The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways

Exposure to toxic polycyclic aromatic hydrocarbons raises a number of toxic and carcinogenic responses in experimental animals and humans mediated for the most part by the aryl hydrocarbon - or dioxin - receptor (AHR), The AHR is a ligand-activated transcription factor whose central role in the induction of drug-metabolizing enzymes has longbeen recognized. For quite some time now, it has become clear that the AHR also functions in pathways outside of its role in detoxification and that perturbation of these pathways by xenobiotic ligands may be an important part of the toxicity of these compounds. AHR activation by some of its ligands participates among others in pathways critical to cell cycle regulation, mitogen-activated protein kinase cascades, immediate-early gene induction, cross-talk within the RB/E2F axis and mobilization of crucial calcium stores. Ultimately, the effect of a particular AHR ligand may depend as much on the adaptive interactions that it established with pathways and proteins expressed in a specific cell or tissue as on the toxic responses that it raises. (C) 2008 Elsevier Inc. All rights reserved.