Rockwood Gary A, Thompson David E, Petrikovics Ilona
Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, USA
Department of Chemistry, Sam Houston State University, Huntsville, TX, USA.
Toxicol Ind Health. 2016 Dec;32(12):2009-2016. doi: 10.1177/0748233715622713. Epub 2016 Mar 3.
In the present studies, the in vitro and in vivo efficacies of a novel cyanide countermeasure, dimethyl trisulfide (DMTS), were evaluated. DMTS is a sulfur-based molecule found in garlic, onion, broccoli, and similar plants. DMTS was studied for effectiveness as a sulfur donor-type cyanide countermeasure. The sulfur donor reactivity of DMTS was determined by measuring the rate of the formation of the cyanide metabolite thiocyanate. In experiments carried out in vitro in the presence of the sulfurtransferase rhodanese (Rh) and at the experimental pH of 7.4, DMTS was observed to convert cyanide to thiocyanate with greater than 40 times higher efficacy than does thiosulfate, the sulfur donor component of the US Food and Drug Administration-approved cyanide countermeasure Nithiodote In the absence of Rh, DMTS was observed to be almost 80 times more efficient than sodium thiosulfate in vitro The fact that DMTS converts cyanide to thiocyanate more efficiently than does thiosulfate both with and without Rh makes it a promising sulfur donor-type cyanide antidote (scavenger) with reduced enzyme dependence in vitro The therapeutic cyanide antidotal efficacies for DMTS versus sodium thiosulfate were measured following intramuscular administration in a mouse model and expressed as antidotal potency ratios (APR = LD of cyanide with antidote/LD of cyanide without antidote). A dose of 100 mg/kg sodium thiosulfate given intramuscularly showed only slight therapeutic protection (APR = 1.1), whereas the antidotal protection from DMTS given intramuscularly at the same dose was substantial (APR = 3.3). Based on these data, DMTS will be studied further as a promising next-generation countermeasure for cyanide intoxication.
在本研究中，对一种新型氰化物解毒剂——二甲基三硫（DMTS）的体外和体内疗效进行了评估。DMTS是一种存在于大蒜、洋葱、西兰花及类似植物中的含硫分子。对DMTS作为硫供体型氰化物解毒剂的有效性进行了研究。通过测量氰化物代谢产物硫氰酸盐的形成速率来确定DMTS的硫供体反应活性。在体外实验中，在硫转移酶硫氰酸酶（Rh）存在且实验pH值为7.4的条件下，观察到DMTS将氰化物转化为硫氰酸盐的效率比美国食品药品监督管理局批准的氰化物解毒剂硫代硫酸钠中的硫供体成分硫代硫酸盐高40倍以上。在没有Rh的情况下，体外实验中观察到DMTS比硫代硫酸钠高效近80倍。无论有无Rh，DMTS将氰化物转化为硫氰酸盐的效率都比硫代硫酸盐更高，这使其成为一种有前景的硫供体型氰化物解毒剂（清除剂），在体外对酶的依赖性较低。在小鼠模型中肌肉注射后，测量了DMTS与硫代硫酸钠的治疗性氰化物解毒疗效，并表示为解毒效力比（APR = 有解毒剂时氰化物的LD/无解毒剂时氰化物的LD）。肌肉注射100 mg/kg的硫代硫酸钠剂量仅显示出轻微的治疗保护作用（APR = 1.1），而相同剂量肌肉注射DMTS的解毒保护作用则很显著（APR = 3.3）。基于这些数据，DMTS将作为一种有前景的下一代氰化物中毒解毒剂进行进一步研究。
