RT Journal Article
SR Electronic
T1 Non-Ahr Gene Susceptibility Loci for Porphyria and Liver Injury Induced by the Interaction of ‘Dioxin’ with Iron Overload in Mice
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 674
OP 681
DO 10.1124/mol.61.3.674
VO 61
IS 3
A1 Susan W. Robinson
A1 Bruce Clothier
A1 Ruth A. Akhtar
A1 Ai Li Yang
A1 Isabelle Latour
A1 Carola Van Ijperen
A1 Michael F. W. Festing
A1 Andrew G. Smith
YR 2002
UL http://molpharm.aspetjournals.org/content/61/3/674.abstract
AB Among the actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in mice is the induction of hepatic porphyria. This is similar to the most common disease of this type in humans, sporadic porphyria cutanea tarda (PCT). Evidence is consistent with the actions of dioxin being mediated through binding to the aryl hydrocarbon receptor (AHR) with different Ahr alleles in mouse strains apparently accounting for differential downstream gene expression and susceptibility. However, studies of dioxin-induced porphyria and liver injury indicate that the mechanisms must involve interactions with other genes, perhaps associated with iron metabolism. We performed a quantitative trait locus (QTL) analysis of an F2 cross between susceptible C57BL/6J (Ahr b1allele) and the highly resistant DBA/2 (Ahr d allele) strains after treatment with dioxin and iron. For porphyria we found QTLs on chromosomes 11 and 14 in addition to the Ahr gene (chromosome 12). Studies with C57BL/6.D2 Ahr d mice confirmed that the Ahr d allele alone did not completely negate the response. SWR mice are syngenic for theAhr d allele with the DBA/2 strain but are susceptible to porphyria after elevation of hepatic iron. Analysis of SWR×D2 F2 mice treated with iron and dioxin showed a QTL on chromosome 11, as well as finding other loci on chromosomes 1 (and possibly 9), for both porphyria and liver injury. These findings show for the first time the location of genes, other thanAhr, that modulate the mechanism of hepatic porphyria and injury caused by dioxin in mice. Orthologous loci may contribute to the pathogenesis of human sporadic PCT.