Genetic factors influence ethanol-induced uroporphyria in Hfe(-/-) mice.
Two major risk factors for porphyria cutanea tarda (PCT) are alcohol consumption and homozygosity for the C282Y mutation in the hereditary hemochromatosis gene (HFE). We recently described an animal model for alcohol-induced uroporphyria, using Hfe(-/-) mice. In the present study we show that this effect is dependent on genetic background and ethanol dose. In the 129S6/SvEvTac (129) strain, treatment with 15% ethanol in the drinking water for 6.5 months produced an accumulation of hepatic uroporphyrin (URO) 4-fold higher than that observed with 10% ethanol, a 90% decrease in uroporphyrinogen decarboxylase activity (UROD), and further increased the activities of hepatic 5-aminolevulinate synthase (ALAS) and CYP1A2. Hepatic nonheme iron (NHFe) and hepatocyte iron staining were not further increased by 15% compared to 10% ethanol. Treatment of C57BL/6 Hfe(-/-) mice with 15% ethanol for 6.5 months did not increase hepatic URO. Although NHFe was increased by ethanol, the resulting level was only half that of ethanol-treated 129 Hfe(-/-) mice. ALAS induction was similar in both Hfe(-/-) strains. In wild-type 129 mice treated with ethanol for 6 to 7 months, administration of iron dextran increased hepatic URO accumulation and decreased UROD activity. In conclusion, this study demonstrates a strong effect of genetic background on ethanol-induced uroporphyria, which is probably due to a greater effect of ethanol on iron metabolism in the susceptible strain.
Gorman
Nadia
N
VA Medical Center, White River Junction, VT 05009, USA.
Trask
Heidi W
HW
Bement
William J
WJ
Szakacs
Juliana G
JG
Elder
George H
GH
Balestra
Dominic
D
Jacobs
Nicholas J
NJ
Jacobs
Judith M
JM
Sinclair
Jacqueline F
JF
Gerhard
Glenn S
GS
Sinclair
Peter R
PR
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007501:Iron / Q000378:metabolism; D007505:Iron-Dextran Complex / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017119:Porphyria Cutanea Tarda / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D014578:Uroporphyrins / Q000378:metabolism
D002492:Central Nervous System Depressants; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014578:Uroporphyrins; D000431:Ethanol; D007505:Iron-Dextran Complex; D007501:Iron; D019388:Cytochrome P-450 CYP1A2; D000624:5-Aminolevulinate Synthetase