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Balszuweit, Frank; Menacher, Georg; Schmidt, Annette; Kehe, Kai; Popp, Tanja; Worek, Franz; Thiermann, Horst; Steinritz, Dirk (2016): Protective effects of the thiol compounds GSH and NAC against sulfur mustard toxicity in a human keratinocyte cell line. In: Toxicology Letters, Vol. 244: pp. 35-43
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Abstract

Sulfur mustard (SM) is a chemical warfare agent causing blistering, inflammation and ulceration of the skin. Thiol compounds such as glutathione (GSH) and N-acetylcysteine (NAC) have been suggested as potential antidotes. We investigated SM toxicity in a human keratinocyte cell line (HaCaT) and used GSH and NAC to counteract its cytotoxic effects. Cells were treated with 1, 5 or 10 mM GSH or NAC and exposed to 30, 100 or 300 mu M SM. Different treatment regimens were applied to model extra-and intra-cellular GSH/NAC effects on SM toxicity. Necrosis, apoptosis and interleukin-6 and -8 levels were determined 24 h post-exposure. Necrosis and apoptosis increased with SM dose. Interleukin-6 and -8 production peaked at 100 mu M and decreased at 300 mu M probably due to reduced ability for interleukin biosynthesis. Intracellular GSH/NAC diminished necrosis induced by 100 mu M SM. Extracellular GSH/NAC protected against necrosis and apoptosis induced by 100 and 300 mu M SM. Interleukin-6 and -8 production, induced by 100 mu M SM was reduced by GSH/NAC. However, low-dose GSH/NAC treatment of cells exposed to 300 mu M SM led to increased interleukin production. Thus, moderately poisoned cells are mostly responsible for SM-induced secretion of pro-inflammatory cytokines. GSH and NAC treatment can reduce SM-induced toxic effects. Protective effects were more pronounced by extracellular GSH or NAC administration. Rescue of severely poisoned cells may result in a strong secretion of pro- inflammatory cytokines. In summary, thiol compounds such as GSH or NAC constitute a promising approach to improve the therapy for SM injury. Additional intervention to prevent adverse effects of interleukin production might be beneficial. (C) 2015 ELSEVIER. All rights reserved.