Pro-Oxidant Activity of Flavonoids Induces EpRE-Mediated Gene Expression.

Y.Y. Lee-Hilz, A.M.J.F. Boerboom, A.H. Westphal, W.J.H. van Berkel, J.M.M.J.G. Aarts, I.M.C.M. Rietjens

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Flavonoids are important bioactive dietary compounds. They induce electrophile-responsive element (EpRE)-mediated expression of enzymes, such as NAD(P)H-quinone oxidoreductase (NQO1) and glutathione S-transferases (GSTs), which are major defense enzymes against electrophilic toxicants and oxidative stress. The induction of EpRE-mediated gene transcription involves the release of the transcription factor Nrf2 from a complex with Keap1, either by a direct interaction of the inducer with Keap1 or by protein kinase C (PKC)-mediated phosphorylation of Nrf2. The inhibition of PKC in Hepa1c1c7 cells, stably transfected with human NQO1-EpRE-controlled luciferase revealed that PKC is not involved in flavonoid-induced EpRE-mediated gene transcription. However, the ability of flavonoids to activate an EpRE-mediated response correlates with their redox properties characterized by quantum mechanical calculations. Flavonoids with a higher intrinsic potential to generate oxidative stress and redox cycling are the most potent inducers of EpRE-mediated gene expression. Modulation of the intracellular glutathione (GSH) level showed that the EpRE-activation by flavonoids increased with decreasing GSH and vice versa, supporting an oxidative mechanism. In conclusion, the pro-oxidant activity of flavonoids can contribute to their health-promoting activity by inducing important detoxifying enzymes, pointing to a beneficial effect of a supposed toxic chemical reaction
Original languageEnglish
Pages (from-to)1499-1505
JournalChemical Research in Toxicology
Issue number11
Publication statusPublished - 2006


  • antioxidant response element
  • protein-kinase-c
  • gamma-glutamylcysteine synthetase
  • oxidative stress
  • transcriptional activation
  • anticancer properties
  • quinone reductase
  • phase-2 response
  • cell-lines
  • nrf2


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