PT - JOURNAL ARTICLE AU - Andrew G. Smith AU - Bruce Clothier AU - Susan Robinson AU - Matthew J. Scullion AU - Philip Carthew AU - Richard Edwards AU - Jinli Luo AU - Chang Kee Lim AU - Michel Toledano TI - Interaction between Iron Metabolism and 2,3,7,8-Tetrachlorodibenzo-<em>p</em>-dioxin in Mice with Variants of the <em>Ahr</em> Gene: A Hepatic Oxidative Mechanism AID - 10.1124/mol.53.1.52 DP - 1998 Jan 01 TA - Molecular Pharmacology PG - 52--61 VI - 53 IP - 1 4099 - http://molpharm.aspetjournals.org/content/53/1/52.short 4100 - http://molpharm.aspetjournals.org/content/53/1/52.full SO - Mol Pharmacol1998 Jan 01; 53 AB - The binding of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) with the aryl hydrocarbon (AH) receptor and subsequent changes in gene expression have been studied intensively, but the mechanisms by which these lead to toxicity are unclear. We investigated the influence of iron, previously implicated in TCDD-induced hepatic porphyria, in mice with alleles of Ahr that encode receptors with varied affinity for TCDD. The administration of iron toAhr b-1 C57BL/6J (AH-responsive) mice before a single dose of TCDD (75 μg/kg) markedly potentiated not only the hepatic porphyria but also general hepatocellular damage and elevation of plasma hepatic enzymes. The formation of hydroxylated and peroxylated derivatives of uroporphyrins formed from uroporphyrinogen and the induction of a μ-glutathione transferase (GST) were consistent with the operation of an oxidative mechanism. In a comparison of C57BL/6J mice with Ahr b-2BALB/c (AH-responsive) and Ahr d SWR and DBA/2 (AH-nonresponsive) mice, iron overcame the weak hepatic porphyria and toxicity responses in BALB/c and SWR strains but not in DBA/2. CYP1A isoforms are strongly implicated in the mechanism of porphyria, but activities were lowered by 20–30% with iron treatment, and a comparison of levels between strains did not fully account for the resistance of DBA/2 mice. Studies with the use of gel shift assays and cytosolic aconitase of the capacity of the iron regulatory protein controlling the translation of some iron metabolism proteins showed a significant difference between C57BL/6J and DBA/2 mice after the administration of TCDD. We conclude that iron potentiates both the hepatic porphyria and toxicity of TCDD in susceptible mice in an oxidative process with disturbance of iron regulatory protein capacity. Iron even overcomes the AH-nonresponsiveAhr d allele in the SWR strain but not in DBA/2 mice, which remain resistant.