Role of inhibition of uroporphyrinogen decarboxylase in PCB-induced porphyria in mice.
The oral administration of 3,4,5,3',4',5'-hexachlorobiphenyl for 3 weeks to mice caused a marked accumulation of porphyrins in the liver of C57BL/6 and C57Bl/10 mice but not in the liver of ddY mice. The time course of induction of delta-aminolevulinic acid synthetase (ALA-S), cytochrome P-450, and mixed function oxidases and inhibition of uroporphyrinogen decarboxylase (URO-D) in the liver of C57BL/6 mice and ddY mice fed a diet containing 500 ppm of a commercial PCB (Kanechlor-500) were investigated to clarify the sole factor in inducing porphyria. The activity of URO-D in the liver of C57BL/6 mice was depressed approximately 80% at 3 weeks when a large amount of uroporphyrin accumulated. Male ddY mice showed only a slight increase in uroporphyrin accumulation in the liver and a moderate decrease of URO-D activity even at the 10th week. ALA-S, cytochrome P-450, and mixed function oxidases were induced in both strains of mice, although the magnitude of these inductions in C57BL/6 mice was greater than that in ddY mice. No differences were detected between the two strains in the content and gas chromatographic pattern of PCB remaining in liver cytosol (6 weeks). In addition there was no relationship between the time of onset of porphyria and that of the maximal induction of drug-metabolizing function in C57BL/6 mice. These results indicate that the development of porphyria is causally related to the inhibition of URO-D rather than the induction of drug-metabolizing function. The hypothesis that porphyria first develops when the ratio of hepatic URO-D and ALA-S activities decreases to less than 1.0 is presented.
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology; D008930:Mitochondria, Liver / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D011164:Porphyrias / Q000139:chemically induced* / Q000201:enzymology; D011166:Porphyrins / Q000096:biosynthesis; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors*; D014578:Uroporphyrins / Q000378:metabolism
D011166:Porphyrins; D014578:Uroporphyrins; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D000624:5-Aminolevulinate Synthetase; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase; C027309:3,4,5,3',4',5'-hexachlorobiphenyl