Dietary flavonoid genistein induces Nrf2 and phase II detoxification gene expression via ERKs and PKC pathways and protects against oxidative stress in Caco‐2 cells

Scope Flavonoids have well‐known antioxidant, anti‐inflammatory, and anti‐cancer activities. Isoflavone genistein is considered a potent antioxidant agent against oxidative stress. Although several mechanisms have been proposed, a clear antioxidant mechanism of genistein is still remained to be answered. Methods and results In this study, we focused on the concerted effects on expression of N rf2 and phase II enzyme pathway components. Transient transfection assays, RT ‐ PCR and immunoblot analysis were performed to study its molecular mechanisms of action. In Caco‐2 cells, treatment with genistein markedly attenuated H 2 O 2 ‐induced peroxide formation; this amelioration was reversed by buthionine sulfoximine( GCLC inhibitor) and zinc protoporphyrin( HO ‐1 inhibitor). Genistein increased HO ‐1 and GCLC m RNA and protein expression. Genistein treatment activated the ERK 1/2 and PKC signaling pathway; therefore increased N rf2 m RNA and protein expression. The roles of the ERK 1/2 and PKC signaling pathway were determined using PD 98059 ( ERK 1/2 inhibitor) and GF 109203X ( PKC inhibitor) and RNA interference directed against N rf2. Both inhibitors and si N rf2 abolished genistein‐induced HO ‐1 and GCLC protein expression. These results suggest the involvement of ERK 1/2, PKC , and N rf2 in inducing HO ‐1 and GCLC by genistein. Conclusion Our studies show that genistein up‐regulated HO ‐1 and GCLC expression through the EKR 1/2 and PKC / N rf2 pathways during oxidative stress.