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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
Author(s) -
Zhai Xiaohan,
Lin Musen,
Zhang Feng,
Hu Yan,
Xu Xiaomei,
Li Yubing,
Liu Kexin,
Ma Xiaochi,
Tian Xiaofeng,
Yao Jihong
Publication year - 2013
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201200536
Subject(s) - gclc , genistein , protein kinase c , oxidative stress , mapk/erk pathway , chemistry , signal transduction , microbiology and biotechnology , pharmacology , biochemistry , biology , downregulation and upregulation , endocrinology , gene
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.