Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 141, Issue 5, Pages 795-802Publisher
WILEY
DOI: 10.1038/sj.bjp.0705591
Keywords
2-chloroethylethyl sulphide; sulphur mustard; apoptosis; N-acetyl cysteine; reactive oxygen species; mitochondrial membrane potential; poly (ADP-ribose) polymerase
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1 The mechanism of toxicity of sulphur mustard was investigated by examining the biochemical effects of the analog 2-chloroethylethyl sulphide ( CEES) in both human Jurkat cells as well as normal human lymphocytes. 2 Exposure of both types of cells to CEES resulted in a marked decrease in the intracellular concentration of the reduced form of glutathione (GSH), and CEES-induced cell death was potentiated by L-buthionine sulphoximine, an inhibitor of GSH synthesis. 3 CEES increased the endogenous production of reactive oxygen species (ROS) in Jurkat cells, and CEES-induced cell death was potentiated by hydrogen peroxide. 4 CEES induced various hallmarks of apoptosis, including collapse of the mitochondrial membrane potential, proteolytic processing and activation of procaspase-3, and cleavage of poly (ADP-ribose) polymerase. 5 The effects of CEES on the accumulation of ROS, the intracellular concentration of GSH, the mitochondrial membrane potential, and caspase-3 activity were all inhibited by pretreatment of cells with the GSH precursor N-acetyl cysteine or with GSH-ethyl ester. Furthermore, CEES-induced cell death was also prevented by these antioxidants. 6 CEES toxicity appears to be mediated, at least in part, by the generation of ROS and consequent depletion of GSH. Given that sulphur mustard is still a potential biohazard, the protective effects of antioxidants against CEES toxicity demonstrated in Jurkat cells and normal human lymphocytes may provide the basis for the development of a therapeutic strategy to counteract exposure to this chemical weapon.
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