Mechanistic studies of the inhibition of hepatic uroporphyrinogen decarboxylase in C57BL/10 mice by iron-hexachlorobenzene synergism.
Porphyria was induced in C57BL/10 mice with iron overload by a single oral dose (100 mg/kg) of hexachlorobenzene (HCB). Within 2 weeks hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was inhibited, reaching a maximum (greater than 95%) at 6-8 weeks. There was no recovery by 14 weeks, despite a fall in liver HCB concentrations to only 6% of the day-3 value. The major rise in hepatic porphyrin levels occurred after 4 weeks and secondary inhibition of uroporphyrinogen synthase (EC 4.2.1.75) was inferred from the progressively greater proportion of uroporphyrin I present relative to the III isomer. Plasma alanine aminotransferase (EC 2.6.1.2) activity was also elevated. Although, in further studies, total microsomal cytochrome P-450 content and ethoxyphenoxazone de-ethylase activity reached a peak a few days after dosing and had declined significantly at the time of maximum inhibition of the decarboxylase, additional treatment of HCB-dosed mice with a cytochrome P1-450 inducer, beta-naphthoflavone, enhanced the inhibition, whereas piperonyl butoxide, an inhibitor of cytochrome P-450, partially protected. Uroporphyrinogen decarboxylase was not radiolabelled in vivo by [14C]HCB. There was no major difference in the ability to hydroxylate HCB between hepatic microsomes from induced C57BL/10 mice and those from the insensitive DBA/2 strain. By contrast, lipid peroxidation, in the presence of NADPH, was 8-fold greater in control C57BL/10 microsomes than in DBA/2 microsomes and was stimulated by iron treatment (although not by HCB). The results suggest that the inhibition of hepatic uroporphyrinogen decarboxylase is unlikely to be due to a direct effect of a metabolite of HCB but to another process requiring a specific cytochrome P-450 isoenzyme and an unknown iron species.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D056486:Chemical and Drug Induced Liver Injury; D002722:Chlorobenzenes / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1; D003600:Cytosol / Q000378:metabolism; D004357:Drug Synergism; D006581:Hexachlorobenzene / Q000494:pharmacology* / Q000506:poisoning; D007501:Iron / Q000494:pharmacology*; D050356:Lipid Metabolism; D008107:Liver Diseases / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010088:Oxidoreductases / Q000096:biosynthesis; D011164:Porphyrias / Q000139:chemically induced / Q000201:enzymology*; D013045:Species Specificity; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors*; D014578:Uroporphyrins / Q000378:metabolism
D002722:Chlorobenzenes; D014578:Uroporphyrins; D006581:Hexachlorobenzene; D007501:Iron; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D000410:Alanine Transaminase; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase