Antioxidant Functions of the Aryl Hydrocarbon Receptor

Abstract

The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix/PER-ARNT-SIM family. It is activated by a variety of ligands, such as environmental contaminants like polycyclic aromatic hydrocarbons or dioxins, but also by naturally occurring compounds and endogenous ligands. Binding of the ligand leads to dimerization of the AhR with aryl hydrocarbon receptor nuclear translocator (ARNT) and transcriptional activation of several xenobiotic phase I and phase II metabolizing enzymes. It is generally accepted that the toxic responses of polycyclic aromatic hydrocarbons, dioxins, and structurally related compounds are mediated by activation of the AhR. A multitude of studies indicate that the AhR operates beyond xenobiotic metabolism and exerts pleiotropic functions. Increasing evidence points to a protective role of the AhR against carcinogenesis and oxidative stress. Herein, I will highlight data demonstrating a causal role of the AhR in the antioxidant response and present novel findings on potential AhR-mediated antioxidative mechanisms.

Murine Myocardial Transcriptome Analysis Reveals a Critical Role of COPS8 in the Gene Expression of Cullin-RING Ligase Substrate Receptors and Redox and Vesicle Trafficking Pathways

“…Ligand-bound or activated AhR moves to the nucleus where it forms heterodimers with aryl hydrocarbon receptor nuclear translocator (ARNT). The AhR/ARNT heterodimer binds to xenobiotic responsive elements (XREs) or dioxin responsive elements (DREs) in the enhancer sequences of genes encoding phase I and II xenobiotic metabolizing enzymes, such as cytochrome P450 monooxygenases (CYP1A1, CYP1A2, and CYP1B1) and glutathione-S-transferases (GSTs), NADPH/quinone oxidoreductase (NQO1), and aldehyde dehydrogenase 3, and activates these genes (Dietrich, 2016 ). Decreased AhR signaling in Hom-CKO hearts may conceivably diminish the ability to detoxify exogenous and endogenous toxic factors, which may contribute to cardiac dysfunction and cardiomyocyte death.…”

“…Decreased AhR signaling in Hom-CKO hearts may conceivably diminish the ability to detoxify exogenous and endogenous toxic factors, which may contribute to cardiac dysfunction and cardiomyocyte death. Beyond activating the canonical xenobiotic metabolism signaling, AhR can also trigger the antioxidant response through transactivating the NRF2 gene and collaborating with NRF2 to activate NRF2 target genes (Dietrich, 2016 ). The NRF2-mediated oxidative stress response is a well-known master pathway that enables the cell to deal with harmful stress including oxidative stress.…”

Cellular adaptation to xenobiotics: Interplay between xenosensors, reactive oxygen species and FOXO transcription factors

“…AhR interacts with a major regulator of the cellular antioxidant response, Nrf2 (see 3.4. ); as summarized in a recent review [45] , this occurs (i) via stimulation of CYP1A1-dependent metabolism of xenobiotics that results in the generation of ROS, which in turn stimulate Nrf2 ( see Fig. 5 ), (ii) via transcriptional stimulation of Nrf2 synthesis by AhR, and (iii) by cooperation of AhR and Nrf2 in regulating antioxidant proteins such as NAD(P)H:quinone oxidoreductase-1 (NQO1; see Fig.…”

Aryl hydrocarbon receptor regulates the expression of LmGSTd7 and is associated with chlorpyrifos susceptibility in Locusta migratoria

“…In the AhR signal pathway, inactive and unliganded AhR binds with chaperone proteins in the cytosol . Binding with ligands leads to activation of the AhR‐chaperone complex, resulting in the translocation of the complex into the nucleus, shedding of chaperone factors, and heterodimerization with the AhR nuclear translocator (ARNT) . The AhR‐ARNT complex recognizes and binds to the enhancer DNA sequence, termed the xenobiotic compound‐responsive element (XRE), and subsequently activates a battery of antioxidant and xenobiotic metabolizing genes encoding quinone reductase, cytochrome P450, UDP‐glucuronosyltransferase, and glutathione S ‐transferases (GSTs) …”