Aryl Hydrocarbon Receptor in Oxidative Stress as a Double Agent and Its Biological and Therapeutic Significance

Abstract

The aryl hydrocarbon receptor (AhR) has long been implicated in the induction of a battery of genes involved in the metabolism of xenobiotics and endogenous compounds. AhR is a ligand-activated transcription factor necessary for the launch of transcriptional responses important in health and disease. In past decades, evidence has accumulated that AhR is associated with the cellular response to oxidative stress, and this property of AhR must be taken into account during investigations into a mechanism of action of xenobiotics that is able to activate AhR or that is susceptible to metabolic activation by enzymes encoded by the genes that are under the control of AhR. In this review, we examine various mechanisms by which AhR takes part in the oxidative-stress response, including antioxidant and prooxidant enzymes and cytochrome P450. We also show that AhR, as a participant in the redox balance and as a modulator of redox signals, is being increasingly studied as a target for a new class of therapeutic compounds and as an explanation for the pathogenesis of some disorders.

Keywords: AhR; Nrf2; antioxidant; aryl hydrocarbon receptor; nuclear factor-erythroid 2-related factor 2; oxidative stress; reactive oxygen species.

Figure 1

Structure of aryl hydrocarbon receptor (AhR). The basic helix–loop–helix (bHLH) motif, common among various transcription factors, is located at the N terminus of the AhR protein and is involved in DNA binding and protein–protein interactions. Per–ARNT–Sim (PAS) domains (PAS-A and PAS-B) participate in binding to ligands and to HSP90 proteins and in dimerization with partner proteins. The transactivation domain (TAD) is located at the C terminus of the AhR protein.

Figure 2

An outline of canonical and non-canonical AhR signaling pathways. Under physiological conditions, AhR is localized to the cytosol and forms a complex with specific proteins, such as hepatitis B virus X-associated protein 2 (XAP-2), heat shock protein 90 (HSP90), cytosolic endoplasmic-reticulum proteins, and protein tyrosine kinase c-Src. After binding to a ligand, AhR changes its conformation and relocates to the nucleus, where it dimerizes with AhR nuclear transporter (ARNT) or other partners such as transcription factor Krüppel-like factor 6 (KLF6) or transcription factors of the nuclear factor kappa B (NF-κB) family (e.g., RelB). Dissociated c-Src interacts with epidermal growth factor receptor (EGFR). AhR signaling is connected with the activity and function of estrogen receptor and E2 promoter-binding factor 1 (E2F1), which is capable of binding to pRB. The AhR–ARNT complex binds to a xenobiotic-responsive element (XRE) and induces the transcription of AhR-controlled genes. Proteins AhR and KLF6 form a heterodimer that recognizes a novel non-consensus XRE (NC-XRE) and initiates the transcription of genes involved in cell cycle regulation. Proteins AhR and RelB (an NF-κB subunit) combine into a heterodimer that recognizes a RelB–XRE complex and induces the transcription of some chemokine genes. AhR and NF-κB form a heterodimer that lead to the inducing of the expression of cytokines and chemokines B-cell-activating factor of the tumor necrosis factor family (BAFF), B-lymphocyte chemoattractant (BLC), CC-chemokine ligand 1 (CCL1), and interferon-responsive factor (IFR3). The AhR/ARNT/NF-κB interaction decreases the expression of CYP1A1. AhR and pRb form a heterodimer that lead to a blocked cell cycle progression by suppressing the expression of S-phase genes. AhR activity is controlled by negative feedback loops, including the metabolism of ligands, the disruption of the AhR/ARNT complex by AhR repressor (AhRR), and proteosomal degradation by the ubiquitin ligase complex. AhR in complex with ER promotes the proteolysis of ER by ubiquitin ligase complex.

Figure 3

The scheme of putative connections between gene batteries of AhR and Nrf2. (1) Nrf2 is a target gene of AhR; (2) indirect activation of Nrf2 by CYP1A1-generated reactive oxygen species (ROS); and (3) direct interaction of complexes AhR–XRE and Nrf2–ARE in a regulatory region of the NQO1 gene.

Figure 4

Pro-oxidant and antioxidant effects of AhR results in wide range of physiological and pathological processes in cells and tissues.