Green tea polyphenol epigallocatechin-3-gallate protects cells against peroxynitrite-induced cytotoxicity: modulatory effect of cellular G6PD status.
Glucose-6-phosphate dehydrogenase (G6PD) plays important roles in the maintenance of cellular redox balance. It was not until recently that the importance of G6PD in regulation of cellular growth and apoptosis emerged. In the present study, we found that G6PD-deficient fibroblasts were more susceptible to peroxynitrite-induced cytotoxicity. Treatment with peroxynitrite generator 3-morpholinosydnonimine (SIN-1) hydrochloride caused apoptosis in human fibroblast in a dose-dependent manner. This was preceded by a decrease in the intracellular level of glutathione (GSH) as well as accumulation of p53. The extent of apoptosis and glutathione depletion were greater in G6PD-deficient fibroblasts than in the normal counterpart. Pretreatment with green tea polyphenol epigallocatechin-3-gallate (EGCG) effectively blocked peroxynitrite-induced glutathione depletion, p53 accumulation, and apoptosis in both normal and G6PD-deficient cells. EGCG, administered to cells alone or as pretreatment, caused activation of Akt. The protective effect was abolished by phosphatidylinositol 3-kinase (PI3K) inhibitors, wortmannin, and LY294002. Our findings suggest that G6PD deficiency enhances the toxicity of peroxynitrite and that EGCG initiates cell survival signaling via the PI3K/akt pathway.
Ho
Hung-Yao
HY
Graduate Institute of Medical Biotechnology and Department of Medical Biotechnology and Laboratory Science, Chang Gung University, 259, Wen-hwa 1st Road, Kwei-san, Taoyuan, Taiwan.
Wei
Tao-Tao
TT
Cheng
Mei-Ling
ML
Chiu
Daniel Tsun-Yee
DT
D017209:Apoptosis / Q000187:drug effects; D028241:Camellia sinensis / Q000737:chemistry*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D005347:Fibroblasts / Q000201:enzymology; D005954:Glucosephosphate Dehydrogenase / Q000502:physiology*; D005955:Glucosephosphate Dehydrogenase Deficiency; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002392:Catechin; D005954:Glucosephosphate Dehydrogenase; D005978:Glutathione; D008981:Molsidomine; D030421:Peroxynitrous Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; C002385:linsidomine; C045651:epigallocatechin gallate