Jost Petr, Pejchal Jaroslav, Kucera Tomas, Muckova Lubica, Stetina Rudolf
University of Defense, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Hradec Kralove, Czech Republic.
J Appl Biomed. 2019 Jun;17(2):136-145. doi: 10.32725/jab.2019.009. Epub 2019 Jun 17.
2-chloroethyl ethyl sulfide (CEES) is a vesicant agent, commonly referred to half mustard due to its ability to form monofunctional adducts with DNA. In this study, we evaluated the chemoprotective potential of 13 compounds and their mixtures with sodium 2-mercaptoethanesulfonate (MESNA) against CEES-induced geno- and cytotoxicity in human lung cell line A-549. MESNA, L-glutathione (GSH), thiourea, sodium thiosulfate, hexamethylenetetramine, 4-acetamidophenol, asoxime dichloride (HI-6), N-acetyl-L-cysteine (NAC), sodium pyruvate, myo-inositol, 3-aminobenzamide (3-AB), nicotinamide, and Nω-nitro-L-arginine methyl ester hydrochloride and combinations of these compounds with MESNA were applied 30 min before CEES. DNA alkylation was measured using modified comet assay 1 and 24 h after the exposure. Cell viability was determined using MTT assay at 24 and 72 h. The mono-therapeutical approach identified MESNA and GSH to provide significant chemoprotection. NAC and 3-AB supported DNA damage repair, while cell viability remained unaffected. Mixtures of GSH or NAC with MESNA showed protective synergism against DNA damage. Other compounds or their combinations with MESNA failed due to the potentiation of CEES-induced cytotoxicity. The chemoprotection against CEES remains limited; however, the combination of substances can provide protective synergy and may represent a promising strategy in the treatment of accidental exposure to monoalkylating agents.
2-氯乙基乙硫醚（CEES）是一种糜烂性毒剂，因其能够与DNA形成单功能加合物，通常被称为半芥子气。在本研究中，我们评估了13种化合物及其与2-巯基乙烷磺酸钠（MESNA）的混合物对人肺细胞系A-549中CEES诱导的基因毒性和细胞毒性的化学保护潜力。MESNA、L-谷胱甘肽（GSH）、硫脲、硫代硫酸钠、六亚甲基四胺、4-乙酰氨基酚、双氯肟（HI-6）、N-乙酰-L-半胱氨酸（NAC）、丙酮酸钠、肌醇、3-氨基苯甲酰胺（3-AB）、烟酰胺、盐酸Nω-硝基-L-精氨酸甲酯以及这些化合物与MESNA的组合在CEES暴露前30分钟应用。在暴露后1小时和24小时使用改良彗星试验测量DNA烷基化。在24小时和72小时使用MTT试验测定细胞活力。单一治疗方法确定MESNA和GSH可提供显著的化学保护。NAC和3-AB支持DNA损伤修复，而细胞活力不受影响。GSH或NAC与MESNA的混合物对DNA损伤显示出保护协同作用。其他化合物或其与MESNA的组合由于增强了CEES诱导的细胞毒性而失败。对CEES的化学保护仍然有限；然而，物质的组合可以提供保护协同作用，可能代表了治疗意外暴露于单烷基化剂的一种有前景的策略。
