The study on non-cholinergic toxicity of Nerve agents

神经毒剂非胆碱能毒性研究

• 批准号: 11670408
• 负责人: NAGAO Nasataka
• 金额: $ 2.3万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670408/
• 关键词: Sarin; Soman; organophosphorous agent; rat; brain; PLCγ; MAPK; JNK; paraoxonase; Soman; organophosphorus agent; astrocyte; MEK; organophosphonous agent; 神経剤; 非コリン性毒性; サリン; ソマン; PLCβ; tyrosine kinase

We report that there is a time-related change in the phospholipase C (PLC) activities of rat brain cytosol and membrane fractions after iv injection of a soman-like or a sarin-like organophosphorous agent (BIMP, bis (isopropyl methyl) phosphonate ; and BPMP, bis (pinacolyl methyl) phosphonate). PLCγ was activated in the brain cytosol fraction from BPMP- injected rats. The phosphorylating activity of rat brain membrane fractions were enhanced by BPMP treatment. The brain membrane fractions from BPMP-treated rats phosphorylated several proteins, including supposedly PLCγ in the brain cytosol fraction from control rats in vitro. These results suggest that soman and sarin may stimulate a membrane tyrosine kinase, including growth factor receptors, directly or indirectly.BIMP and BPMP were injected intravenously (iv) in rats. An increase in the tyrosine phosphorylation of several proteins in the cytosol fraction of the brain was observed. Activation of c-Jun N-terminal kinase (JNK) and slight activation of mitogen activated protein kinase (MAPK) in the cytosol were also observed. The activation of these enzymes may be related to the high toxicity of these nerve agents.We reported the polymorphism of the high density lipoprotein-associated enzyme paraoxonase (PON1), in the 10 sarin poisoning victims in the Tokyo subway terrorist attack. Arg_192 PON1, which has tow sarin hydrolysing activity, was found to be more common in the Japanese population than in people of other races. However, from our analyses seven of the victims expressed the phenotype with high sarin hydrolysing activity and three with low sarin hydrolysing activity. These results indicate that the main factor contributing to the tragedy of the Tokyo subway terrorist attack was high toxicity of sarin rather than the race-dependent genetic difference in the Arg_l92 PON1 polymorphism.

我们报道了静脉注射一种苏曼样或沙林样有机磷剂(BIMP，二甲基膦酸异丙酯；BPMP，双（甲基）膦酸酯)。在注射BPMP的大鼠脑细胞质中，PLCγ被激活。BPMP可增强大鼠脑膜磷酸化活性。bpmp处理大鼠的脑膜组分磷酸化了几种蛋白质，包括体外对照大鼠的脑细胞质组分中的PLCγ。这些结果表明，索曼和沙林可能直接或间接地刺激膜酪氨酸激酶，包括生长因子受体。大鼠静脉注射BIMP和BPMP。观察到脑细胞质部分中几种蛋白质的酪氨酸磷酸化增加。胞浆中c-Jun n末端激酶（JNK）被激活，丝裂原活化蛋白激酶（MAPK）被轻微激活。这些酶的活化可能与这些神经毒剂的高毒性有关。本文报道了东京地铁恐怖袭击中10名沙林中毒受害者的高密度脂蛋白相关酶对氧磷酶（PON1）的多态性。Arg_192 PON1具有两种沙林水解活性，在日本人群中比在其他种族人群中更常见。然而，从我们的分析中，7名受害者表达了高沙林水解活性的表型，3名表达了低沙林水解活性的表型。这些结果表明，导致东京地铁恐怖袭击悲剧的主要因素是沙林的高毒性，而不是Arg_l92 PON1多态性的种族依赖性遗传差异。

项目成果

Niijima H., Nagao M., Nakajima M. Takatori T., Matsuda Y., et al.: "Sarin-like and soman-like organophosphorous agents activate PLCγ in rat brains"Toxicol Appl Pharmacol. 156(1). 64-69 (1999)

Niijima H.、Nagao M.、Nakajima M. Takatori T.、Matsuda Y. 等人：“沙林样和梭曼样有机磷制剂激活大鼠大脑中的 PLCγ”Toxicol Appl Pharmacol 156(1)。 69（1999）

Niijima,H.,Nagao,M.,Nakajima,M.et al.: "Sarin-like and Soman-like organophosphorus Agents Activate PLCγin Rat Brains"Toxicology and Applied Pharmacology. 156・1. 64-69 (1999)

Niijima, H.、Nagao, M.、Nakajima, M. 等：“沙林样和梭曼样有机磷制剂激活大鼠大脑中的 PLCγ”毒理学和应用药理学 156・1（1999）。

Niijima et al.: "The effects of sarin like and soman-like organo phoshporus agents on MAPK and JNK in rat brains."Forensic Sci.Int.. 112(2/3). 171-178 (2000)

Niijima 等人：“沙林样和梭曼样有机磷制剂对大鼠大脑中 MAPK 和 JNK 的影响。”Forensic Sc​​i.Int.. 112(2/3)。

Niijima H., Nagao M., Nakajima M., Takatori T. et al.: "The effects of sarin-like and soman-like organophosphorous agents on MAPK and JNK in rat brains"Forensic Sci. Int.. 112(2/3). 171-178 (2000)

Niijima H.、Nagao M.、Nakajima M.、Takatori T. 等人：“沙林样和梭曼样有机磷制剂对大鼠脑中 MAPK 和 JNK 的影响”法医科学。

Yamada Y., Takatori T., Nagao M. et al.: "Expression of paraoxonase isoform did not confer protection from acute sarin poisoning in the Tokyo subway terrorist attack"Int J Legal Med.. 115(2). 82-84 (2001)

Yamada Y.、Takatori T.、Nagao M. 等人：“在东京地铁恐怖袭击中，对氧磷酶同工型的表达并未赋予人们免受急性沙林中毒的保护”Int J Legal Med. 115(2)。