Hepatic uroporphyrin accumulation and uroporphyrinogen decarboxylase activity in cultured chick-embryo hepatocytes and in Japanese quail (Coturnix coturnix japonica) and mice treated with polyhalogenated aromatic compounds.
The relationship between hepatic uroporphyrin accumulation and uroporphyrinogen decarboxylase (EC 4.1.1.37) activity was investigated in cultured chick-embryo hepatocytes, Japanese quail (Coturnix coturnix japonica) and mice that had been treated with polyhalogenated aromatic compounds. Chick-embryo hepatocytes treated with 3,3',4,4'-tetrachlorobiphenyl accumulated uroporphyrin in a dose-dependent fashion without a detectable decrease in uroporphyrinogen decarboxylase activity when either pentacarboxyporphyrinogen III or uroporphyrinogen III were used as substrates in the assay. Other compounds, such as hexachlorobenzene, parathion, carbamazepine and nifedipine, which have been shown previously to cause uroporphyrin accumulation in these cells, did not decrease uroporphyrinogen decarboxylase activity. Japanese quail treated with hexachlorobenzene for 7-10 days also accumulated hepatic uroporphyrin without any decrease in uroporphyrinogen decarboxylase activity. In contrast, hepatic uroporphyrin accumulation in male C57BL/6 mice treated with iron and hexachlorobenzene was accompanied by a 20-80% decrease in uroporphyrinogen decarboxylase activity, demonstrating that the assay used for uroporphyrinogen decarboxylase, using pentacarboxyporphyrinogen III as substrate, could detect decreased enzyme activity. Our results with chick hepatocytes and quail, showing uroporphyrin accumulation without a decrease in uroporphyrinogen decarboxylase activity, are consistent with a new two-stage model of the uroporphyria: initially uroporphyrinogen is oxidized by a cytochrome P-450-mediated reaction, followed in rodents by a progressive decrease in uroporphyrinogen decarboxylase activity.
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002262:Carboxy-Lyases / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D002722:Chlorobenzenes / Q000494:pharmacology*; D003305:Coproporphyrinogens / Q000096:biosynthesis; D003370:Coturnix; D005260:Female; D006581:Hexachlorobenzene / Q000494:pharmacology*; D007501:Iron / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D011165:Porphyrinogens / Q000378:metabolism*; D011166:Porphyrins / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000378:metabolism*; D014578:Uroporphyrins / Q000378:metabolism*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D002722:Chlorobenzenes; D003305:Coproporphyrinogens; D011165:Porphyrinogens; D011166:Porphyrins; D011506:Proteins; D014578:Uroporphyrins; C041927:pentacarboxylic porphyrinogen; D006581:Hexachlorobenzene; D019324:beta-Naphthoflavone; D011078:Polychlorinated Biphenyls; D007501:Iron; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase; C028451:3,4,3',4'-tetrachlorobiphenyl