Polychlorinated biphenyls as inducers of hepatic microsomal enzymes: Structure-activity rules |
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Authors: | A. Parkinson L. Robertson Lorna Safe S. Safe |
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Affiliation: | a Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry, University of Guelph, Guelph, Ontario, N1G 2W1, Canada b School of Public Health, The University of Michigan, Ann Arbor, MI 48109, U.S.A. |
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Abstract: | 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 μmol · 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), 2,3,3′,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. |
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Keywords: | CO carbon monoxide DMAP dimethylaminoantipyrene EC electron capture EIC ethylisocyanide GLC gas-liquid chromatography HCBP-1 2,3,3′,4,4′,5-hexachlorobiphenyl HCBP-2 2,3,3′,4′,5,6-hexachlorobiphenyl HCBP-3 2,3,3′,5,5′-hexachlorobiphenyl HCBP-4 2,2′,3,5,5′,6-hexachlorobiphenyl HCBP-5 2,3,3′,4,5,5′-hexachlorobiphenyl MC 3-methylcholanthrene PB phenobarbitone PCB polychlorinated biphenyl PCBP-1 2,3′,4,4′,5-pentachlorobiphenyl PCBP-2 2,3,4,4′,5-pentachlorobiphenyl PMR proton magnetic resonance TCBP-1 3,4,4′,5-tetrachlorobiphenyl TCBP-2 2,3′,4,4′-tetrachlorobiphenyl TCDF 2,3,7,8-tetrachlorodibenzofuran TLC thin layer chromatography |
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