Metabolism of 4-chlorobiphenyl by guinea pig adrenocortical and hepatic microsomes.
Studies were carried out to determine if 4-chlorobiphenyl (4-CB) was a substrate for adrenal monooxygenases and to compare its interactions with adrenal and hepatic microsomal enzymes. Addition of 4-CB to guinea pig adrenal microsomes produced a typical type I spectral change, indicative of binding to cytochrome(s) P-450 and similar to that seen in hepatic microsomal preparations. The activities of several adrenal and hepatic microsomal monooxygenases were decreased by 4-CB in vitro. High pressure liquid chromatographic analyses revealed that both adrenal and hepatic microsomes, in the presence of NADPH, converted 4-CB to a major metabolite which eluted with a retention time identical to that of 4-chloro-4'-biphenylol (4'-OH-4-CB). The identity of 4'-OH-4-CB was confirmed by mass spectrometry. The maximal rate of 4-CB metabolism was greater in adrenal, compared with liver microsomes, but 4-CB had a higher affinity for hepatic than for adrenal enzymes. The rate of adrenal 4-CB metabolism was four to five times greater in microsomes derived from the inner cortical zone (zona reticularis) than those from the outer zones (zona fasciculata and zona glomerulosa). Hepatic microsomes also converted 4-CB to a minor metabolite whose production was blocked by epoxide hydrolase inhibitors, suggesting it might be a diol. 4-CB metabolism was not demonstrable in adrenal mitochondrial preparations. The results indicate that chlorinated biphenyls can serve as substrates for adrenal microsomal monooxygenases, suggesting that local activation may contribute to their adrenocortical toxicity.
D000302:Adrenal Cortex / Q000378:metabolism*; D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D001713:Biphenyl Compounds / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D009928:Organ Specificity; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000378:metabolism
D001713:Biphenyl Compounds; D003577:Cytochrome P-450 Enzyme System; D001579:Benzopyrene Hydroxylase; C019781:benzphetamine N-demethylase; D013255:Steroid 21-Hydroxylase; D010089:Oxidoreductases, N-Demethylating; C006983:4-chlorobiphenyl