Identification of Ketoconazole as an AhR-Nrf2 Activator in Cultured Human Keratinocytes: The Basis of Its Anti-Inflammatory Effect
Open accessAbstract
Ketoconazole (KCZ) has been shown to exhibit anti-inflammatory effects in addition to its inhibitory effects against fungi; however, the underlying molecular mechanism remains poorly understood. Aryl hydrocarbon receptor (AhR), a receptor that is activated by polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons such as dioxin, is a sensor of the redox system against oxidative stress and regulates nuclear factor-erythroid 2-related factor-2 (Nrf2), a master switch of the redox machinery. To clarify whether KCZ modulates AhR-Nrf2 function leading to redox system activation, cultured human keratinocytes were treated with KCZ. Confocal microscopic analysis revealed that KCZ induced AhR nuclear translocation, resulting in the upregulation of CYP1A1 mRNA and protein expression. Furthermore, KCZ actively switched on Nrf2 nuclear translocation and quinone oxidoreductase 1 expression. Tumor necrosis factor-α- and benzo(a)pyrene (BaP)-induced reactive oxidative species (ROS) and IL-8 production were effectively inhibited by KCZ. Knockdown of either AhR or Nrf2 abolished the inhibitory capacity of KCZ on ROS and IL-8 production. In addition, KCZ-induced Nrf2 activation was canceled by AhR knockdown. Moreover, KCZ inhibited BaP-induced 8-hydroxydeoxyguanosine and IL-8 production. In conclusion, the engagement of AhR by KCZ exhibits the cytoprotective effect mediated by the Nrf2 redox system, which potently downregulates either cytokine-induced (AhR-independent) or PAH-induced (AhR-dependent) oxidative stress.
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Activation of the AHR/NRF2 pathway by ketoconazole shows cytoprotective effects and inhibition of TNF-α-induced production of ROS.
“Additionally, activation of the AHR/NRF2 pathway by ketoconazole showed cytoprotective effects and inhibition of TNF-α–induced production of ROS (55).”
From Particulate matter causes skin barrier dysfunction. (2021) · cites this paper as [55]
Antioxidant phytochemicals activate and induce cytoplasmic-to-nuclear translocation of NRF2, a master transcription factor for gene expression of antioxidant enzymes such as NQO1 and HO1 in keratinocytes.
“In general, antioxidant phytochemicals activate and induce the cytoplasmic-to-nuclear translocation of nuclear factor-erythroid 2-related factor-2 (NRF2), which is a master transcription factor for gene expression of antioxidant enzymes such as NAD(P)H dehydrogenase quinone 1 (NQO1) and heme oxygenase 1 (HO1) in keratinocytes [19,20].”
From Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway (2017) · cites this paper as [20]
AHR-targeting antioxidant phytochemicals or antioxidant medicinal chemicals do not generate appreciable amounts of reactive oxygen species, probably due to efficient induction of antioxidant enzymes mediated by NRF2 activation.
“Notably, the AHR-targeting antioxidant phytochemicals or antioxidant medicinal chemicals do not generate appreciable amounts of reactive oxygen species probably due to efficient induction of antioxidant enzymes mediated by NRF2 activation [19,20,21,27].”
From Antioxidant Artemisia princeps Extract Enhances the Expression of Filaggrin and Loricrin via the AHR/OVOL1 Pathway (2017) · cites this paper as [20]
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“To understand this discrepancy, we further investigated the expression of NRF2 in keratinocytes, a potent suppressor of ROS (36, 55), in response to these AHR ligands.”
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Self-citation
- Authors
- Tsuji, G., Takahara, M., Uchi, H., Matsuda, T., Chiba, T., Takeuchi, S., Yasukawa, F., Moroi, Y., & Furue, M.
- Affiliations
- Kyushu University (JP)
- Corresponding author
- Tsuji, Gaku
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 132
- Issue
- 1
- Pages
- 59-68
- ISSN
- 0022-202X (ISSN-L)
- OpenAlex
- W2006749681
- Cited by
- 169
- References
- 42
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 11 · 2023: 17 · 2022: 15 · 2021: 12 · 2020: 13 · 2019: 12 · 2018: 11 · 2017: 14 · 2016: 9 · 2015: 14 · 2014: 11 · 2013: 9 · 2012: 5
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Health, Labour and Welfare
- Ministry of the Environment, Government of Japan
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- ketoconazole, aryl hydrocarbon receptor, Nrf2, keratinocytes, anti-inflammatory activity, oxidative stress, benzo[a]pyrene, reactive oxygen species, interleukin-8, CYP1A1, quinone oxidoreductase 1, 8-hydroxy-2'-deoxyguanosine, redox systems, cytoprotection
- MeSH terms
- Resveratrol, Terbinafine, Anti-Inflammatory Agents, Antifungal Agents, Antioxidants, Benzo(a)pyrene, Cell Survival, Cells, Cultured, Humans, Ketoconazole, Naphthalenes, Oxidation-Reduction, Stilbenes, Tumor Necrosis Factor-alpha, Signal Transduction, Keratinocytes, Interleukin-8, Receptors, Aryl Hydrocarbon, Oxidative Stress, NF-E2-Related Factor 2
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