AIM Genistein is a member of the flavoniod family.Flavonoids have well-known antioxidant, anti-inflammatory and anti-cancer activities.In this work, we examined whether genistein affect H2O2-induced oxidative injury and the possible mechanism involved in the colon cancer cells.We focused on concerted effects on the expression of Nrf2 and phase Ⅱ enzymes pathway components.METHODS Caco-2 cells were treated for 3 h with different concentrations of genistein before being exposed to 10 mmol· L-1H2O2.MTT was used to measure cell viability.Oxidation of 2,7-dichlorodihydrofluorescin diacetate (H2DCFDA) was used to measure production of intracellular ROS in Caco-2 cells.Genistein and H2O2-induced Nrf2, HO-1 and GCLC mRNA and protein levels were assessed using RT-PCR and Western blot.Genistein-induced phosphorylation of PKC and ERK1/2 was visualized using Western blot.RESULTS Treatment with genistein markedly attenuated H2O2-induced peroxide formation, and this amelioration was reversed by Buthionine sulfoximine (GCLC inhibitor) and zinc protoporphyrin(HO-1 inhibitor).Genistein dose dependently increased HO-1 and GCLC mRNA and protein expressions.Genistein treatment activated the ERK1/2 and PKC signaling pathway and increased Nrf2 mRNA and protein expression.The roles of the ERK1/2 as partly as PKC signaling pathway were determined by using PD98059 (ERK1/2 inhibitor) and GF109203X(PKC inhibitor) and RNA interference directed against Nrf2.Both inhibitors and siNrf2 abolished genistein-induced HO-1 and GCLC protein expression.These results suggested the involvement of ERK1/2 and PKC and Nrf2 in the induction of HO-1 and GCLC by genistein.CONCLUSION Genistein up-regulated HO-land GCLC expression through the EKR1/2 and PKC/Nrf2 pathway against oxidative stress.