Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways.
OBJECTIVE
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 (100 mM) and quercetin (10-200 microM), 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.
Yao
Ping
P
Department of General-, Visceral-, and Transplantation Surgery, Humboldt University, Charité, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany.
Nussler
Andreas
A
Liu
Liegang
L
Hao
Liping
L
Song
Fangfang
F
Schirmeier
Anja
A
Nussler
Natascha
N
D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011794:Quercetin / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology
D051267:NF-E2-Related Factor 2; D000431:Ethanol; D011794:Quercetin; D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases