Activation of glutathione peroxidase via Nrf1 mediates genistein's protection against oxidative endothelial cell injury.
Cellular actions of isoflavones may mediate the beneficial health effects associated with high soy consumption. We have investigated protection by genistein and daidzein against oxidative stress-induced endothelial injury. Genistein but not daidzein protected endothelial cells from damage induced by oxidative stress. This protection was accompanied by decreases in intracellular glutathione levels that could be explained by the generation of glutathionyl conjugates of the oxidised genistein metabolite, 5,7,3',4'-tetrahydroxyisoflavone. Both isoflavones evoked increased protein expression of gamma-glutamylcysteine synthetase-heavy subunit (gamma-GCS-HS) and increased cytosolic accumulation and nuclear translocation of Nrf2. However, only genistein led to increases in the cytosolic accumulation and nuclear translocation of Nrf1 and the increased expression of and activity of glutathione peroxidase. These results suggest that genistein-induced protective effects depend primarily on the activation of glutathione peroxidase mediated by Nrf1 activation, and not on Nrf2 activation or increases in glutathione synthesis.
Hernandez-Montes
Eva
E
Molecular Nutrition Group, School of Chemistry, Food Biosciences and Pharmacy, University of Reading, Reading RG6 6AP, UK.
Pollard
Susan E
SE
Vauzour
David
D
Jofre-Montseny
Laia
L
Rota
Cristina
C
Rimbach
Gerald
G
Weinberg
Peter D
PD
Spencer
Jeremy P E
JP
D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D007529:Isoflavones / Q000494:pharmacology; D051265:NF-E2-Related Factor 1 / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010545:Peroxides / Q000494:pharmacology
D007529:Isoflavones; D051265:NF-E2-Related Factor 1; D051267:NF-E2-Related Factor 2; D010545:Peroxides; D019833:Genistein; D005979:Glutathione Peroxidase; D005978:Glutathione