Polychlorinated biphenyls as inducers of hepatic microsomal enzymes: structure-activity rules.
A number of highly purified polychlorinated biphenyl (PCB) isomers and congeners were synthesized and administered to male Wistar rats at dosage levels of 30 and 150 mumol . kg-1. The effects of this in vivo treatment on the drug-metabolizing enzymes were determined by measuring the microsomal benzo[a]pyrene (B[a]P) hydroxylase, dimethylaminoantipyrine (DMAP) N-demethylase and NADPH-cytochrome c reductase enzyme activities, the cytochrome b5 content and the relative peak intensities and spectral shifts of the reduced microsomal cytochrome P-450  CO and ethylisocyanide (EIC) binding difference spectra. The results were compared to the effects of administering phenobarbitone (PB), 3-methylcholanthrene (MC) and PB plus MC (coadministered) to the test animals. The synthetic PCB congeners used in this study included 3,4,4',5-tetrachlorobiphenyl (TCBP-1), 2,3',4,4'-tetrachlorobiphenyl (TCBP-2), 2,3',4,4',5'-pentachlorobiphenyl (PCBP-1), 2,3,4,-4',5-pentachlorobiphenyl (PCBP-2), 2,3,3',4,4',5-hexachlorobiphenyl (HCBP-1) 2,3',4',5,6-hexachlorobiphenyl (HCBP-2), 2,3,3',5,5',6-hexachlorobiphenyl (HCBP-3), 2,2',3,5,5',6-hexachlorobiphenyl (HCBP-4) and 2,3,3',4,5,5'-hexachlorobiphenyl (HCBP-5) and were used to reappraise the structure-activity rules for PCBs as hepatic microsomal enzyme inducers. The results suggested that (a) PCBs which induce MC or mixed-type activity must be substituted at both para positions, at least two meta positions but not necessarily on the same phenyl ring and can also contain one ortho chloro substituent; (b) due to the considerable structural diversity of the PB-type inducers the rules for induction of this activity by PCB congeners are not readily defined.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001579:Benzopyrene Hydroxylase / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003579:Cytochrome Reductases / Q000096:biosynthesis*; D004790:Enzyme Induction; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D009245:NADH Dehydrogenase / Q000096:biosynthesis*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D001579:Benzopyrene Hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; D010089:Oxidoreductases, N-Demethylating; C023680:dimethylaminoantipyrine N-demethylase; D003579:Cytochrome Reductases; D009245:NADH Dehydrogenase; D010634:Phenobarbital