Effects of polychlorinated biphenyl compounds, 2,3,7,8-tetrachlorodibenzo-p-dioxin, phenobarbital and iron on hepatic uroporphyrinogen decarboxylase. Implications for the pathogenesis of porphyria.
Treatment of cultured chick embryo hepatocytes with phenobarbital, polychlorinated biphenyl compounds and 2,3,7,8-tetrachlorodibenzo-p-dioxin resulted in increased delta-aminolaevulinate synthase and decreased uroporphyrinogen decarboxylase activities and porphyrin accumulation; uroporphyrin and heptacarboxyporphyrin predominated. Iron had no effect on these changes. Simultaneous treatment of cultures with dioxin and phenobarbital produced a synergistic response in delta-aminolaevulinate synthase induction, uroporphyrinogen decarboxylase inhibition and porphyrin accumulation. These data suggest that an inhibitor of uroporphyrinogen decarboxylase may be generated in the liver from polychlorinated biphenyl compounds or dioxin by metabolic activation. Additionally these findings bear on the postulated role of these and related chemicals in determining the low levels of uroporphyrinogen decarboxylase activity in porphyria cutanea tarda patients.
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D004147:Dioxins / Q000494:pharmacology*; D007501:Iron / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011164:Porphyrias / Q000201:enzymology; D011166:Porphyrins / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors*; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D011166:Porphyrins; D019324:beta-Naphthoflavone; D011078:Polychlorinated Biphenyls; D007501:Iron; D000624:5-Aminolevulinate Synthetase; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase; D010634:Phenobarbital