Uroporphyria in the Cyp1a2-/- mouse

作者：Phillips John D^*; Kushner James P; Bergonia Hector A; Franklin Michael R

来源：Blood Cells, Molecules, and Diseases, 2011, 47(4): 249-254.

DOI：10.1016/j.bcmd.2011.07.006

• Porphyria cutanea tarda
• Iron
• Aminolevulinic acid
• Polychlorinated biphenyls
• Uroporphyrinogen decarboxylase

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 delta-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 delta-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 delta-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.

• 出版日期2011-12-15