Comparative toxicity of 4-chlorobiphenyl and its metabolite 4-chloro-4'-biphenylol in isolated rat liver mitochondria.
4-Chlorobiphenyl (4-CB) is converted by the microsomal cytochrome P-450 system to its hydroxylated metabolite 4-chloro-4'-biphenylol (4'-OH-4-CB). A study of the effects of 4-CB and 4'-OH-4-CB on the energy-linked functions of rat liver mitochondria was carried out. 4'-OH-4-CB was more effective than 4-CB in causing the inhibition of state 3 respiration of mitochondria with both succinate and glutamate/malate. As a substrate specificity, with glutamate/malate the inhibition by each compound (ID50, 30 microM for 4'-OH-4-CB, 76 microM for 4.CB) was more significant than that with succinate (ID50, 200 microM for 4'-OH-4-CB, never reached 50% for 4-CB). From the effects on DNP-stimulated respiration, it was indicated that the electron transport from both glutamate/malate and succinate to oxygen was more sensitively inhibited by 4'-OH-4-CB than by 4-CB, with the same substrate specificity as for state 3 respiration (i.e. the inhibition by both compounds was greater with glutamate/malate than with succinate). Since there existed a good coincidence in the inhibition between state 3 and DNP-stimulated respiration with both substrates, the inhibition of state 3 respiration by both compounds was due to the inhibition of the electron transport. With succinate, the uncoupling of oxidative phosphorylation by both compounds was observed, the extent of which was greater with 4'-OH-4-CB than with 4-CB, although the uncoupling by higher concentrations of 4'-OH-4-CB was masked because of the increased inhibition in respiration. With glutamate/malate, the uncoupling action of 4-CB was largely, while that of 4'-OH-4-CB was completely, masked by progressive respiratory inhibition. 4'-OH-4-CB was more effective than 4-CB in causing stimulation of latent ATPase in mitochondria. These results indicate that both 4-CB and 4'-OH-4-CB impair mitochondrial energy-transducing functions, but 4'-OH-4-CB is more effective than 4-CB in damaging these functions. Thus, the product of the metabolism is more biologically active than the parent compound. The impairment of energy-linked mitochondrial reactions by the metabolite as well as of the parent compound may be an important factor in the toxicity of 4-CB.
Nishihara
Y
Y
Department of Medical Biology, Kochi Medical School, Japan.
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism / Q000633:toxicity*; D005971:Glutamates / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013386:Succinates / Q000378:metabolism
D001713:Biphenyl Compounds; D005971:Glutamates; D013386:Succinates; D013385:Succinate Dehydrogenase; D000251:Adenosine Triphosphatases; C056545:4-chloro-4'-biphenylol; C006983:4-chlorobiphenyl