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Tracing and attribution of V-type nerve agents in human exposure by strategy of assessing the phosphonylated and disulfide adducts on ceruloplasmin.
Toxicology ( IF 4.5 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.tox.2019.152346
Feiyan Fu 1 , Jialin Chen 2 , Pengcheng Zhao 1 , Xiaogang Lu 1 , Runli Gao 1 , Dong Chen 1 , Haibo Liu 1 , Hongmei Wang 1 , Chengxin Pei 1
Affiliation  

V-type agents are highly toxic organophosphorus nerve agents that inhibit acetylcholinesterase in the nervous system, causing a series of poison symptoms. Trace analytical methods are essential for the specific verification of exposure to these agents, especially for human exposure. This paper investigates the phosphonylated and disulfide adducts between human ceruloplasmin and O-ethyl S-(2-(diisopropylamino)ethyl) methylphosphonothioate (VX), O-isobutyl S-(2-(diethylamino)ethyl) methylphosphonothioate (VR), and O-butyl S-(2-(diethylamino)ethyl) methylphosphonothioate (Vs). After being digested by trypsin, the mixture of peptides was separated by a nano-liquid chromatography (nano-LC) and analyzed using quadrupole-orbitrap mass spectrometry (Q-Orbitrap-MS). The sensitive LC-MS/MS-assisted proteomics approach was developed to achieve the identification of human exposure to V-type agents based on these modified sites; results revealed that potential biomarkers could be derived from adducts based on the sulfur- and phosphorus-containing groups of V-type agents. This work offered a novel insight into the mechanism of disulfide-containing adducts resulting from the replacement of disulfide bridges by the thiolate groups from the V-type agents. Moreover, four disulfide adducts on human ceruloplasmin were also discovered during this research, specifically confirming exposure to the V-type agents. Furthermore, molecular simulation testified to the reactivity of the modified sites. Collectively, our findings suggest that the eleven binding sites on human ceruloplasmin have the potential use as a selective marker for prediction the V-type agent exposure in humans.

中文翻译:

通过评估铜蓝蛋白上的膦酰化和二硫键加合物的策略来追踪和评估人类接触中的V型神经毒剂。

V型药剂是剧毒的有机磷神经药剂,可抑制神经系统中的乙酰胆碱酯酶,引起一系列中毒症状。痕量分析方法对于具体验证这些试剂的暴露至关重要,特别是对于人类暴露。本文研究了人类铜蓝蛋白和O-乙基S-(2-(二异丙氨基氨基)乙基)甲基硫代磷酸酯(VX),O-异丁基S-(2-(二乙基氨基)乙基)甲基硫代磷酸酯(VR)和O之间的膦酰化和二硫键加合物S-(2-(二乙基氨基)乙基)甲基硫代磷酸正丁基酯(Vs)。用胰蛋白酶消化后,将肽混合物通过纳米液相色谱(nano-LC)分离,并使用四极-轨道质谱仪(Q-Orbitrap-MS)进行分析。开发了灵敏的LC-MS / MS辅助蛋白质组学方法,以基于这些修饰位点确定人类对V型试剂的暴露。结果表明,潜在的生物标志物可能来自于基于V型试剂中含硫和磷基团的加合物。这项工作提供了新的见解,由V型试剂中的硫醇盐基团取代了二硫键,从而产生了含二硫键的加合物的机理。此外,在这项研究中还发现了人类铜蓝蛋白上的四个二硫化物加合物,具体证实了其与V型药物的接触。此外,分子模拟证明了修饰位点的反应性。总的来说,
更新日期:2019-12-17
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