title: Pro-oxidant activity of flavonoids induces EpRE-mediated gene expression.
abstract: 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.
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands. yee.lee@wur.nl
authors.forename: Yee Y
authors.initials: YY
authors.lastname: Lee-Hilz
authors.forename: Anne-Marie J F
authors.initials: AM
authors.lastname: Boerboom
authors.forename: Adrie H
authors.initials: AH
authors.lastname: Westphal
authors.forename: Willem J H van
authors.initials: WJ
authors.lastname: Berkel
authors.forename: Jac M M J G
authors.initials: JM
authors.lastname: Aarts
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D000818:Animals; D002460:Cell Line; D005419:Flavonoids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051379:Mice; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects* / Q000235:genetics
chemical_list: D005419:Flavonoids; D011493:Protein Kinase C