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Z‐Ligustilide inhibits benzo(a)pyrene‐induced CYP1A1 upregulation in cultured human keratinocytes via ROS‐dependent Nrf2 activation
Author(s) -
Wu Zhouwei,
Uchi Hiroshi,
MorinoKoga Saori,
NakamuraSatomura Akiko,
Kita Kazuyo,
Shi Weimin,
Furue Masutaka
Publication year - 2014
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12360
Subject(s) - downregulation and upregulation , chemistry , aryl hydrocarbon receptor , benzo(a)pyrene , reactive oxygen species , ly294002 , pyrene , microbiology and biotechnology , pharmacology , signal transduction , biochemistry , pi3k/akt/mtor pathway , carcinogen , biology , organic chemistry , transcription factor , gene
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.