title: Uroporphyria in the uroporphyrinogen decarboxylase-deficient mouse: Interplay with siderosis and polychlorinated biphenyl exposure.
abstract: Several methods have been used to develop rodent models with the hepatic manifestations of porphyria cutanea tarda (PCT). Acute iron administration or mutations of the hemochromatosis gene (Hfe) have been used to generate hepatic siderosis, a nearly uniform finding in PCT. Heterozygosity for a null mutation at the uroporphyrinogen decarboxylase (Uro-D+/-) locus has been developed to mimic familial PCT in humans. This study examines the interplay of these 2 genetic risk factors and their influence, alone and combined with polychlorinated-biphenyl exposure. Neither an Hfe-null mutation nor iron-dextran administration alone or in combination with polychlorinated biphenyl exposure was porphyrinogenic in a 3-week model using mice wild-type at the Uro-D locus. Homozygosity for an Hfe-null mutation significantly elevated hepatic iron but not to the extent seen with parenteral iron-dextran administration. Homozygosity for an Hfe-null mutation but not iron-dextran administration was porphyrinogenic in animals heterozygous for the Uro-D mutation. Polychlorinated biphenyls were also porphyrinogenic in these animals. Uroporphyria in Uro-D+/- animals was exacerbated by combinations of the homozygous Hfe-null mutation and polychlorinated biphenyls and iron-dextran and polychlorinated biphenyls. In all cases in which uroporphyria developed, a greater degree of experimental uroporphyria was seen in female animals. All elevated hepatic uroporphyrin concentrations were accompanied by depressed uroporphyrinogen decarboxylase activity and the presence of a factor in cytosol that inhibits recombinant human uroporphyrinogen decarboxylase. In conclusion, the expression of the uroporphyric phenotype, dependent on the susceptibility imparted by a genetic mutation, provides a uniquely facile model for dissecting the molecular pathogenesis of the disease.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA. mfranklin@alanine.pharm.utah.edu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Franklin
authors.forename: John D
authors.initials: JD
authors.lastname: Phillips
authors.forename: James P
authors.initials: JP
authors.lastname: Kushner
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006432:Hemochromatosis / Q000235:genetics; D007501:Iron / Q000032:analysis; D007505:Iron-Dextran Complex / Q000494:pharmacology; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D017119:Porphyria Cutanea Tarda / Q000150:complications / Q000235:genetics*; D011166:Porphyrins / Q000032:analysis; D012806:Siderosis / Q000150:complications / Q000235:genetics*; D014575:Uroporphyrinogen Decarboxylase / Q000235:genetics*
chemical_list: D013956:Antithyroid Agents; D011166:Porphyrins; D020111:Chlorodiphenyl (54% Chlorine); D007505:Iron-Dextran Complex; D011078:Polychlorinated Biphenyls; D007501:Iron; D014575:Uroporphyrinogen Decarboxylase