Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957, USA.
Toxicol Appl Pharmacol. 2013 Feb 1;266(3):439-42. doi: 10.1016/j.taap.2012.11.020. Epub 2012 Nov 30.
Mustard gas, used in chemical warfare since 1917, is a mutagenic and carcinogenic agent that produces severe dermal lesions for which there are no effective therapeutics; it is currently seen as a potential terrorist threat to civilian populations. Sulforaphane, found in cruciferous vegetables, is known to induce enzymes that detoxify compounds such as the sulfur mustards that react through electrophilic intermediates. Here, we observe that a single topical treatment with sulforaphane induces mouse epidermal levels of the regulatory subunit of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, and also increases epidermal levels of reduced glutathione. Furthermore, a glutathione S-transferase, GSTA4, is also induced in mouse skin by sulforaphane. In an in vivo model in which mice are given a single mutagenic application of the sulfur mustard analog 2-(chloroethyl) ethyl sulfide (CEES), we now show that therapeutic treatment with sulforaphane abolishes the CEES-induced increase in mutation frequency in the skin, measured four days after exposure. Sulforaphane, a natural product currently in clinical trials, shows promise as an effective therapeutic against mustard gas.
芥子气自 1917 年以来被用于化学战，是一种诱变剂和致癌剂，会导致严重的皮肤损伤，目前尚无有效的治疗方法；它目前被视为对平民的潜在恐怖威胁。存在于十字花科蔬菜中的萝卜硫素可诱导解毒酶，这些酶可使硫芥等化合物（通过亲电中间体起反应）解毒。在这里，我们观察到，萝卜硫素的单次局部处理可诱导小鼠表皮中谷氨酰胺半胱氨酸连接酶的调节亚基（谷胱甘肽生物合成的限速酶）的水平，并且还增加了表皮中还原型谷胱甘肽的水平。此外，萝卜硫素还可诱导小鼠皮肤中的谷胱甘肽 S-转移酶 GSTA4。在一个体内模型中，用硫芥类似物 2-（氯乙基）乙基硫醚（CEES）对小鼠进行单次诱变处理，我们现在发现，用萝卜硫素进行治疗可消除 CEES 引起的皮肤突变频率增加，在暴露四天后进行测量。萝卜硫素是一种天然产物，目前正在进行临床试验，有望成为对抗芥子气的有效治疗方法。
