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Uroporphyria in Hfe mutant mice given 5-aminolevulinate: a new model of Fe-mediated porphyria cutanea tarda.
Hepatology. 2001 Feb; 33(2):406-12.Hep

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+Show Affiliations

VA Medical Center, White River Junction, VT 05009, USA. psinc@dartmouth.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11172342

Citation

Sinclair, P R., et al. "Uroporphyria in Hfe Mutant Mice Given 5-aminolevulinate: a New Model of Fe-mediated Porphyria Cutanea Tarda." Hepatology (Baltimore, Md.), vol. 33, no. 2, 2001, pp. 406-12.
Sinclair PR, Gorman N, Walton HS, et al. Uroporphyria in Hfe mutant mice given 5-aminolevulinate: a new model of Fe-mediated porphyria cutanea tarda. Hepatology. 2001;33(2):406-12.
Sinclair, P. R., Gorman, N., Walton, H. S., Bement, W. J., Sinclair, J. F., Gerhard, G. S., Szakacs, J. G., Andrews, N. C., & Levy, J. E. (2001). Uroporphyria in Hfe mutant mice given 5-aminolevulinate: a new model of Fe-mediated porphyria cutanea tarda. Hepatology (Baltimore, Md.), 33(2), 406-12.
Sinclair PR, et al. Uroporphyria in Hfe Mutant Mice Given 5-aminolevulinate: a New Model of Fe-mediated Porphyria Cutanea Tarda. Hepatology. 2001;33(2):406-12. PubMed PMID: 11172342.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Uroporphyria in Hfe mutant mice given 5-aminolevulinate: a new model of Fe-mediated porphyria cutanea tarda. AU - Sinclair,P R, AU - Gorman,N, AU - Walton,H S, AU - Bement,W J, AU - Sinclair,J F, AU - Gerhard,G S, AU - Szakacs,J G, AU - Andrews,N C, AU - Levy,J E, PY - 2001/2/15/pubmed PY - 2001/3/17/medline PY - 2001/2/15/entrez SP - 406 EP - 12 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 33 IS - 2 N2 - 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. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/11172342/Uroporphyria_in_Hfe_mutant_mice_given_5_aminolevulinate:_a_new_model_of_Fe_mediated_porphyria_cutanea_tarda_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270913901328045 DB - PRIME DP - Unbound Medicine ER -