Cited by 175Toxic Organic Pollutants ImpactDermatology and Skin Diseasesmelanin and skin pigmentation

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Role of AhR/ARNT system in skin homeostasis

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Furue, Masutaka, Takahara, Masakazu, Nakahara, Takeshi, Uchi, Hiroshi·2014·Archives of Dermatological Research

DOI 10.1007/s00403-014-1481-7PMC PMC4220966

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Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that binds to structurally diverse synthetic and naturally occurring chemicals including dioxins, flavonoids, tryptophan photoproducts, and Malassezia metabolites. Upon binding to its ligands, cytoplasmic AhR translocates to the nucleus, heterodimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT), and mediates numerous biological and toxicological effects by inducing the transcription of various AhR-responsive genes. AhR ligation controls oxidation/antioxidation, epidermal barrier function, photo-induced response, melanogenesis, and innate immunity. This review summarizes recent advances in the understanding of the regulatory mechanisms of skin homeostasis mediated by the AhR/ARNT system.

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Fig. 1 Schematic representation of the AhR/ARNT signaling system. Aryl hydrocarbon receptor (AhR) resides in the cytoplasm as a protein complex with hsp90, XAP2, and p23. Various external and internal ligands like dioxins, dietary flavonoids, Malassezia metabolites, and ultraviolet light-induced metabolites bind to and activate AhR. Upon ligand binding, ligand–AhR protein complex translocates into the nucleus, where AhR nuclear translocator (ARNT) binds to it, releasing hsp90, XAP2, p23, and pp60src. The ligand–AhR–ARNT complex binds to the xenobiotic-responsive element (XRE) and induces the transcription of responsive genes such as cyp1A1. During the process of metabolism of ligands (e.g., dioxins) by CYP1A1, a large number of reactive oxygen species (ROS) are produced. This ROS generation is closely related to various cellular responses, such as cytokine production and DNA damage. Meanwhile, the dissociated pp60src activates epidermal growth factor receptor (EGFR) and induces its internalization and nuclear translocation. Moreover, the AhR signaling induces the transcription of AhR repressor (AhRR). This induced AhRR forms a heterodimer with ARNT, which competes with AhR/ARNT heterodimer to bind to the XRE sequence, consequently inhibiting AhR transcriptional activityCC BY · PubMed Central

Fig. 2 AhR ligation induces not only oxidative stress but also antioxidative response in a ligand-dependent manner. Environmental pollutants such as benzo[a]pyrene and TCDD bind to AhR and induce ROS production, DNA damage, and inflammatory cytokine production. In contrast, ketoconazole and certain flavonoids bind to AhR, resulting in the activation of Nrf2 and subsequent induction of antioxidative enzymes such as Nqo1. These antioxidative enzymes inhibit ROS production, DNA damage, and inflammatory cytokine production. Thus, AhR acts as a master switch for oxidation and antioxidationCC BY · PubMed Central

Fig. 3 Severe chloracne in Yusho patients (oral intoxication of a high concentration of 2,3,4,7,8-pentachlorodibenzofuran)CC BY · PubMed Central

Fig. 4 Hyperpigmentation in Yusho patientsCC BY · PubMed Central

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Authors: Furue, M., Takahara, M., Nakahara, T., & Uchi, H.
Affiliations: Kyushu University (JP)
Corresponding author: Furue, Masutaka
ORCID: Furue, Masutaka
Nakahara, Takeshi
Uchi, Hiroshi
Venue: Archives of Dermatological Research
Publisher: Springer Science and Business Media LLC
Published: 2014-06-26
Volume: 306
Issue: 9
Pages: 769-779
ISSN: 0003-9187 (ISSN-L)
0340-3696
1432-069X
DOI: 10.1007/s00403-014-1481-7
PMC: PMC4220966
OpenAlex: W1991467319
Cited by: 175
References: 97
Citations by year: 2026: 6 · 2025: 9 · 2024: 14 · 2023: 18 · 2022: 20 · 2021: 17 · 2020: 21 · 2019: 18 · 2018: 22 · 2017: 14 · 2016: 4 · 2015: 9 · 2014: 2
FWCI: 1.00
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (unspecified)
Locations: Archives of Dermatological Research (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Ministry of Education, Culture, Sports, Science and Technology
Ministry of Health, Labour and Welfare
Topics: Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
Keywords: aryl hydrocarbon receptor, ARNT, skin homeostasis, dioxins, flavonoids, tryptophan photoproducts, skin barrier function, melanogenesis, innate immunity, oxidative stress, transcriptional regulation, xenobiotic toxicity
MeSH terms: Animals, Gene Expression Regulation, Homeostasis, Humans, Immunity, Innate, Ligands, Melanins, Permeability, Skin, Skin Diseases, Signal Transduction, Receptors, Aryl Hydrocarbon, Oxidative Stress, Aryl Hydrocarbon Receptor Nuclear Translocator

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Role of AhR/ARNT system in skin homeostasis

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