Role of Inducible Cytochrome P450 in the Liver Toxicity of Polyhalogenated Aromatic Compounds

Summary

Both major inducible forms of liver cytochrome P450 can interact with polyhalogenated biphenyls (PBCS) of the appropriate configuration to produce oxidizing species, as judged by the degradation of bilirubin, a readily oxidizable compound, by isolated microsomes in vitro. Planar PCBs are active with cytochrome P450 IA1, while non-planar di-orthosubstituted compounds are effective with cytochrome P450 IIB1.Evidence for uroporphyrinogen oxidation under similar conditions has also been obtained with 3-methylcholanthrene-induced rat liver microsomes, where the stimulatory effect of a planar biphenyl, though not as great and consistent as with bilirubin, could also be demonstrated. The nature of the oxidizing species produced by the microsomes is still uncertain, but bilirubin undergoing enzymic oxidation shows similar spectral changes as in a chemical oxidation system. we suggest that a PCB of the appropriate steric configuration may first induce the relevant cytochrome in vivo, then become bound to the active site of the induced cytochrome and lead to production of oxidative species. These may then attack not only bilirubin, but also other key targets in the cell, including hexahydroporphyrins (porphyrinogens) and DNA bases.