Uroporphyria in HFE mutant mice given 5-aminolevulinate: A new model of Fe-mediated porphyria cutanea tarda

Porphyria cutanea tarda (PCT), a liver disease with skin lesions caused by excess liver production of uroporphyrin (URO), is associated with consumpti on of alcoholic beverages or estrogens, and moderate iron overload. Recentl y, it has been shown that many PCT patients carry mutations in the HFE gene , which is responsible for hereditary hemochromatosis, Mice homozygous for either the null mutation in the Hfe gene or the C282Y missense mutation rap idly accumulate hepatic parenchymal iron similar to patients with hemochrom atosis. Here we investigated whether disruption of the murine Hfe gene woul d result in hepatic uroporphyria, Mice homozygous for the Hfe-null mutation accumulated high levels of hepatic URO when fed 5-aminolevulinate (ALA), H fe (+/-) mice also accumulated hepatic URO when fed ALA, but at a much slow er rate. The amount of accumulated URO in the null mutant mice was similar to that in wild-type mice treated with iron carbonyl in the diet, or inject ed with iron dextran, Iron in both wildtype and Hfe (+/-) mice was mostly i n Kupffer cells. In contrast, Hfe (-/-) mice had considerable parenchymal i ron deposition as well, in a pattern similar to that observed in wild-type mice treated with iron carbonyl, URO accumulation was accompanied by 84% an d 33% decreases in hepatic uroporphyrinogen decarboxylase activities in Hfe (-/-) and Hfe (+/-) mice, respectively, No increases in CYP1A2, or other c ytochrome P450s were detected in the Hfe-null mutant mice. We conclude that this experimental model of uroporphyria is a valid model for further inves tigations into the mechanism of PCT.