title: Uroporphyria in the Cyp1a2-/- mouse.
abstract: Cytochrome P4501A2 (Cyp1a2) is important in the development of uroporphyria in mice, a model of porphyria cutanea tarda in humans. Heretofore, mice homozygous for the Cyp1a2-/- mutation do not develop uroporphyria with treatment regimens that result in uroporphyria in wild-type mice. Here we report uroporphyria development in Cyp1a2-/- mice additionally null for both alleles of the hemochromatosis (Hfe) gene and heterozygous for deletion of the uroporphyrinogen decarboxylase (Urod) gene (genotype: Cyp1a2-/-;Hfe-/-;Urod+/-), demonstrating that upon adding porphyria-predisposing genetic manipulations, Cyp1a2 is not essential. Cyp1a2-/-;Hfe-/-;Urod+/- mice were treated with various combinations of an iron-enriched diet, parenteral iron-dextran, drinking water containing δ-aminolevulinic acid and intraperitoneal Aroclor 1254 (a polychlorinated biphenyl mixture) and analyzed for uroporphyrin accumulation. Animals fed an iron-enriched diet alone did not develop uroporphyria but uroporphyria developed with all treatments that included iron supplementation and δ-aminolevulinic acid, even with a regimen without Aroclor 1254. Hepatic porphyrin levels correlated with low UROD activity and high levels of an inhibitor of UROD but marked variability in the magnitude of the porphyric response was present in all treatment groups. Gene expression profiling revealed no major differences between genetically identical triple cross mice exhibiting high and low magnitude porphyric responses from iron-enriched diet and iron-dextran supplementation, and δ-aminolevulinic acid. Even though the variation in porphyric response did not parallel the hepatic iron concentration, the results are compatible with the presence of a Cyp1a2-independent, iron-dependent pathway for the generation of uroporphomethene, the UROD inhibitor required for the expression of uroporphyria in mice and PCT in humans.
authors: University of Utah School of Medicine, Department of Internal Medicine, Division of Hematology, Salt Lake City, UT 84132, USA. john.phillips@hsc.utah.edu
authors: John D
authors: JD
authors: Phillips
authors: James P
authors: JP
authors: Kushner
authors: Hector A
authors: HA
authors: Bergonia
authors: Michael R
authors: MR
authors: Franklin
mesh_terms: D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005838:Genotype; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017119:Porphyria Cutanea Tarda / Q000178:diet therapy / Q000235:genetics* / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism; D014575:Uroporphyrinogen Decarboxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D011166:Porphyrins; D007501:Iron; D019388:Cytochrome P-450 CYP1A2; D014575:Uroporphyrinogen Decarboxylase