Induction of cellular oxidative stress by aryl hydrocarbon receptor activation

The aryl hydrocarbon receptor (AHR) has long been associated with the induction of a battery of genes involved in the metabolism of foreign and endogenous compounds. Depending on experimental conditions, AHR can mediate either activation or amelioration of chemical toxicity. For the past decade, evidence has mounted that AHR is associated with a cellular oxidative stress response that must be considered when evaluating the mechanism of action of xenobiotics capable of activating AHR, or capable of metabolic activation by enzymes encoded by genes under control of AHR. In this review, we have evaluated the diverse mechanisms by which AHR generates an oxidative stress response, including inflammation, antioxidant and prooxidant enzymes and cytochrome P450. A review of the regulation of Ahr transcription and functional polymorphisms especially related to oxidative stress is also included. We have carefully avoided placing a value judgment on the degree of toxicity produced by such a response, in view of the realization that an oxidative response is involved in many normal physiological processes. Since the interface between physiological, adaptive and toxicological responses elicited by the AHR-mediated oxidative stress response is not clearly defined, it behooves the researcher to evaluate both toxicological and physiological features of the response.