Modulation of sulphur mustard cellular toxicity by ATP. A possible mechanism of action of sulphur mustard

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Authors
  1. Lundy, P.M.
  2. Frew, R.
  3. Vair, C.
  4. Hamilton, M.G.
  5. Sawyer, T.W.
  6. Nelson, P.
  7. Gong, W.
  8. Mi, L.
Corporate Authors
Defence Research Establishment Suffield, Ralston ALTA (CAN);Kinchyle Enterprises Inc, Medicine Hat ALTA (CAN)
Abstract
HD caused apoptosis and to a lesser degree, necrosis in a wide variety of cell types. As the concentration of HD was increased the proportion of necrotic cells became more predominant. HD produced a modest elevation of intracellular calcium levels in J774 and CHOK-1 cells, as well as in human skin keratinocytes, although this rise did not seem causally related to HD induced cell death. However, very recent evidence indicates that HD induced DNA fragmentation may not be directly related to cytotoxicity. HD also activated caspase-3 in CHOK-1 cells, but neither specific nor general caspase inhibitors nor proteosome inhibitors reduced HD cytotoxicity. These results suggest that the toxicity of HD is fundamentally different than apoptotic stimulae such as dexamethasone or X-irradiation, in which the apoptosis induced by both of these treatments can be reduced by the above mentioned protease inhibitors. Subtypes of the P2X receptors were identified in neuronal synaptosomes, J774 cells and CHOK-1 cells. In CHOK-1 cells P2K7 receptor subtypes were identified and the specific P2X7 inhibitor, oxidized ATP, was found effective in reducing HD induced DNA fragmentation and the appearance of soluable DNA. However, this treatment appeared only to shunt the mechanism of cell death from being predominantly apoptotic, to more necrotic in nature; however, the overall cytotoxicity remained unchanged.
Keywords
Sulphur mustard;Sulfur mustard;HD agent;Cytotoxicity;Intracelluar calcium;Apoptosis;ATP receptors
Report Number
DRES-ECR-2000-214 — External Contract Report
Date of publication
01 Feb 2001
Number of Pages
75
DSTKIM No
CA011827
CANDIS No
516361
Format(s):
Hardcopy;Document Image stored on Optical Disk

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