抄録
Since its discovery, glutathione S-transferase (GST) or glutathione transferase has remained in the forefront in fields of toxicology including, chemical carcinogenesis, mechanisms of detoxification, chemoprevention, and lately in the field of oxidative stress and stress mediated signaling. Isozymes of seven sub-families of cytosolic GSTs along with several microsomal GSTs are present in mammalian tissues. The discoveries that GSTs detoxify chemical carcinogens, could be used as a marker of chemical carcinogenesis, and are over expressed in many resistant cancer cell lines made these enzymes as a favorite target for diagnostic, preventative, and therapeutic approaches in cancer. Certain GST isozymes catalyze GSH dependent reduction of lipid hydroperoxides and play a major role in defense against lipid peroxidation (LPO) and oxidative stress. GSTs can also limit the intracellular accumulation of end-products of LPO including 4-hydroxynonenal (4-HNE), a pro-apoptotic second messenger which affects cell cycle signaling in a concentration dependent manner. 4-HNE is a common denominator in stress- induced signaling and GSTs can regulate signaling for apoptosis, differentiation, and gene expression by modulating the interactions of 4-HNE with transcriptional factors, transcriptional repressors, and membrane receptors. GSTs regulate expression/function of these factors in vitro and in vivo. Thus GSTs, particularly those involved in the regulation of 4-HNE concentrations, can have a global effect on cell cycle signaling. A major outcome of these findings is that by blocking GST mediated detoxification of 4-HNE through inhibition of the GS-HNE transporter (RLIP76) a complete remission of many human cancer xenografts in mice can be achieved. (NIH grants ES012171, EY 04396, CA77495)
