Chemically-induced formation of an inhibitor of hepatic uroporphyrinogen decarboxylase in inbred mice with iron overload.
An inhibitor of hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was demonstrated in heat-treated extracts of livers from C57BL/10ScSn mice with iron overload after a single dose (100 mg/kg; 350 mumol/kg) of hexachlorobenzene (HCB). Inhibition was not due to accumulated uroporphyrin since this could be removed by a SEP-PAK C18 cartridge without affecting inhibitor activity. The presence of the inhibitor could be first demonstrated 2 weeks after mice received HCB and before major elevation of hepatic porphyrin levels. Maximum inhibitory potential was reached at about 8 weeks and was still detected 25 weeks after the chemical, thus paralleling the depression of enzyme activity reported previously [Smith, Francis, Kay, Greig & Stewart (1986) Biochem. J. 238, 871-878]. The inhibitor was not detected following treatment of mice with either iron or HCB alone or after the decarboxylase activity was destroyed in vitro by the combination of uroporphyrin and light. The formation of the inhibitor by inbred mouse strains nominally Ah-responsive (C57BL/6J, C57BL/10ScSn, BALB/c, C3H/HeJ, CBA/J and A/J) and Ah-nonresponsive (SWR, AKR, 129, SJL, LP and DBA/2) did not correlate fully with their reported Ah-phenotype. There was a correlation amongst the Ah-responsive strains only, with hepatic ethoxyphenoxazone de-ethylase activity induced in parallel experiments by treatment with beta-naphthoflavone. De-ethylase activity induced by HCB, however, was considerably less than that with beta-naphthoflavone, which has not been reported as porphyrogenic. Other polyhalogenated chemicals, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, 2,3,4,2',3',4'-hexachlorobiphenyl and hexabromobenzene, also caused the formation of the inhibitor of uroporphyrinogen decarboxylase.
Smith
A G
AG
MRC Toxicology Unit, Medical Research Council Laboratory, Carshalton, Surrey, U.K.
Francis
J E
JE
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors*; D002722:Chlorobenzenes / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1; D006581:Hexachlorobenzene / Q000494:pharmacology*; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology*; D008027:Light; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000037:antagonists & inhibitors* / Q000235:genetics; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D002722:Chlorobenzenes; D006846:Hydrocarbons, Halogenated; D011166:Porphyrins; D006581:Hexachlorobenzene; D019324:beta-Naphthoflavone; D007501:Iron; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D002262:Carboxy-Lyases; D014575:Uroporphyrinogen Decarboxylase