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Effects of specific inhibitors of cellular functions on sulfur mustard-induced cell death

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Abstract

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 μM to 1000 μM) of an inhibitor and exposed to an estimated 87% effect concentration (EC87) of HD (170 μM) 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.

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Abbreviations

ATP:

adenosine triphosphate

DNA:

deoxyribonucleic acid

EC50 :

concentration which gives 50% of maximum effect

GSH:

glutathione

HD:

sulfur mustard (β,β′-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

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Authors and Affiliations

  1. Basic Assessment Branch, US, Army Medical Research Institute of Chemical Defense, 21010-5425, Aberdeen Proving Ground, Maryland, USA

    Edward T. Clayson, Susan A. Kelly & Henry L. Meier Commander

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  1. Edward T. Clayson
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  2. Susan A. Kelly
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  3. Henry L. Meier Commander
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Clayson, E.T., Kelly, S.A. & Meier, H.L. Effects of specific inhibitors of cellular functions on sulfur mustard-induced cell death. Cell Biol Toxicol 9, 165–175 (1993). https://doi.org/10.1007/BF00757578

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