The study on non-cholinergic toxicity of Nerve agents

我们报告了静脉注射类梭曼或类沙林有机磷剂(BIMP，双(异丙基甲基)膦；BPMP，双(频)甲酯)后，大鼠脑细胞液和细胞膜部分的磷脂酶C(PLC)活性随时间的变化。注射BPMP的大鼠脑组织胞浆部分中PLCγ被激活。BPMP可增强大鼠脑膜部分的磷酸化活性。BPMP处理的大鼠的脑膜部分可以磷酸化几种蛋白质，包括体外实验中对照组大鼠的脑胞浆部分中可能存在的PLCγ。这些结果表明，梭曼和沙林可以直接或间接地兴奋包括生长因子受体在内的细胞膜酪氨酸激酶。观察到大脑胞浆部分中几种蛋白质的酪氨酸磷酸化水平增加。胞浆中c-jun氨基末端激酶(JNK)和丝裂原活化蛋白激酶(MAPK)轻度激活。这些酶的激活可能与这些神经毒剂的高毒性有关。我们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。具有两种沙林水解酶活性的Arg_192PON1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名受害者表现出高沙林水解酶活性的表型，3名患者表现出低沙林水解酶活性的表型。这些结果表明，造成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_1992PON1基因多态的种族相关性遗传差异。

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.