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

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.