title: Z-Ligustilide inhibits benzo(a)pyrene-induced CYP1A1 upregulation in cultured human keratinocytes via ROS-dependent Nrf2 activation.
abstract: Benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is an environmental contaminant that can induce cytochrome P4501A1 (CYP1A1) upregulation via aryl hydrocarbon receptor (AhR) activation and provoke inflammation. Here, we investigated the effect of Z-Ligustilide, an active ingredient isolated from the medicinal plants Cnidium officinale and Angelica acutiloba, on BaP-induced CYP1A1 upregulation in normal human epidermal keratinocytes (NHEKs) as well as its underlying mechanisms. Z-Ligustilide significantly inhibited BaP-induced CYP1A1 upregulation in NHEKs. Treatment of NHEKs with Z-Ligustilide induced Nuclear factor-E2-related factor 2 (Nrf2) nuclear translocation and expression of the Nrf2-regulated genes for haeme oxygenase-1 (HO-1) and
  quinine oxidoreductase-1 (NQO1). AhR silencing, SB203580 (a p38 inhibitor), SP600125 (a JNK inhibitor), U0126 (a MEK inhibitor) and LY294002 (a PI3K inhibitor) did not suppress Z-Ligustilide-induced Nrf2 activation. Moreover, treatment of NHEKs with Z-Ligustilide increased reactive oxygen species (ROS) and L-N-acetylcysteine (L-NAC, an antioxidant) attenuated Z-ligustilide-induced Nrf2 nuclear translocation and HO-1 expression. L-NAC or knock-down of Nrf2 significantly attenuated the inhibitory effects of Z-Ligustilide on BaP-induced CYP1A1 upregulation in NHEKs. Taken together, these findings suggest that Z-Ligustilide can suppress BaP-induced CYP1A1 upregulation through ROS-dependent Nrf2 pathway activation and may be beneficial in preventing or treating BaP-induced skin damage.
authors.affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Dermatology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zhouwei
authors.initials: Z
authors.lastname: Wu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchi
authors.forename: Saori
authors.initials: S
authors.lastname: Morino-Koga
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakamura-Satomura
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Kita
authors.forename: Weimin
authors.initials: W
authors.lastname: Shi
authors.forename: Masutaka
authors.initials: M
authors.lastname: Furue
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D029969:Angelica; D001564:Benzo(a)pyrene / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D031048:Cnidium; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D003872:Dermatitis / Q000209:etiology / Q000517:prevention & control*; D004353:Drug Evaluation, Preclinical; D004785:Environmental Pollutants / Q000633:toxicity; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004785:Environmental Pollutants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010936:Plant Extracts; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; C027820:ligustilide; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; D015107:4-Butyrolactone
keywords: Nrf2; aryl hydrocarbon receptor; cytochrome P450; keratinocytes; polycyclic aromatic hydrocarbon