Induction of cellular oxidative stress by aryl hydrocarbon receptor activation

Abstract

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.

Introduction

The aryl hydrocarbon receptor (AHR) is a ligand-activated member of the per-arnt-sim (PAS) family of basic-helix-loop-helix transcription factors [1], [2]. Prior to activation, AHR is found in the cytosol in association with heat shock protein (HSP)90 and HSP90 accessory proteins. Ligand binding releases it from this complex and promotes nuclear translocation. In the nucleus, the ligand-activated AHR forms a heterodimeric complex with the aryl hydrocarbon nuclear translocator (ARNT) [1]. The complex binds to aryl hydrocarbon response elements (AhRE)—also known as xenobiotic response elements (XRE), and dioxin response elements (DRE)—which function as cis-acting enhancers in the regulatory domains of a growing number of genes collectively known as the AHR gene battery[3]. Ligands for AHR include planar polycyclic and halogenated aromatic hydrocarbons and diverse classes of plant-derived chemicals. It has been hypothesized that the AHR–ARNT transcriptional complex and the genes that it regulates evolved for defense against an increasingly diverse array of plant toxins and as a result it is unlikely to serve endogenous physiological functions [4]. Recent studies, however, suggest that many important physiological and developmental processes are regulated by AHR. The activation of AHR results in rapid transcriptional activation of a large number of genes whose products control a broad spectrum of cellular functions [3], [5], [6]. This is likely, in part, due to interactions between AHR and transcription factors other than ARNT, some of which are involved in the control of complex cellular programs, such as cell division and cell fate [6], [7], [8], [9], [10] (see also Puga, Xia and Elferink herein). Furthermore, AHR-null mutant mice, although viable, suffer numerous age-related pathologies involving multiple organ systems [11]. In light of such studies, it is likely that AHR has also an important role in cellular homeostasis and that its activation by environmental chemicals may have the dual effect of triggering its homeostatic functions in some cases and disrupting them in others. Whether or not AHR activation leads to toxic effects will probably be determined by the diversity of AHR interactions, the complexity of the cellular transcriptome, the persistence of AHR activation, and the nature of the AHR ligand.

In addition to the control of physiological processes, AHR is mechanistically involved in toxicological processes involving oxidative stress. In this review, we will use the term oxidative stress for any condition that increases the cellular oxidation state to produce an oxidative stress response. This generally results from increasing the production of reactive oxygen species (ROS) (superoxide, hydrogen peroxide, hydroxyl radical, peroxynitrite, singlet oxygen) relative to cellular antioxidant defenses (antioxidants, antioxidant enzymes). Although an oxidative stress response does not necessarily result in toxicity, it is a component in the mechanism of many toxic events. In this review, we will only deal in passing with the classical concept that AHR regulates the expression of phase I and phase II detoxification enzymes that, by the nature of their enzymatic activities, generate electrophilic reactions, which cause oxidative stress, and conjugation reactions, which combat it. We chose to focus on systems in which AHR activation results in a shift in the cellular redox balance, resulting in an oxidative stress response. The literature reporting this phenomenon is vast and diverse; we apologize to those colleagues whose work is not cited.