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.

A mouse model of hereditary coproporphyria identified in an ENU mutagenesis screen

“…Animal models representing the hereditary porphyrias have been generated for all porphyria subtypes except for HCP and aminolevulinic acid dehydratase deficiency porphyria (ADP) ( Richard et al, 2008 ; Homedan et al, 2015 ; Medlock et al, 2002 ; Phillips et al, 2011 ). These animal models have been vital for the understanding of mitochondrial biosynthesis pathways and the development of novel gene replacement therapies.…”

Activity of cytochrome P450 1A2 in relation to hepatic iron accumulation in transfusion‐dependent β‐thalassaemia major patients

“…Phillips et al . demonstrated that the development of uroporphyria may be CYP1A2 independent but iron dependent. Thus, although the interaction between CYP1A2 and iron in uroporphyria is not fully understood, it is likely that they share a similar pathway.…”

“…Still, the direct link between CYP1A2 and iron metabolism in mice is not fully elucidated. Recent work suggests that uroporphyria may be CYP1A2 independent . Although there is a great homology in CYP1A2 gene between human and mouse , in human, there is wide genotype variability and no definite genotype–phenotype correlation .…”

Clinical Guide and Update on Porphyrias

“…Moreover, ferrous iron was found to generate uroporphomethene independently of CyP450-enzymes. 75,78 This mechanism has only been confirmed in homogenates of human liver biopsies, where an inhibitor of UROD has been identified in patients with PCT. Patients with PCT usually carry polymorphic variants of CyP450 genes, leading to higher enzyme activities, whereas patients with familial PCT express a polymorphic variant of glycerol phosphate Oacyltransferase that is associated with iron accumulation in HFE-associated hemochromatosis.…”