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Vol. 53, Issue 1, 52-61, January 1998

Interaction between Iron Metabolism and 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Mice with Variants of the Ahr Gene: A Hepatic Oxidative Mechanism

Andrew G. Smith, Bruce Clothier, Susan Robinson, Matthew J. Scullion, Philip Carthew, Richard Edwards, Jinli Luo, Chang Kee Lim and Michel Toledano1

Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, UK (A.G.S, B.C, M.S, P.C, R.E, J.L, C.K.L, S.R.), and Environmental and Occupational Health Sciences Institute, New Jersey Medical School and Rutgers University, Piscataway, New Jersey 08855-1179 (M.T.)

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 to Ahrb-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 Ahrb-2 BALB/c (AH-responsive) and Ahrd 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-nonresponsive Ahrd allele in the SWR strain but not in DBA/2 mice, which remain resistant.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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