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 ofpoly(ADP-ribose) polymerase (PADPRP), inhibitors of mono(ADP-ribose) transferase (MADPRT), inhibitors of lipidperoxidation, and an inhibitor ofprotein synthesis. To determine the effects of these compounds on HD-induced cell death, human lymphocyte preparations were treated with known concentrations (0.1 M to 1000 M) of an inhibitor and exposed to an estimated 87% effect concentration (EC₈₇) of HD (170 M) for loss in cell viability. Cell viability was determined at 24–26hr 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 ofHD-induced cell death.A signijicant 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.Abbreviations ATP adenosine triphosphate - DNA deoxyribonucleic acid - EC₅₀ concentration which gives 50% of maximum effect - GSH glutathione - HD sulfur mustard (,-dichloroethyl sulfide) - HEPA high efficiency particulate adsorbing - HEGA high efficiency gas adsorbing - IC₅₀ concentration that inhibits 50% of enzyme activity - MADPRT mono(ADP-ribose) transferase - NAD nicotinamide adenine dinucleotide - PADPRP poly(ADP-ribose) polymerase