Development of sodium tetrathionate as a cyanide and methanethiol antidote.
Development of sodium tetrathionate as a cyanide and methanethiol antidote.
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DOI：
10.1080/15563650.2021.1953517
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Boss GR
中科院分区：
文献类型：
--
作者：
Chan A;Lee J;Bhadra S;Bortey-Sam N;Hendry-Hofer TB;Bebarta VS;Mahon SB;Brenner M;Logue B;Pilz RB;Boss GR
氰化氢和甲硫醇是抑制线粒体细胞色素C氧化酶的两种有毒气体。结构火灾中会产生氰化物，腐烂的有机物会释放出甲硫醇。目前对氰化物暴露的治疗方法不适合现场治疗，也不存在甲硫醇中毒的治疗方法。硫代硫酸盐氧化产物四硫酸钠可能是氰化物的解毒剂，根据其化学结构，我们推测它可以与甲硫醇反应。我们证明，与硫代硫酸盐不同，四硫酸盐在生理条件下在体外与氰化物直接反应，并且基于我们实时监测氰化物中毒的兔研究，四硫酸盐很可能在体内与氰化物直接反应。我们发现，肌肉注射四硫酸盐可以拯救80%的幼年、青年和老年成年小鼠，使其免于吸入氰化氢气体，而氰化氢气体的致死率为80%。四硫酸盐还从静脉注射氰化钠中拯救了年轻的成年兔子。四硫酸盐对小鼠和大鼠耐受性良好，对幼年和成年小鼠的治疗指数为~5，对老年小鼠的治疗指数为~3.3；对中国仓鼠卵巢细胞和Ames细菌试验均无致突变作用。我们通过气相色谱-质谱仪发现，四硫酸盐和硫代硫酸盐都能与甲硫醇反应生成二甲基二硫化物，但在恢复COS-7细胞内ATP和拯救暴露在甲硫醇气体中的小鼠方面，四硫酸盐比硫代硫酸盐要有效得多。我们认为，四硫酸盐有可能成为一种有效的氰化物和甲硫醇中毒的解毒剂。
Hydrogen cyanide and methanethiol are two toxic gases that inhibit mitochondrial cytochrome c oxidase. Cyanide is generated in structural fires and methanethiol is released by decaying organic matter. Current treatments for cyanide exposure do not lend themselves to treatment in the field and no treatment exists for methanethiol poisoning. Sodium tetrathionate (tetrathionate), a product of thiosulfate oxidation, could potentially serve as a cyanide antidote, and, based on its chemical structure, we hypothesized it could react with methanethiol. We show that tetrathionate, unlike thiosulfate, reacts directly with cyanide in vitro under physiological conditions, and based on rabbit studies where we monitor cyanide poisoning in real-time, tetrathionate likely reacts directly with cyanide in vivo. We found that tetrathionate administered by intramuscular injection rescues >80% of juvenile, young adult, and old adult mice from exposure to inhaled hydrogen cyanide gas that is >80% lethal. Tetrathionate also rescued young adult rabbits from intravenously administered sodium cyanide. Tetrathionate was reasonably well-tolerated by mice and rats, yielding a therapeutic index of ~5 in juvenile and young adult mice, and ~3.3 in old adult mice; it was non-mutagenic in Chinese Hamster ovary cells and by the Ames bacterial test. We found by gas chromatography-mass spectrometry that both tetrathionate and thiosulfate react with methanethiol to generate dimethyldisulfide, but that tetrathionate was much more effective than thiosulfate at recovering intracellular ATP in COS-7 cells and rescuing mice from a lethal exposure to methanethiol gas. We conclude that tetrathionate has the potential to be an effective antidote against cyanide and methanethiol poisoning.
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影响因子：
2.1
作者：
Hendry-Hofer TB;Ng PC;McGrath AM;Soules K;Mukai DS;Chan A;Maddry JK;White CW;Lee J;Mahon SB;Brenner M;Boss GR;Bebarta VS
通讯作者：
Bebarta VS
影响因子：
7.3
作者：
Chan, Adriano;Jiang, Jingjing;Boss, Gerry R.
通讯作者：
Boss, Gerry R.
影响因子：
3.1
作者：
Chen, KK;Rose, CL;Clowes, GBA
通讯作者：
Clowes, GBA
影响因子：
--
作者：
GILMAN, A;PHILIPS, FS;STJOHN, E
通讯作者：
STJOHN, E
影响因子：
6.2
作者：
Bebarta VS;Brittain M;Chan A;Garrett N;Yoon D;Burney T;Mukai D;Babin M;Pilz RB;Mahon SB;Brenner M;Boss GR
通讯作者：
Boss GR