Relevance of the aryl hydrocarbon receptor (AhR) for clinical toxicology

Introduction. The aryl hydrocarbon receptor (AhR) is a cellular signaling molecule infamous for mediating the toxicity of dioxins and related compounds. Aim. The aim of this review is to provide a background of AhR and to examine critically its role in chemical toxicity, in physiological systems, and its interaction with drugs and other compounds. Toxicity. The AhR is essential for the toxicity of dioxins and related chemicals. The AhR mediates the exquisite sensitivity of animals to dioxins, where as little as 2 ng/kg/day can yield striking adverse effects. Physiological role of AhR. The wide variety of adverse effects of dioxin argues for an important role of the AhR in a variety of physiological systems. Recent investigations have highlighted the role of AhR in the development of the brain and vasculature. Drugs and other chemical activators of AhR. The development of AhR agonists during drug development programs is sometimes inadvertent, but sometimes the target of development, and is yet further confirmation of the likely importance of AhR signaling in constitutive physiology. The presence of AhR agonists in the diet such as indolo-(3,2-b)-carbazole and 3,3'-diindolylmethane (metabolized from indole 3-carbinol), flavonoids, and sulforaphane and of endogenous activators of this signaling system such as eicosanoids, indirubin, bilirubin, cAMP, and tryptophan are suggestive that AhR activation is a normal physiological process and that it is the persistent and high-level stimulation of AhR by dioxins that is responsible for toxicity. Conclusions. AhR-mediated toxicity and physiology are highly relevant to clinical toxicology and drug development.