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Sulfur mustard (SM) is a potent vesicant. The lack of an effective antidote makes SM a continued threat to both military and civilian settings. A surrogate agent, namely mechlorethamine (HN2), was used here to mimic the toxicity of SM, and the main objective of this study was to demonstrate if selected organoselenium analogs could protect cultured A-431 skin cells from HN2 toxicity. Test compounds included ebselen (EB-1) and three related organoselenium analogs (EB-2, EB-3 and EB-4). In the absence of test compound, a reproducible and robust cell death was observed in the cells following incubation with HN2 (25 µM, 24 or 48 h) while cells treated with test compound alone (15, 30 or 60 µM) for similar periods of time were generally not affected. When incubated in the presence of both HN2 and test compound for 24 or 48 h, it was found that EB-1, EB-2, EB-3 and EB-4 could spare the cells from death, with the EB-4 compound being the most effective at reducing HN2 toxicity. Light microscopy confirmed these findings. The organoseleniums were also examined for their effects on reducing lipid peroxidation in the A-431 skin cells. Among the test compounds, EB-4 reduced lipid peroxidation by HN2 to the greatest extent. These studies, taken together, validate that the organoselenium antioxidants tested here may serve a purpose in the discovery of medical countermeasures to vesicants.

Mechlorethamine (HN2) and 2-chloroethylethyl sulfide (CEES) are mustard vesicants. Butylated hydroxyanisole (BHA) is a phenolic antioxidant. In the present work, the ability of BHA to reduce the toxicity of HN2 and CEES was investigated using A-431 skin cells. HN2 toxicity was found to be dependent, at least in part, on the cellular glutathione (GSH) status. BHA also decreased HN2-induced DNA damage and lipid peroxidation. The cytoprotective activity of BHA was also compared with that of the structurally unrelated antioxidant ebselen. Whereas ebselen (30 microM) protected skin cells from the toxicity of both HN2 (10-80 microM) and CEES (10-40 microM), BHA (100 microM) reduced the toxicity of HN2 only. Taken together, these data suggest that antioxidants such as BHA or ebselen may serve as useful treatments for injury caused by blistering agents.