Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oxidative stress could have a dual action on glutathione S-transferase (GST) P1-1 metabolism: transcriptional induction and/or polymerization. The former should represent a form of adaptation to oxidative stress and contribute to protect the cell, the latter one should activate apoptosis via c-Jun N-terminal kinase (JNK). We studied the effect of etoposide on human neuroblastoma cell line SH-SY5Y and on an etoposide-resistant clone to investigate whether a pleiotropic effect of etoposide on the redox status of the cell exists which is able to interfere with apoptosis through the GST P1-1 system. Etoposide treatment was able to induce GST P1-1 polymerization and activation of apoptosis. The data obtained from our etoposide-resistant clone and the possibility to reverse the sensitive phenotype to a resistant one by means of hexyl-glutathione preincubation, seem to suggest that cellular levels of glutathione have a key role in protecting GST P1-1 by oxidation and consequently the cell's decision between life and death.
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PMID:Role of GST P1-1 in mediating the effect of etoposide on human neuroblastoma cell line Sh-Sy5y. 1211 3

Etoposide is a widely used antineoplastic agent that has provided great success in the treatment of childhood leukemias and other malignancies. Unfortunately, its use is associated with the increased risk of development of secondary acute myelogenous leukemias involving translocations at the MLL gene in chromosome band 11q23. Previous studies showed that the phenoxyl radical of etoposide can be generated by myeloperoxidase (MPO), an enzyme prevalent in myeloid progenitor cells that can derive myelogenous leukemias. Disproportionation of this radical leads to formation of the redox active etoposide ortho-quinone metabolite. We hypothesized that etoposide ortho-quinone could therefore form in myeloid progenitor cells and might be a contributor to the development of treatment-related secondary leukemias. Etoposide ortho-quinone is an inherently unstable compound and readily reacts with glutathione in aqueous media without any requirement for catalytic assistance from glutathione S-transferase. We looked for the presence of its glutathione adduct as an indicator of etoposide ortho-quinone in cells. MPO-expressing human myeloid leukemia HL60 cells were treated with etoposide for 0.5 h in the presence and absence of the cosubstrate of MPO, hydrogen peroxide. Cell lysates and medium were analyzed by LC-ESI-ion trap-MS and MS/MS, which yielded clear evidence of the intracellular formation of the etoposide ortho-quinone-glutathione adduct. A stable isotope-labeled form of the GSH adduct was synthesized and employed as an isotope dilution internal standard in LC-ESI-quadrupole-MS analyses. The glutathione adduct level was dependent on the concentration of etoposide added to the cells. More importantly, the formation of the glutathione adduct was significantly suppressed by the pretreatment of HL60 cells with the heme synthesis inhibitor succinylacetone (p < 0.001), which resulted in a decreased level and activity of MPO. These results are consistent with the idea that MPO is responsible for the conversion of etoposide to its ortho-quinone in these cells.
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PMID:Myeloperoxidase-catalyzed metabolism of etoposide to its quinone and glutathione adduct forms in HL60 cells. 1684 62