You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Aryl Hydrocarbon Receptor in Oxidative Stress: Comparison
View Latest Version
Please note this is a comparison between Version 4 by Camila Xu and Version 3 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.

  • reactive oxygen species
  • oxidative stress
  • antioxidant
  • aryl hydrocarbon receptor
  • AhR
  • nuclear factor-erythroid 2-related factor 2
  • Nrf2

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].
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].
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 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].
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

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].

AhR is a unique and versatile biological sensor of planar chemical compounds of endogenous and exogenous origin [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

AhR is reported to be responsible for the toxic cellular effects of TCDD via pro-oxidant mechanisms [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]. 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].

4. 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].
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

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].

6. 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).
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.
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.

References

  1. Pierre, S.; Chevallier, A.; Teixeira-Clerc, F.; Ambolet-Camoit, A.; Bui, L.C.; Bats, A.S.; Fournet, J.C.; Fernandez-Salguero, P.; Aggerbeck, M.; Lotersztajn, S.; et al. Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin. Toxicol. Sci. 2014, 137, 114–124.
  2. Kalkhof, S.; Dautel, F.; Loguercio, S.; Baumann, S.; Trump, S.; Jungnickel, H.; Otto, W.; Rudzok, S.; Potratz, S.; Luch, A.; et al. Pathway and time-resolved benzopyrene toxicity on Hepa1c1c7 cells at toxic and subtoxic exposure. J. Proteome Res. 2015, 14, 164–182.
  3. Esser, C.; Bargen, I.; Weighardt, H.; Haarmann-Stemmann, T.; Krutmann, J. Functions of the aryl hydrocarbon receptor in the skin. Semin. Immunopathol. 2013, 35, 677–691.
  4. Peng, F.; Xue, C.H.; Hwang, S.K.; Li, W.H.; Chen, Z.; Zhang, J.Z. Exposure to fine particulate matter associated with senile lentigo in Chinese women: A cross-sectional study. J. Eur. Acad. Dermatol. Venereol 2017, 31, 355–360.
  5. Guo, Y.L.; Yu, M.L.; Hsu, C.C.; Rogan, W.J. Chloracne, goiter, arthritis, and anemia after polychlorinated biphenyl poisoning: 14-year follow-Up of the Taiwan Yucheng cohort. Environ. Health Perspect. 1999, 107, 715–719.
  6. Caputo, R.; Monti, M.; Ermacora, E.; Carminati, G.; Gelmetti, C.; Gianotti, R.; Gianni, E.; Puccinelli, V. Cutaneous manifestations of tetrachlorodibenzo-p-dioxin in children and adolescents. Follow-up 10 years after the Seveso, Italy, accident. J. Am. Acad. Dermatol. 1988, 19, 812–819.
  7. Furue, M.; Uenotsuchi, T.; Urabe, K.; Ishikawa, T.; Kuwabara, M. Overview of Yusho. J. Dermatol. Sci. Suppl. 2005, 1, S3–S10.
  8. Mitoma, C.; Mine, Y.; Utani, A.; Imafuku, S.; Muto, M.; Akimoto, T.; Kanekura, T.; Furue, M.; Uchi, H. Current skin symptoms of Yusho patients exposed to high levels of 2,3,4,7,8-pentachlorinated dibenzofuran and polychlorinated biphenyls in 1968. Chemosphere 2015, 137, 45–51.
  9. Hu, T.; Pan, Z.; Yu, Q.; Mo, X.; Song, N.; Yan, M.; Zouboulis, C.C.; Xia, L.; Ju, Q. Benzo(a)pyrene induces interleukin (IL)-6 production and reduces lipid synthesis in human SZ95 sebocytes via the aryl hydrocarbon receptor signaling pathway. Environ. Toxicol. Pharmacol. 2016, 43, 54–60.
  10. Sun, Y.V.; Boverhof, D.R.; Burgoon, L.D.; Fielden, M.R.; Zacharewski, T.R. Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences. Nucleic Acids Res. 2004, 32, 4512–4523.
  11. Hidaka, T.; Ogawa, E.; Kobayashi, E.H.; Suzuki, T.; Funayama, R.; Nagashima, T.; Fujimura, T.; Aiba, S.; Nakayama, K.; Okuyama, R.; et al. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin. Nat. Immunol. 2017, 18, 64–73.
  12. Schallreuter, K.U.; Salem, M.A.; Gibbons, N.C.; Maitland, D.J.; Marsch, E.; Elwary, S.M.; Healey, A.R. Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: Epidermal H2O2/ONOO(-)-mediated stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl hydrocarbon receptor-mediated immune response signaling. FASEB J. 2012, 26, 2471–2485.
  13. van den Bogaard, E.H.; Bergboer, J.G.; Vonk-Bergers, M.; van Vlijmen-Willems, I.M.; Hato, S.V.; van der Valk, P.G.; Schroder, J.M.; Joosten, I.; Zeeuwen, P.L.; Schalkwijk, J. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J. Clin. Investig. 2013, 123, 917–927.
  14. Di Meglio, P.; Duarte, J.H.; Ahlfors, H.; Owens, N.D.; Li, Y.; Villanova, F.; Tosi, I.; Hirota, K.; Nestle, F.O.; Mrowietz, U.; et al. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity 2014, 40, 989–1001.
  15. Di Meglio, P.; Perera, G.K.; Nestle, F.O. The multitasking organ: Recent insights into skin immune function. Immunity 2011, 35, 857–869.
  16. Kostyuk, V.A.; Potapovich, A.I.; Lulli, D.; Stancato, A.; De Luca, C.; Pastore, S.; Korkina, L. Modulation of human keratinocyte responses to solar UV by plant polyphenols as a basis for chemoprevention of non-melanoma skin cancers. Curr. Med. Chem. 2013, 20, 869–879.
  17. Sheipouri, D.; Braidy, N.; Guillemin, G.J. Kynurenine Pathway in Skin Cells: Implications for UV-Induced Skin Damage. Int. J. Tryptophan Res. 2012, 5, 15–25.
  18. Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002, 82, 47–95.
  19. Podkowinska, A.; Formanowicz, D. Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease. Antioxidants 2020, 9, 752.
  20. Mo, Y.; Lu, Z.; Wang, L.; Ji, C.; Zou, C.; Liu, X. The Aryl Hydrocarbon Receptor in Chronic Kidney Disease: Friend or Foe? Front. Cell Dev. Biol. 2020, 8, 589752.
  21. Liu, J.R.; Miao, H.; Deng, D.Q.; Vaziri, N.D.; Li, P.; Zhao, Y.Y. Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation. Cell. Mol. Life Sci. 2021, 78, 909–922.
  22. Ichii, O.; Otsuka-Kanazawa, S.; Nakamura, T.; Ueno, M.; Kon, Y.; Chen, W.; Rosenberg, A.Z.; Kopp, J.B. Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLoS ONE 2014, 9, e108448.
  23. Ng, H.Y.; Yisireyili, M.; Saito, S.; Lee, C.T.; Adelibieke, Y.; Nishijima, F.; Niwa, T. Indoxyl sulfate downregulates expression of Mas receptor via OAT3/AhR/Stat3 pathway in proximal tubular cells. PLoS ONE 2014, 9, e91517.
  24. Mutsaers, H.A.; Stribos, E.G.; Glorieux, G.; Vanholder, R.; Olinga, P. Chronic Kidney Disease and Fibrosis: The Role of Uremic Retention Solutes. Front. Med. 2015, 2, 60.
  25. Bahorun, T.; Soobrattee, M.A.; Luximon-Ramma, V.; Aruoma, O.I. Free Radicals and Antioxidants in Cardiovascular Health and Disease. Internet J. Med. Update. 2006, 1, 25–41.
  26. Quattrochi, L.C.; Tukey, R.H. Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: Transcriptional activation of the human CYP1A1 gene. Mol. Pharmacol. 1993, 43, 504–508.
  27. Ciolino, H.P.; Daschner, P.J.; Yeh, G.C. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem. J. 1999, 340 Pt 3, 715–722.
  28. Goya-Jorge, E.; Jorge Rodriguez, M.E.; Veitia, M.S.; Giner, R.M. Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor. Molecules 2021, 26, 2315.
  29. Rothhammer, V.; Quintana, F.J. The aryl hydrocarbon receptor: An environmental sensor integrating immune responses in health and disease. Nat. Rev. Immunol. 2019, 19, 184–197.
  30. Hubbard, T.D.; Murray, I.A.; Perdew, G.H. Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab. Dispos. 2015, 43, 1522–1535.
  31. Phelan, D.; Winter, G.M.; Rogers, W.J.; Lam, J.C.; Denison, M.S. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch. Biochem. Biophys. 1998, 357, 155–163.
  32. Larigot, L.; Juricek, L.; Dairou, J.; Coumoul, X. AhR signaling pathways and regulatory functions. Biochim. Open 2018, 7, 1–9.
  33. Schaldach, C.M.; Riby, J.; Bjeldanes, L.F. Lipoxin A4: A new class of ligand for the Ah receptor. Biochemistry 1999, 38, 7594–7600.
  34. Stejskalova, L.; Dvorak, Z.; Pavek, P. Endogenous and exogenous ligands of aryl hydrocarbon receptor: Current state of art. Curr. Drug Metab. 2011, 12, 198–212.
  35. Burczynski, M.E.; Lin, H.K.; Penning, T.M. Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxidative stress: Implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydrogenase. Cancer Res. 1999, 59, 607–614.
  36. Hockley, S.L.; Arlt, V.M.; Brewer, D.; Giddings, I.; Phillips, D.H. Time- and concentration-dependent changes in gene expression induced by benzo(a)pyrene in two human cell lines, MCF-7 and HepG2. BMC Genom. 2006, 7, 260.
  37. Yamashita, N.; Kanno, Y.; Saito, N.; Terai, K.; Sanada, N.; Kizu, R.; Hiruta, N.; Park, Y.; Bujo, H.; Nemoto, K. Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells. Biochem. Biophys. Res. Commun. 2019, 516, 693–698.
  38. Albertolle, M.E.; Guengerich, F.P. The relationships between cytochromes P450 and H2O2: Production, reaction, and inhibition. J. Inorg. Biochem. 2018, 186, 228–234.
  39. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 2007, 39, 44–84.
  40. Veith, A.; Moorthy, B. Role of Cytochrome P450s in the Generation and Metabolism of Reactive Oxygen Species. Curr. Opin. Toxicol. 2018, 7, 44–51.
  41. Kuthan, H.; Ullrich, V. Oxidase and Oxygenase Function of the Microsomal Cytochrome-P450 Mono-Oxygenase System. Eur. J. Biochem. 1982, 126, 583–588.
  42. Kukielka, E.; Cederbaum, A.I. Nadph-Dependent and Nadh-Dependent Oxygen Radical Generation by Rat-Liver Nuclei in the Presence of Redox Cycling Agents and Iron. Arch. Biochem. Biophys. 1990, 283, 326–333.
  43. Hatherell, S.; Baltazar, M.T.; Reynolds, J.; Carmichael, P.L.; Dent, M.; Li, H.; Ryder, S.; White, A.; Walker, P.; Middleton, A.M. Identifying and Characterizing Stress Pathways of Concern for Consumer Safety in Next-Generation Risk Assessment. Toxicol. Sci. 2020, 176, 11–33.
  44. Wincent, E.; Bengtsson, J.; Bardbori, A.M.; Alsberg, T.; Luecke, S.; Rannug, U.; Rannug, A. Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA 2012, 109, 4479–4484.
  45. Vogel, C.F.A.; Li, W.; Sciullo, E.; Newman, J.; Hammock, B.; Reader, J.R.; Tuscano, J.; Matsumura, F. Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression. Am. J. Pathol. 2007, 171, 1538–1548.
  46. Pathak, S.K.; Sharma, R.A.; Steward, W.P.; Mellon, J.K.; Griffiths, T.R.L.; Gescher, A.J. Oxidative stress and cyclooxygenase activity in prostate carcinogenesis: Targets for chemopreventive strategies. Eur. J. Cancer 2005, 41, 61–70.
  47. Vogel, C.; Boerboom, A.M.J.F.; Baechle, C.; El-Bahay, C.; Kahl, R.; Degen, G.H.; Abel, J. Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: Possible c-Src-mediated pathway. Carcinogenesis 2000, 21, 2267–2274.
  48. Fritsche, E.; Schafer, C.; Calles, C.; Bernsmann, T.; Bernshausen, T.; Wurm, M.; Hubenthal, U.; Cline, J.E.; Hajimiragha, H.; Schroeder, P.; et al. Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc. Natl. Acad. Sci. USA 2007, 104, 8851–8856.
  49. Munoz, M.; Sanchez, A.; Martinez, M.P.; Benedito, S.; Lopez-Oliva, M.E.; Garcia-Sacristan, A.; Hernandez, M.; Prieto, D. COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats. Free Radic. Biol. Med. 2015, 84, 77–90.
  50. Hernanz, R.; Briones, A.M.; Alonso, M.A.J.; Vila, E.; Salaices, M. Hypertension alters role of iNOS, COX-2, and oxidative stress in bradykinin relaxation impairment after LPS in rat cerebral arteries. Am. J. Physiol.-Circ. Physiol. 2004, 287, H225–H234.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Academic Video Service
Feedback