Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways ☆

Background/Aims Flavonoids, including quercetin, have been reported to have potent hepatoprotective effects, which may be associated with HO-1 induction. However, since the effect and signaling pathway of quercetin involved in HO-1 induction against alcoholic liver damage are still not fully understood, this is the target of the present study. Methods Human hepatocytes were incubated with ethanol (100mM) and quercetin (10–200μM), and cellular damage and HO-1 activity were measured. Nrf2 expression in cytosolic and nuclear fractions was studied following the incubation with MAPK inhibitor(s). Results Ethanol exposure resulted in a sustained glutathione depletion, malondialdehyde elevation, and evident release of cellular LDH and AST. Quercetin exerted a dose-dependent protective effect against alcoholic oxidative stress, and increased the EC50 of ethanol by approx. 40%, which is parallel to HO-1 induction with quercetin. Zinc protoporphyrin-9 abrogated the protective effect and dramatically enhanced ethanol cytotoxicity. SB203580 (p38 inhibitor) and especially PD98059 (ERK inhibitor) blocked quercetin-derived HO-1 induction and Nrf2 translocation, and subsequently inhibited the quercetin-related protection. Conclusions HO-1 up-regulation by quercetin protected human hepatocytes from ethanol-induced oxidative stress. Among MAPK signaling pathways, p38 and ERK mediated quercetin-derived Nrf2 translocation into nuclei and subsequent induction of HO-1 activity, and the latter showed a stronger mediating effect.