Study of effects of novel PAM analogues on the treatment of poisoning by nerve agents

新型PAM类似物治疗神经毒剂中毒的效果研究

• 批准号: 20592133
• 负责人: SAKURADA Koichi
• 金额: $ 2.33万
• 依托单位: National Research Institute of Police Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20592133/
• 关键词: 神経ガス; オキシム; パム; 2-PAM; 4-PAO; BBB; LC-MS/MS; LC-MS; MS; コリンオキシダーゼ; チトクロームCオキシダーゼ; ミトコンドリア; 電子伝達系

A liquid chromatography-tandem mass spectrometry(LC-MS/MS) method was validated and applied to the in vitro determination of novel PAM-type oximes, which can penetrate the blood-brain barrier(BBB) and reactivate acetylcholinesterase(AChE) inhibited by alkylphosphonate in various organs. It was indicated that the LC-MS/MS method could be a reliable method with high precision and accuracy for quantification of PAM-type oximes in various biological samples. On the other hand, although the oximes are potential antidotes to poisonings that inhibit AChE, but they are also toxic. To investigate the mechanism of their toxicity, the effects of oximes on the enzymes choline oxidase(ChOD) and cytochrome c oxidase(CyCOD) of the respiratory chain in mitochondria were examined. The results showed that the toxicities of oximes might be related to their inactivation of mitochondrial oxidase enzymes and generation of reactive oxygen species.

建立了液相色谱-串联质谱（LC-MS/MS）联用方法，并将其应用于新型pam型肟类化合物的体外测定。新型pam型肟类化合物能穿透血脑屏障（BBB），激活被烷基膦酸盐抑制的各器官乙酰胆碱酯酶（AChE）。结果表明，LC-MS/MS法是一种精密度高、准确度高的定量测定各种生物样品中pam型肟的可靠方法。另一方面，虽然这些肟类化合物是抑制乙酰胆碱酯酶的潜在解毒剂，但它们也是有毒的。为探讨其毒性作用机制，研究了氧肟对呼吸链线粒体胆碱氧化酶（ChOD）和细胞色素c氧化酶（CyCOD）的影响。结果表明，肟类化合物的毒性可能与其使线粒体氧化酶失活和活性氧的产生有关。

项目成果

Effects of oximes on mitochondrial oxidase activity

• DOI: 10.1016/j.toxlet.2009.05.007
• 发表时间: 2009-09-10
• 期刊: TOXICOLOGY LETTERS
• 影响因子: 3.5
• 作者: Sakurada, Koichi;Ikegaya, Hiroshi;Watanabe, Ken
• 通讯作者: Watanabe, Ken

神経ガス中毒治療における新規パム類似体のBBB通過に関する検討

新型Pam类似物治疗神经毒气中毒血脑屏障的研究

• 发表时间: 2008
• 作者: 小笠原理恵;菱川大介;進藤英雄;清水孝雄;林秀一郎;吉田康夫;遠山稿二郎;諏訪部章;櫻田宏一
• 通讯作者: 櫻田宏一

Liquid chromatography-tandem mass spectrometry method for determination of the pyridinium aldoxime 4-PAO in brain, liver, lung, and kidney.

液相色谱-串联质谱法测定脑、肝、肺、肾中吡啶醛肟4-PAO。

• DOI: 10.1016/j.jchromb.2010.01.021
• 发表时间: 2010
• 期刊: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences
• 作者: Koichi Sakurada;H. Ohta
• 通讯作者: H. Ohta