Quercetin, one of the most widely distributed flavonoids in plants, possesses strong free radical scavenging ability and potent hepatoprotective effects. However, the protective effect and mechanism of quercetin on ethanol-induced oxidative damage in hepatocytes remain unclear. In this study, primary rat hepatocytes were incubated with ethanol and quercetin in the presence or absence of ZnPP 9, an antagonist of HO-1 induction. The ethanol-induced hepatotoxicity was found to be greatly diminished by pre-treatment of quercetin and this hepatoprotective effect could be partly blocked by ZnPP 9. This study also showed that quercetin significantly stimulated HO-1 expression at both mRNA and protein levels, then subsequently induced HO-1 activity. To further study the signaling pathways underlying quercetin-induced HO-1 up-regulation, HO-1 expression and activity in cytosolic microsomal fractions and Nrf2 expression in nuclear fractions were analyzed following quercetin or/and MAPK inhibitor(s) as well as PI3K inhibitor incubation for primary rat hepatocytes. These results indicated that ERK was required to induce HO-1 expression in rat hepatocytes. In summary, these data suggested that quercetin attenuates ethanol-induced oxidative stress through a pathway which involves ERK activation and HO-1 upregulation. (C) 2011 Elsevier Ltd. All rights reserved.