Dimethylmonothioarsinic acid (DMMTAV) induces NQO1 expression through coordinated activation of NRF2 and AHR pathways

Abstract

Dimethylmonothioarsinic acid (DMMTA^V), a potent toxic metabolite of arsenic, exhibits higher cytotoxicity than other arsenicals. This study investigates its influence on NAD(P)H:quinone oxidoreductase (NQO1) regulation in C57BL/6 mice and Hepa-1c1c7 cells. Mice were administered DMMTA^V (6 mg/kg, IP) with or without TCDD (15 µg/kg, IP), and hepatic and extrahepatic tissues were analyzed for NQO1 expression. In vitro, Hepa-1c1c7 cells were treated with 0–2 µM DMMTA^V in the presence and absence of TCDD (1 nM), and NQO1 levels were assessed over time. Western blot, real-time PCR, and ARE-luciferase assays determined protein and transcriptional regulation. DMMTA^V upregulated NQO1 in liver tissues and induced a time-dependent increase in vitro, peaking at 12 h. It enhanced TCDD-induced NQO1 expression and increased nuclear NRF2 and AHR levels, with peak accumulation at two hours. ARE-luciferase activity confirmed transcriptional activation. These findings reveal DMMTA^V enhances NQO1 primarily via NRF2/AHR pathway activation, providing insight into cellular responses to thioarsenicals.