title: Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: the basis of its anti-inflammatory effect.
abstract: 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.
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. gakku@dermatol.med.kyushu-u.ac.jp
authors.forename: Gaku
authors.initials: G
authors.lastname: Tsuji
authors.forename: Masakazu
authors.initials: M
authors.lastname: Takahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Matsuda
authors.forename: Takahito
authors.initials: T
authors.lastname: Chiba
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Yasukawa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Moroi
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology; D000077291:Terbinafine; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000935:Antifungal Agents; D000975:Antioxidants; C508606:CXCL8 protein, human; D016209:Interleukin-8; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009281:Naphthalenes; D018336:Receptors, Aryl Hydrocarbon; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D001564:Benzo(a)pyrene; D000077291:Terbinafine; D000077185:Resveratrol; D007654:Ketoconazole