Hydroxytyrosol induces antioxidant/detoxificant enzymes and Nrf2 translocation via extracellular regulated kinases and phosphatidylinositol-3-kinase/protein kinase B pathways in HepG2 cells

Mol Nutr Food Res. 2010 Jul;54(7):956-66. doi: 10.1002/mnfr.200900159.


Hydroxytyrosol (HTy) is a natural polyphenol abundant in olive oil, which possesses multiple biological actions. Particularly, HTy has cytoprotective activity against oxidative-stress-induced cell damage, but the underlying mechanisms of action remain unclear. Here, we have investigated the molecular mechanism involved in the protection exerted by HTy on tert-butyl hydroperoxide-induced damage in human HepG2 liver cells. Treatment of HepG2 cells with HTy increased the expression and the activity of glutathione-related enzymes such as glutathione peroxidase, glutathione reductase and glutathione S-transferase. HTy also induced the nuclear transcription factor erythroid 2p45-related factor (Nrf2), a transcription factor implicated in the expression of several antioxidant/detoxificant enzymes. Moreover, two important signalling proteins involved in Nrf2 translocation, the protein kinase B and the extracellular regulated kinases, were also activated by HTy. Further studies with specific inhibitors confirmed that both molecular pathways are critical for the nuclear translocation of Nrf2, the increased enzyme expression and activity and the beneficial effect against oxidative stress induced by HTy. In conclusion, together with the inherent radical scavenging activity of HTy, our results provide an additional mechanism of action to prevent oxidative stress damage through the modulation of signalling pathways involved in antioxidant/detoxifying enzymes regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Diet, Mediterranean
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Glutathione / metabolism
  • Hep G2 Cells
  • Humans
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidants / toxicity
  • Oxidative Stress / drug effects
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / pharmacology
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protective Agents / pharmacology*
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects*
  • tert-Butylhydroperoxide / toxicity


  • Antineoplastic Agents, Phytogenic
  • Enzyme Inhibitors
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Oxidants
  • Phosphoinositide-3 Kinase Inhibitors
  • Protective Agents
  • RNA, Messenger
  • 3,4-dihydroxyphenylethanol
  • tert-Butylhydroperoxide
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Glutathione
  • Phenylethyl Alcohol