The time-dependent effect of 2,2′-dichlorodiethyl sulfide (sulfur mustard, HD, 1,1′-thiobis [2-chloroethane]) on the lymphocyte viability and the kinetics of protection by poly(ADP-ribose) polymerase inhibitors

Abstract

2,2′-Dichlorodiethyl sulfide (sulfur mustard, HD, 1,1′-thiobis [2-chloroethane]) is a potent vesicant which can cause severe lesions to skin, lung, and eyes. Due to the high number of debilitating exposures during the Iran — Iraq war to the alkylating agent, HD, there is an increased interest in its mechanism of action and in the development of therapeutic interventions to prevent HD-induced lesions. Recently we reported anin vitro assay using human mononuclear leukocytes for studying HD-induced pathology. To study the time dependence of HD-induced mononuclear leukocyte cell death and to determine the parameters of any potential therapeutic intervention, an assay was developed and automated using a flow cytometer to measure propidium iodide exclusion by mononuclear cells. This assay demonstrated that HD-initiated cell death did not begin before 4 h post-exposlure, but after 4 h proceeded in a concentration-dependent manner. In this assay both niacinamide and 3-aminobenzamide, poly(ADP-ribose) polymerase inhibitors, were shown to be effective in blocking HD-induced cell death when added to the cultures during the first 4 h post-exposure. They offered partial protection when added between 6 and 12 h and were of no benefit when added after 12 h post-exposure.