain only lateral bromine groups may also give compounds which are aryl hydrocarbon hydroxylase (AHH) inducers. One of the MC-type PBBs, namely 3,3',4,4'-tetrabromobiphenyl, which has been tentatively identified in the commercial PBB mixture, fireMaster BP-6, was at least 50 times more potent as an inducer of AHH activity than the commercial PBB mixture. The induction of AHH by 3,3',4,4'-tetrabromobiphenyl was accompanied by a dose-dependent decrease in both thymus and spleen weights. The thymus and/or spleen weights were decreased in rats treated with the other MC-type PBBs which further supports the correlation between the toxicity of the PBBs and their ability to induce AHH.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis / Q000096:biosynthesis*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011075:Polybrominated Biphenyls / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D001713:Biphenyl Compounds; D011075:Polybrominated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases