Protective role of HO-1 for alcohol-dependent liver damage

Dig Dis. 2010;28(6):792-8. doi: 10.1159/000324287. Epub 2011 Apr 27.


Background/aims: Alcoholic liver disease is continuously increasing in developed countries being a leading cause of death worldwide. Chronic ethanol consumption induces oxidative stress by accumulation of reactive oxygen intermediates (ROI) while reducing the cellular antioxidant defense. Induction of heme oxygenase-1 (HO-1) may protect primary human hepatocytes (hHeps) from such damage. Thus, the aim of this study was to investigate the potential of polyphenols to protect hHeps from ethanol-dependent oxidative damage.

Methods: hHeps were isolated by collagenase perfusion. ROI and cellular glutathione (GSH) were measured by fluorescent-based assays. Cellular damage was determined by lactate dehydrogenase (LDH) leakage and staining for apoptosis and necrosis. Nuclear translocation of Nrf2 and HO-1 expression were analyzed by Western blot.

Results: Ethanol and TGF-β rapidly increase ROI and reduce GSH in hHeps, causing apoptosis with a release of approximately 40% total LDH after 72 h. Similar to incubation with hemin preincubation and co-incubation of cells with nifedipine, verapamil and quercetin significantly reduce oxidative stress and resulting cellular damage, in a dose-dependent manner, by initiating nuclear translocation of Nrf2 which in turn induces HO-1 under the control of p38 and ERK. Blocking of HO-1 activity with ZNPP9 reverses the protective effect of all three substances.

Conclusion: Our results suggest that increasing HO-1 activity in hHeps protects them from oxidative stress-dependent damage. As polyphenols have great potential to induce HO-1 expression, they may play an important role for future therapeutic strategies to protect liver from oxidative stress-dependent damage observed during chronic alcohol consumption.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Buffers
  • Cytoprotection / drug effects
  • Ethanol / toxicity
  • Flavonoids / pharmacology
  • Heme Oxygenase-1 / metabolism*
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • Liver Diseases, Alcoholic / enzymology*
  • Liver Diseases, Alcoholic / pathology
  • Liver Diseases, Alcoholic / prevention & control*
  • Models, Biological
  • Oxidative Stress / drug effects
  • Phenols / pharmacology
  • Polyphenols
  • Protective Agents / metabolism*
  • Transforming Growth Factor beta / toxicity
  • Up-Regulation / drug effects


  • Buffers
  • Flavonoids
  • Phenols
  • Polyphenols
  • Protective Agents
  • Transforming Growth Factor beta
  • Ethanol
  • L-Lactate Dehydrogenase
  • Heme Oxygenase-1