Induction of cellular oxidative stress by aryl hydrocarbon receptor activation
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.
Section snippets
The role of AHR in the induction of genes associated with inflammation
The inflammatory response involves an extremely complex system of cross-talk interactions between cells of the immune system and non-immune cells. This response is generally beneficial to the organism; however, under certain conditions, an aggressive inflammatory response can be pathological, and much of this pathology has been attributed to the production of inflammatory cytokines. For example, high levels of TNFα, such as those seen as a result of bacterial sepsis, have been demonstrated to
Superoxide dismutase
The incomplete reduction of O2 by several enzyme systems results in the generation of superoxide. The primary cellular defense against superoxide is reduction by superoxide dismutase (SOD). Eukaryotic cells have two genes that encode two different SOD enzymes. Following translation, the Mn-dependent SOD, MnSOD, is imported into the mitochondria, while the Cu/Zn-dependent enzyme, Cu/ZnSOD, remains in the cytoplasm. Although endogenous expression analysis of the gene was not reported, the rat
AHR activation alters estrogen metabolism to produce an oxidative stress response
In long-term bioassays, TCDD significantly increased the incidence of liver tumors in female, but not in male, rats [79], [80]. It is a general observation that female rats are more susceptible to TCDD-induced oxidative stress [81], DNA oxidative damage [82] and hepatocarcinogenesis [83]. These responses are mediated, at least in part, by estrogen [84], [85]. The presumption that oxidative stress and carcinogenesis is mediated by estrogen was confirmed in Syrian hamsters, which show 100% kidney
Oxidant stress downregulates AHR-dependent transcription
The numerous studies cited above support the notion that AHR activation shifts the cellular redox state towards oxidizing conditions, perhaps as a consequence of the increased expression of CYP1 family genes. In this regard, it is interesting to note that oxidant stress in turn downregulates CYP1A1 expression [119], [120]. Under physiological oxidant stress conditions, the AHR–ARNT transcriptional complex is not redox-sensitive; however, AHR–ARNT acts in synergy with a redox-sensitive
Functional polymorphisms in AHR
Toxic responses, including oxidative stress, are modified by naturally occurring polymorphisms of AHR. Like many other transcription factors, AHR has been amenable to dissection into functional domains. In broad terms, the N-terminal half of AHR consists of the basic-region-helix-loop-helix domain and of two PAS domains which overlap in function and are responsible for DNA binding, ligand binding and dimerization [1]. The C-terminal half of AHR is responsible for transactivation. In the context
Concluding remarks
Studies aimed at understanding AHR-mediated toxicity have led to the discovery of AHR variants that appear to maintain physiological function and yet confer greatly to diminish toxicity. This is probably due to the remarkable structural plasticity of AHR, as the studies in inbred mouse strains and rats have shown. The human AHRs thus far studied demonstrate ligand-binding affinity characteristics similar to those of the low-affinity mouse strains, which might be an important factor explaining
Acknowledgements
Preparation of this review and the work done in our labs cited herein were supported in part by NIH Grants RO1 ES10133, ES06273, ES10807, and P30 ES06096.
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