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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 

Metabolism of dichlorobiphenyls by highly purified isozymes of rat liver cytochrome P-450.

Hepatic mixed-function oxidase metabolism of the ubiquitous pollutant polychlorinated biphenyls (PCBs) is implicated in their toxification and detoxification. We used dichlorobiphenyls (DCBs) as models to investigate the effect of the chloro substituent sites on this metabolism experimentally and by molecular orbital calculations. Reconstituted, purified cytochrome P-450 PB-B and BNF-B, the major terminal oxidase isozymes of this system, from phenobarbital (PB)- and beta-naphthoflavone (BNF)-induced rats were used to investigate this metabolism. Both isozymes are also induced by PCBs. High-performance liquid chromatography (HPLC) was used to detect, quantify, and isolate metabolites. Metabolite structures were identified by mass spectrometry, dechlorination to identifiable hydroxybiphenyls, and HPLC retention times. All DCBs yielded 3- and 4- but no 2-monohydroxylated metabolites (3,3'-DCB also yielded a dihydroxy metabolite). Di-o-chloro-substituted DCBs were metabolized primarily by cytochrome P-450 PB-B, mono-o-chloro substituted DCBs by both isozymes approximately equivalently, and DCBs without o-chloro substituents by BNF-B primarily. Thus PB-B preferentially metabolizes noncoplanar DCBs and BNF-B coplanar DCBs. The cytochrome isozymes exhibited differing regioselectivities for DCB metabolism - PB-B hydroxylated unchlorinated phenyl rings and BNF-B chlorinated rings. Incorporation of epoxide hydrolase yielded DCB dihydrodiols, and hydroxy metabolite patterns were consistent with those calculated from ring-opened arene oxide intermediates. Thus the rates and regioselectivities of metabolism and thus possibly the toxicity and carcinogenicity of DCBs are dependent on the cytochrome P-450 isozymes induced.[1]

References

  1. Metabolism of dichlorobiphenyls by highly purified isozymes of rat liver cytochrome P-450. Kaminsky, L.S., Kennedy, M.W., Adams, S.M., Guengerich, F.P. Biochemistry (1981) [Pubmed]
 
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