The flavonoid, eriodictyol, induces long-term protection in ARPE-19 cells through its effects on Nrf2 activation and phase 2 gene expression

These findings indicate that the greatest benefit from eriodictyol may be its ability to regulate gene expression and enhance multiple cellular defenses to oxidative injury.

The ability of eriodictyol to activate Nrf2 and to induce the phase 2 proteins heme-oxygenase (HO)-1 and NAD(P)H:quinone oxidoreductase (NQO)-1, and the cellular antioxidant glutathione (GSH) were analyzed. Cytoprotection assays in ARPE-19 cells that were overexpressing HO-1 or NQO-1 were performed, cell survival after short-term and long-term eriodictyol treatment was compared, and the mechanism of protection using a dominant negative Nrf2 and shRNA specific for HO-1 was tested.

Eriodictyol, a flavonoid found in citrus fruits, is among the most potent compounds reported to protect human RPE cells from oxidative stress-induced cell death. The present study sought to determine whether eriodictyol-induced phase 2 protein expression further enhances the resistance of human ARPE-19 cells to oxidative stress.

Eriodictyol induced the nuclear translocation of Nrf2, enhanced the expression of HO-1 and NQO-1, and increased the levels of intracellular glutathione. ARPE-19 cells that overexpress HO-1 or NQO-1 were more resistant to oxidative stress-induced cell death than control cells. Eriodictyol induced long-term protection significantly greater than its short-term protection. This effect was correlated temporally with the activation of Nrf2 and the induction of phase 2 enzymes and could be blocked with the use of a dominant negative Nrf2 and shRNA specific to HO-1. Conclusions: These findings indicate that the greatest benefit from eriodictyol may be its ability to regulate gene expression and enhance multiple cellular defenses to oxidative injury.