Z-Ligustilide inhibits benzo(a)pyrene-induced CYP1A1 upregulation in cultured human keratinocytes via ROS-dependent Nrf2 activation

• Published in: Experimental dermatology Vol. 23; no. 4; pp. 260 - 265
• Main Authors: Wu, Zhouwei, Uchi, Hiroshi, Morino-Koga, Saori, Nakamura-Satomura, Akiko, Kita, Kazuyo, Shi, Weimin, Furue, Masutaka
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.04.2014
• Subjects: 4-Butyrolactone - analogs & derivatives; 4-Butyrolactone - pharmacology; 4-Butyrolactone - therapeutic use; Angelica; aryl hydrocarbon receptor; Benzo(a)pyrene - toxicity; Cell Survival - drug effects; Cells, Cultured; Cnidium; Cytochrome P-450 CYP1A1 - metabolism; cytochrome P450; Dermatitis - etiology; Dermatitis - prevention & control; Drug Evaluation, Preclinical; Environmental Pollutants - toxicity; Humans; keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; NF-E2-Related Factor 2 - metabolism; Nrf2; Phytotherapy; Plant Extracts - therapeutic use; polycyclic aromatic hydrocarbon; Reactive Oxygen Species - metabolism; Receptors, Aryl Hydrocarbon - metabolism; Up-Regulation - drug effects; cytochrome P450; keratinocytes; Nrf2; aryl hydrocarbon receptor; polycyclic aromatic hydrocarbon
• ISSN: 0906-6705; 1600-0625
• DOI: 10.1111/exd.12360

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 NAD(P)H: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.