Uroporphyria caused by ethanol in Hfe(-/-) mice as a model for porphyria cutanea tarda.
Two major risk factors for the development of porphyria cutanea tarda (PCT) are alcohol consumption and homozygosity for the C282Y mutation in the hereditary hemochromatosis gene (HFE). To develop an animal model, Hfe knockout mice were treated continuously with 10% ethanol in drinking water. By 4 months, uroporphyrin (URO) was detected in the urine. At 6 to 7 months, hepatic URO was increased and hepatic uroporphyrinogen decarboxylase (UROD) activity was decreased. Untreated Hfe(-/-) mice or wild-type mice treated with or without ethanol did not show any of these biochemical changes. Treatment with ethanol increased hepatic nonheme iron and hepatic 5-aminolevulinate synthase activity in Hfe(-/-) but not wild-type mice. The increases in nonheme iron in Hfe(-/-) mice were associated with diffuse increases in iron staining of parenchymal cells but without evidence of significant liver injury. In conclusion, the results of this study suggest that the uroporphyrinogenic effect of ethanol is mediated by its effects on hepatic iron metabolism. Ethanol-treated Hfe(-/-) mice seem to be an excellent model for studies of alcohol-mediated PCT.
Sinclair
Peter R
PR
VA Medical Center, White River Junction, VT 05009, USA. psinc@dartmouth.edu
Gorman
Nadia
N
Trask
Heidi W
HW
Bement
William J
WJ
Szakacs
Juliana G
JG
Elder
George H
GH
Balestra
Dominic
D
Sinclair
Jacqueline F
JF
Gerhard
Glenn S
GS
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D017119:Porphyria Cutanea Tarda / Q000139:chemically induced* / Q000378:metabolism*; D014018:Tissue Distribution; D014578:Uroporphyrins / Q000652:urine*
D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014578:Uroporphyrins; D000431:Ethanol; D007501:Iron; D019388:Cytochrome P-450 CYP1A2; D000624:5-Aminolevulinate Synthetase