Methylated pentavalent arsenic metabolites are bifunctional inducers, as they induce cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase through AhR- and Nrf2-dependent mechanisms

摘要: Activation of the aryl hydrocarbon receptor (AhR) ultimately leads to induction carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1), and activation nuclear factor-erythroid 2 p45-related factor (Nrf2) in addition AhR pathway induces expression NADP(H):quinone oxidoreductase (NQO1). Therefore, aim this study was examine effect As(III) pentavalent metabolites, MMA(V), DMA(V), TMA(V), on Nrf2 their prototypical downstream targets CYP1A1 NQO1, respectively. Our results showed that treatment HepG2 cells with or TMA(V) absence presence 2,3,7,8-tetrachlorodibenzo-p-dioxin sulforaphane significantly induced both NQO1 at mRNA, protein, catalytic activity levels. Furthermore, these metabolites increased AhR-dependent XRE-driven Nrf2-dependent ARE-driven luciferase reporter activities, which coincided accumulation transcription factors. However, none were shown be ligands. The by seems ligand-independent, possibly through a decrease HSP90 protein also ROS production, higher than produced As(III). Upon knockdown MMA(V)-, DMA(V)-, TMA(V)-mediated proteins decreased. In conclusion, demonstrates for first time methylated arsenic are bifunctional inducers, as they increase activating AhR/XRE signaling Nrf2/ARE pathway.