title: Uroporphyria in Hfe mutant mice given 5-aminolevulinate: a new model of Fe-mediated porphyria cutanea tarda.
abstract: Porphyria cutanea tarda (PCT), a liver disease with skin lesions caused by excess liver production of uroporphyrin (URO), is associated with consumption of alcoholic beverages or estrogens, and moderate iron overload. Recently, 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 rapidly accumulate hepatic parenchymal iron similar to patients with hemochromatosis. Here we investigated whether disruption of the murine Hfe gene would result in hepatic uroporphyria. Mice homozygous for the Hfe-null mutation accumulated high levels of hepatic URO when fed 5-aminolevulinate (ALA). Hfe (+/-) mice also accumulated hepatic URO when fed ALA, but at a much slower 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 injected with iron dextran. Iron in both wild-type and Hfe (+/-) mice was mostly in Kupffer cells. In contrast, Hfe (-/-) mice had considerable parenchymal iron deposition as well, in a pattern similar to that observed in wild-type mice treated with iron carbonyl. URO accumulation was accompanied by 84% and 33% decreases in hepatic uroporphyrinogen decarboxylase activities in Hfe (-/-) and Hfe (+/-) mice, respectively. No increases in CYP1A2 or other cytochrome P450s were detected in the Hfe-null mutant mice. We conclude that this experimental model of uroporphyria is a valid model for further investigations into the mechanism of PCT.
authors.affiliation: VA Medical Center, White River Junction, VT 05009, USA. psinc@dartmouth.edu
authors.forename: P R
authors.initials: PR
authors.lastname: Sinclair
authors.forename: N
authors.initials: N
authors.lastname: Gorman
authors.forename: H S
authors.initials: HS
authors.lastname: Walton
authors.forename: W J
authors.initials: WJ
authors.lastname: Bement
authors.forename: J F
authors.initials: JF
authors.lastname: Sinclair
authors.forename: G S
authors.initials: GS
authors.lastname: Gerhard
authors.forename: J G
authors.initials: JG
authors.lastname: Szakacs
authors.forename: N C
authors.initials: NC
authors.lastname: Andrews
authors.forename: J E
authors.initials: JE
authors.lastname: Levy
mesh_terms: D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004195:Disease Models, Animal; D006432:Hemochromatosis / Q000235:genetics*; D007501:Iron / Q000378:metabolism / Q000502:physiology*; D054354:Iron Carbonyl Compounds; D007505:Iron-Dextran Complex / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000502:physiology*; D009942:Organometallic Compounds / Q000494:pharmacology; D017119:Porphyria Cutanea Tarda / Q000235:genetics* / Q000378:metabolism; D012016:Reference Values; D014575:Uroporphyrinogen Decarboxylase / Q000378:metabolism; D014578:Uroporphyrins / Q000378:metabolism*
chemical_list: D009942:Organometallic Compounds; D014578:Uroporphyrins; D054354:Iron Carbonyl Compounds; D000622:Aminolevulinic Acid; D007505:Iron-Dextran Complex; D007501:Iron; D019388:Cytochrome P-450 CYP1A2; D014575:Uroporphyrinogen Decarboxylase