Effects of specific inhibitors of cellular functions on sulfur mustard-induced cell death.
This study was conducted to determine whether inhibitors of normal cellular functions can reduce cytotoxicity induced by sulfur mustard (HD). The compounds examined include inhibitors of poly(ADP-ribose) polymerase (PADPRP), inhibitors of mono(ADP-ribose) transferase (MADPRT), inhibitors of lipid peroxidation, and an inhibitor of protein synthesis. To determine the effects of these compounds on HD-induced cell death, human lymphocyte preparations were treated with known concentrations (0.1 microM to 1000 microM) of an inhibitor and exposed to an estimated 87% effect concentration (EC87) of HD (170 microM) for loss in cell viability. Cell viability was determined at 24-26 hr post-exposure to HD using a dye (propidium iodide) exclusion assay and a flow cytometer. All of the selected PADPRP inhibitors were found to be effective at reducing the cytotoxic effects of HD. These inhibitors were rank-ordered based on the concentration that gives 50% (EC50) reduction of HD-induced cell death. A significant correlation (r = 0.94) was observed between the compounds' ability to inhibit PADPRP and the compounds' ability to reduce HD- induced cell death, suggesting that PADPRP plays a role in HD-induced cell death. Inhibitors of MADPRT, lipid peroxidation, and protein synthesis were not effective at reducing HD-induced cell death.
Clayson
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Basic Assessment Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425.
Kelly
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Meier
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D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors; D000328:Adult; D016923:Cell Death / Q000187:drug effects*; D004336:Drug Antagonism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects*; D008297:Male; D009151:Mustard Gas / Q000633:toxicity*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011500:Protein Synthesis Inhibitors; D036002:ADP Ribose Transferases; D009151:Mustard Gas