Quercetin and its metabolites protect hepatocytes against ethanol-induced oxidative stress by activation of Nrf2 and AP-1

Alcohol-induced liver disease progresses due to increased reactive oxygen species (ROS) and cellular lipid peroxidation. Quercetin is a flavonoid with strong antioxidant and hepatoprotective effects. We investigated whether 3′-O-methyl quercetin (3′MQ) and quercetin-3-O-glucuronide (Q3GA), two metabolites of quercetin, have protective effects against ethanol-induced hepatotoxicity. Cell viability was increased by quercetin, 3′MQ, and Q3GA in HepG2 hepatocarcinoma cells exposed to ethanol. Our results show that this effect was mediated by diminished ROS generation, decreased lipid peroxidation and up-regulation of antioxidant capacity, including glutathione, superoxide dismutase and catalase. Moreover, down-regulated heme oxygenase-1 (HO-1) expression by ethanol was restored by quercetin, 3′MQ, and Q3GA through the activation of nuclear factor E2-related factor 2 and activator protein-1, but not nuclear factor-kappa B. Overall results suggest that 3′MQ, Q3GA, and quercetin attenuate oxidative stress in hepatocytes exposed to ethanol by up-regulating HO-1 expression and can be used as therapeutic agents for ameliorating alcohol-induced liver disease.