Effects of chlorinated organics on intermediates in the heme pathway and on uroporphyrinogen decarboxylase.
Experimental porphyria induced by PHAHs is characterized by a progressive reduction in the activity of UROD. After intoxication with TCDD, the most porphyrogenic compound known to date, the liver was the principal site of action, as regards both porphyrin accumulation (mostly uroporphyrin) and the degree of enzyme impairment; the kidney was the site of the second greatest accumulation; the brain and erythrocytes were unaffected. Additional modifications of the heme pathway involved induction of the activity of ALAS and, at least in HCB-induced porphyria after iron pretreatment, may have involved reduced activity of uroporphyrinogen III cosynthetase. These changes can alter the amount and the isomeric composition of uroporphyrinogens and uroporphyrins present in the liver in a way that is likely to help reduce formation of coproporphyrinogen III in porphyric animals. As in the human syndrome porphyria cutanea tarda, iron administration increased porphyrin accumulation and the degree of reduction of UROD activity in mice fed HCB. Mice fed HCB also presented an activation of the type O form of XO. This activation was independent of tissue injury derived from the lipid peroxidation that was concomitant with iron administration. The increase in activity of the type O form of XO may be a characteristic feature of the liver damage found in PHAH intoxication and, in intoxicated animals, could be a source in the liver of oxidant species involved in the mechanism of UROD inactivation--if this inactivation is in fact due to an oxidative reaction.
Istituto di Ricerche Farmacologiche, Mario Negri, Milan, Italy.
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Cantoni
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Rizzardini
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Graziani
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Carugo
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Garattini
D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism*; D002722:Chlorobenzenes / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D006418:Heme; D006581:Hexachlorobenzene / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D014575:Uroporphyrinogen Decarboxylase / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism
D002722:Chlorobenzenes; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D006418:Heme; D006581:Hexachlorobenzene; D014969:Xanthine Oxidase; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase