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ToxSci Advance Access published online on April 12, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm085
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Persistent Binding of Ligands to the Aryl Hydrocarbon Receptor

Jessica E. Bohonowych and Michael S. Denison*

Department of Environmental Toxicology, University of California, Davis 95616

* Address correspondence to: Michael S. Denison, Department of Environmental Toxicology, Meyer Hall, One Shields Avenue, University of California, Davis, CA 95616, Phone: (530) 752-3879, Fax: (530) 752-3394, E-Mail: msdenison{at}ucdavis.edu

Received January 10, 2007; revision received April 6, 2007; accepted April 7, 2007


  Abstract

The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor that mediates many of the biological and toxic effects of halogenated aromatic hydrocarbons (HAHs), polycyclic aromatic hydrocarbons (PAHs), and other structurally diverse ligands. While HAHs are several orders of magnitude more potent in producing AhR-dependent biochemical effects than PAHs or other AhR agonists, only the HAHs have been observed to produce AhR-dependent toxicity in vivo. Here we have characterized the dissociation of a prototypical HAH ligand ([3H] 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) and PAH-like ligand ([3H] ß-naphthoflavone (ßNF)) from the guinea pig, hamster, mouse, and rat hepatic cytosolic AhR in order to elucidate the relationship between the apparent ligand binding affinities and the divergent potency of these chemicals. Both compounds dissociated very slowly from the AhR with the amount of specific binding remaining at 96 hours ranging from 53% to 70% for [3H]TCDD and 26% to 85% for [3H] ßNF, depending upon the species examined. The rate of ligand dissociation was unaffected by protein concentration or incubation temperature. Pre-incubation of cytosol with 2,3,7,8-tetrachlorodibenzofuran (TCDF), carbaryl or primaquine, prior to the addition of [3H]TCDD, shifted the apparent IC50 of these compounds as competitive AhR ligands by ~10-50-fold. Our results support the need for reassessment of previous AhR ligand binding affinity calculations and competitive binding analysis since these measurements are not carried out at equilibrium binding conditions. Our studies suggest that AhR binding affinity/occupancy have little effect on the observed differences in the persistence of gene expression by HAHs and PAHs. (246 words)

Key Words: Ah Receptor; 2,3,7,8-Tetrachlorodibenzo-p-dioxin; TCDD; ß-naphthoflavone.


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