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Aryl Hydrocarbon Receptor in Oxidative Stress: Comparison
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Please note this is a comparison between Version 2 by Maria L Perepechaeva and Version 5 by Camila Xu.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor necessary for the launch of transcriptional responses important in health and disease. Its partner protein aryl hydrocarbon receptor nuclear translocator (ARNT), and AhR repressor protein (AhRR) are members of a family of structurally related transcription factors (basic helix–loop–helix (bHLH) motif-containing Per–ARNT–Sim (PAS), whose members carry out critical functions in the gene expression networks that underlie many physiological and developmental processes, especially those participating in responses to signals from the environment.

Aryl Hydrocarbon Receptor in Oxidative Stress as a Double Agent and Its Biological and Therapeutic Significance
 
  • reactive oxygen species
  • oxidative stress
  • antioxidant
  • aryl hydrocarbon receptor
  • AhR
  • nuclear factor-erythroid 2-related factor 2
  • Nrf2

1. Introduction

  1. Introduction

In live cells, reactive oxygen species are continuously generated, for example, by xanthine oxidase to degrade purine nucleotides, by nitric oxide synthase to form nitric oxide, and by other biochemical reactions as a byproduct of the oxidative energy metabolism for the formation of adenosine triphosphate from glucose in mitochondria [1][2][3][4].

In live cells, reactive oxygen species are continuously generated, for example, by xanthine oxidase to degrade purine nucleotides, by nitric oxide synthase to form nitric oxide, and by other biochemical reactions as a byproduct of the oxidative energy metabolism for the formation of adenosine triphosphate from glucose in mitochondria [1-4].

Under normal physiological conditions, small amounts of oxygen are constantly converted into superoxide anions, hydrogen peroxide, and hydroxyl radicals. The biological activity of reactive oxygen species at a physiological concentration plays an important role in cell homeostasis and in a wide range of cellular parameters (proliferation, differentiation, cell cycle, and apoptosis) [5][6][7][8].

Under normal physiological conditions, small amounts of oxygen are constantly converted into superoxide anions, hydrogen peroxide, and hydroxyl radicals. The biological activity of reactive oxygen species at a physiological concentration plays an important role in cell homeostasis and in a wide range of cellular parameters (proliferation, differentiation, cell cycle, and apoptosis) [5-8].

In the cell, reactive oxygen species arise under the influence of such exogenous pro-oxidant factors as environmental pollutants, ionizing and ultraviolet radiation, xenobiotics, air pollutants, and heavy metals [9][10].

In the cell, reactive oxygen species arise under the influence of such exogenous pro-oxidant factors as environmental pollutants, ionizing and ultraviolet radiation, xenobiotics, air pollutants, and heavy metals [9, 10].

The main endogenous sites of production of cellular redox-reactive compounds include complexes I and III of the mitochondrial electron transport chain, endoplasmic reticulum, peroxisomes, and such enzymes as membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms 1–5 (NOX1–NOX5), complexes of dual oxidases 1 and 2, xanthine oxidase, polyamine and amine oxidases, enzymes catabolizing lipids, and cytochrome P450 family 1 (CYP1A) [11][12][13][14][15][16].

The main endogenous sites of production of cellular redox-reactive compounds include complexes I and III of the mitochondrial electron transport chain, endoplasmic reticulum, peroxisomes, and such enzymes as membrane-bound nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms 1–5 (NOX1–NOX5), complexes of dual oxidases 1 and 2, xanthine oxidase, polyamine and amine oxidases, enzymes catabolizing lipids, and cytochrome P450 family 1 (CYP1A) [11-16].

The high reactivity of oxygen and its active species necessitates a multi-level antioxidant defense system that blocks the formation of highly active free radicals [10].

Free radicals are usually eliminated by the body’s natural antioxidant system. Redox homeostasis in normal cells is maintained by a nonenzymatic system consisting of carotenoids, flavonoids, glutathione, anserine, carnosine, homocarnosine, melatonin, thioredoxin, and vitamins C and E, as well as a network of antioxidant enzymes such as superoxide dismutases, catalases, peroxiredoxins, glutathione peroxidase (GPX), glutaredoxins, and paraoxonases [17][18]. In redox homeostasis, a certain role is played by the enzymes of phase II xenobiotic biotransformation, e.g., NADPH:quinone oxidoreductase 1 (NQO1), glutathione-S-transferase (GST) P1, GSTA1/2, UDP glucuronosyltransferase (UGT) 1A6, GPX4, and heme oxygenase 1 [19].

Free radicals are usually eliminated by the body’s natural antioxidant system. Redox homeostasis in normal cells is maintained by a nonenzymatic system consisting of carotenoids, flavonoids, glutathione, anserine, carnosine, homocarnosine, melatonin, thioredoxin, and vitamins C and E, as well as a network of antioxidant enzymes such as superoxide dismutases, catalases, peroxiredoxins, glutathione peroxidase (GPX), glutaredoxins, and paraoxonases [17, 18]. In redox homeostasis, a certain role is played by the enzymes of phase II xenobiotic biotransformation, e.g., NADPH:quinone oxidoreductase 1 (NQO1), glutathione-S-transferase (GST) P1, GSTA1/2, UDP glucuronosyltransferase (UGT) 1A6, GPX4, and heme oxygenase 1 [19].

An imbalance between the formation of oxidative free radicals and the antioxidant defense capacity of the body’s cells is defined as oxidative stress. An important function in the regulation of oxidative stress is performed by the AhR signaling pathway via pro-oxidant and antioxidant mechanisms.

2. AhR

  1. AhR

The aryl hydrocarbon receptor (AhR), its partner protein aryl hydrocarbon receptor nuclear translocator (ARNT), and AhR repressor protein (AhRR) are members of a family of structurally related transcription factors (basic helix–loop–helix (bHLH) motif-containing Per–ARNT–Sim (PAS), whose members carry out critical functions in the gene expression networks that underlie many physiological and developmental processes, especially those participating in responses to signals from the environment [20][21][20, 21].

AhR is a unique and versatile biological sensor of planar chemical compounds of endogenous and exogenous origin [22][23][22, 23] and is the only member of the PAS family that binds naturally occurring xenobiotics [24]. By functioning as a transcription factor, AhR takes part in many physiological and pathological processes in cells and tissues.

3. AhR Regulates Enzyme Systems Generating Reactive Oxygen Species

  1. AhR Regulates Enzyme Systems Generating Reactive Oxygen Species

AhR is reported to be responsible for the toxic cellular effects of TCDD via pro-oxidant mechanisms [25][26][25, 26]. There is convincing evidence that the activation of AhR-dependent detoxification of such environmental stressors as TCDD, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and effects of ultraviolet radiation gives rise to oxidative stress and to the production of reactive oxygen species, thus inducing oxidative damage to DNA, lipids, and other cellular macromolecules [27][28][29][30][27-30]. Several enzyme systems, including CYP1A, NOX, COX, and possibly aldo–keto reductase (AKR) 1, are regulated through the AhR signaling pathway in terms of their ability to generate reactive oxygen species in various cell types and tissues [31][32][33][34][31-34].

4. Participation of AhR in Antioxidant Defense

  1. Participation of AhR in Antioxidant Defense

Aside from the AhR-dependent production of intracellular reactive oxygen species, the AhR signaling pathway modulates the expression of genes of the antioxidant system and thereby regulates cell functions that ensure protection from oxidative stress. Numerous studies indicate that the protective action of antioxidants against oxidative stress is mediated by AhR through a response to such AhR ligands as flavonoids, phytochemicals, and azoles [35][36][37][38][39][40][41][42].

Aside from the AhR-dependent production of intracellular reactive oxygen species, the AhR signaling pathway modulates the expression of genes of the antioxidant system and thereby regulates cell functions that ensure protection from oxidative stress. Numerous studies indicate that the protective action of antioxidants against oxidative stress is mediated by AhR through a response to such AhR ligands as flavonoids, phytochemicals, and azoles [35-42].

When this type of ligand binds to AhR, the production of reactive oxygen species does not occur because of the induction of the nuclear translocation of AhR; instead, Nrf2 is activated. Nrf2 is a key biomolecule that provides cell protection against the oxidative damage caused by reactive oxygen species: Nrf2 is a transcription factor that regulates the genes encoding enzymes of the antioxidant system [43][44].

When this type of ligand binds to AhR, the production of reactive oxygen species does not occur because of the induction of the nuclear translocation of AhR; instead, Nrf2 is activated. Nrf2 is a key biomolecule that provides cell protection against the oxidative damage caused by reactive oxygen species: Nrf2 is a transcription factor that regulates the genes encoding enzymes of the antioxidant system [43, 44].

5. AhR in the Pathogenesis of Diseases Related to Oxidative Stress

  1. AhR in the Pathogenesis of Diseases Related to Oxidative Stress

Although initial studies on AhR were focused on its function as a signaling molecule of a chemical sensor responsive to environmental pollutants, lately, the range of subject areas has widened significantly. The understanding has expanded regarding the role of the AhR signaling pathway in the regulation of a variety of physiological and pathological phenomena. AhR’s functions cover many cellular processes, including the regulation of cell survival, metabolic and protein homeostasis, inflammation, cell proliferation and differentiation, apoptosis, and cellular adhesion and migration. Reactive oxygen species-induced activation of transcription factors and proinflammatory genes increases inflammation. Accordingly, research on various diseases in which AhR induces an oxidative stress response—by switching on inflammation and antioxidant, prooxidant, and cytochrome P450 enzymes—is now within the scope of the interest of investigators.

Although initial studies on AhR were focused on its function as a signaling molecule of a chemical sensor responsive to environmental pollutants, lately, the range of subject areas has widened significantly. Our understanding has expanded regarding the role of the AhR signaling pathway in the regulation of a variety of physiological and pathological phenomena. AhR’s functions cover many cellular processes, including the regulation of cell survival, metabolic and protein homeostasis, inflammation, cell proliferation and differentiation, apoptosis, and cellular adhesion and migration. Reactive oxygen species-induced activation of transcription factors and proinflammatory genes increases inflammation. Accordingly, research on various diseases in which AhR induces an oxidative stress response—by switching on inflammation and antioxidant, prooxidant, and cytochrome P450 enzymes—is now within the scope of the interest of investigators.

It is known that oxidative stress causes inflammation and toxicity, and these problems can lead to such pathologies as cardiovascular, liver, kidney, lung, brain, eye, skin, and joint diseases, as well as aging and cancer [7][45][46][47][48][49]. In recent decades, AhR has been increasingly recognized as an important modulator of disease because of AhR’s role in the regulation of the redox system and of immune and inflammatory responses [30][50].

It is known that oxidative stress causes inflammation and toxicity, and these problems can lead to such pathologies as cardiovascular, liver, kidney, lung, brain, eye, skin, and joint diseases, as well as aging and cancer [7, 45-49]. In recent decades, AhR has been increasingly recognized as an important modulator of disease because of AhR’s role in the regulation of the redox system and of immune and inflammatory responses [31, 50].

6. Conclusions

  1. Conclusions

Major breakthroughs were recently made in the biology of redox modulation by AhR. Despite all the gained knowledge, the remaining intriguing questions concern the mechanism underlying the cell- and tissue-specific effects of AhR ligands and the dependence of responses on the type of ligands. The function of AhR is complicated because the outcome of its activation depends on a wide range of endogenous and exogenous ligands (which are characterized by different affinity values and diverse combinatorial effects) and on different AhR functions in many physiological and pathological processes in cells and tissues. The molecular mechanisms of AhR signaling and of the crosstalk between AhR signaling and other signal transduction cascades require further research. It is mostly the inconsistency of scientific findings that makes it difficult to determine the signaling pathways through which AhR can exert its beneficial or detrimental actions. There is growing evidence that AhR activation can have multidirectional effects on many aspects of human physiology and pathology, and that these may depend on cell and tissue types, or on the interaction of the AhR complex with non-traditional XRE sequences, or interaction with various coactivators and corepressors. Depending on many factors, the action of AhR agonists or antagonists can cause positive or negative effects on human health (Figure 1).

Major breakthroughs were recently made in the biology of redox modulation by AhR. Despite all the gained knowledge, the remaining intriguing questions concern the mechanism underlying the cell- and tissue-specific effects of AhR ligands and the dependence of responses on the type of ligands. The function of AhR is complicated because the outcome of its activation depends on a wide range of endogenous and exogenous ligands (which are characterized by different affinity values and diverse combinatorial effects) and on different AhR functions in many physiological and pathological processes in cells and tissues. The molecular mechanisms of AhR signaling and of the crosstalk between AhR signaling and other signal transduction cascades require further research. It is mostly the inconsistency of scientific findings that makes it difficult to determine the signaling pathways through which AhR can exert its beneficial or detrimental actions. There is growing evidence that AhR activation can have multidirectional effects on many aspects of human physiology and pathology, and that these may depend on cell and tissue types, or on the interaction of the AhR complex with non-traditional XRE sequences, or interaction with various coactivators and corepressors. Depending on many factors, the action of AhR agonists or antagonists can cause positive or negative effects on human health (Figure 4).

Figure 1. Pro-oxidant and antioxidant effects of AhR results in wide range of physiological and pathological processes in cells and tissues.

The recognition that AhR is implicated in the pathogenesis of many human diseases has arisen in conjunction with numerous examples of diseases in which AhR modulates disease activity through interaction with environmental factors. The pathogenesis driven by AhR often includes oxidative stress and immune and inflammatory responses. The weight of evidence indicates that, in diseases of various organs and tissues, AhR activation can be beneficial or detrimental. The ultimate effect depends both on the context of the disease and on the nature of AhR ligands. In this context, AhR activation aggravates the symptoms of some diseases, but alleviates the symptoms of other diseases.

The recognition that AhR is implicated in the pathogenesis of many human diseases has arisen in conjunction with numerous examples of diseases in which AhR modulates disease activity through interaction with environmental factors. The pathogenesis driven by AhR often includes oxidative stress and immune and inflammatory responses. The weight of evidence indicates that, in diseases of various organs and tissues, AhR activation can be beneficial or detrimental. The ultimate effect depends both on the context of the disease and on the nature of AhR ligands. In this context, AhR activation aggravates the symptoms of some diseases, but alleviates the symptoms of other diseases.

Currently, in the literature, there are few examples of disorders where the molecular mechanisms of AhR’s involvement in the pathogenesis are clear. More numerous are findings about various biological responses to the stimulation or inhibition of AhR in various diseases. At the current stage of our insight into AhR’s biology and its role in the pathogenesis of diverse diseases, the utility of AhR as a therapeutic target has already been established, and a foundation has been laid for the selection and design of effective AhR ligands as new treatments of various diseases. Although much basic research has been conducted on the functions of AhR in pathological processes, clinical studies about the effects on the mechanism of the AhR signaling pathway in different pathologies are still scarce, and further investigation is necessary.

Currently, in the literature, there are few examples of disorders where the molecular mechanisms of AhR’s involvement in the pathogenesis are clear. More numerous are findings about various biological responses to the stimulation or inhibition of AhR in various diseases. At the current stage of the insight into AhR’s biology and its role in the pathogenesis of diverse diseases, the utility of AhR as a therapeutic target has already been established, and a foundation has been laid for the selection and design of effective AhR ligands as new treatments of various diseases. Although much basic research has been conducted on the functions of AhR in pathological processes, clinical studies about the effects on the mechanism of the AhR signaling pathway in different pathologies are still scarce, and further investigation is necessary.

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