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.

Polyphenolic extract association with renin inhibitors in experimental arterial hypertension

“…Statistically speaking, the uric acid values remain significantly high both in the AHT group, and in the AHT + PA group in comparison with control group (Figure 2). The ability of dietary polyphenols to generate both NO and ROS in endothelial cells and activate ARE/EpRE (Antioxidant response element/Electrophile response element) mediated gene expression underlies their cardioprotective properties [6].…”

Thymus vulgaris alleviates UVB irradiation induced skin damage via inhibition of MAPK/AP‐1 and activation of Nrf2‐ARE antioxidant system

“…Our results showed that ROS significantly induced the activation of Nrf2, and TV treatment increased nuclear localization of Nrf2, resulting in the enhanced production of antioxidants, such as HO‐1 and NQO‐1. The mechanism of TV activated Nrf2 may belongs to the polyphenols disrupt the Keap1‐Nrf2 complex, probably through interaction with the thiols present on Keap1 44. However, the mechanism of TV modified the Keap1‐Nrf2 complex remain open that need further investigation to confirm.…”

Short- and long-term exposure to low levels of pesticide and flavonoid mixtures modify endogenous antioxidants in tissues of rats

“…This suggests that the addition of purified flavonoids to the diet could increase tissue and circulating total glutathione concentrations after prolonged administration and to some extent support the studies of Carlsen et al [24] in cultured HEP G2 cells. The increase in glutathione concentrations may be related to the role of this thiol in the detoxification of the electrophiles and free radicals; [25,26] these functions of glutathione have been recently reviewed by Pastore et al [27] Glutathione peroxidase is an antioxidant seleno-enzyme (found in most tissues) that reduces hydrogen peroxide and alkyl peroxide in tissues and uses glutathione as an essential redox substrate. Previous studies have shown that glutathione peroxidase activity is influenced by pesticide exposure.…”