Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes
Kinetic analysis of interactions between human acetylcholinesterase, structurally different organophosphorus compounds and oximes
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DOI：
10.1016/j.bcp.2004.07.038
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发表时间：
2004-12-01
影响因子：
5.8
通讯作者：
Eyer, P
中科院分区：
文献类型：
--
作者：
Worek, F;Thiermann, H;Eyer, P
有机磷化合物作为杀虫剂的广泛使用以及剧毒有机磷类化学战剂（神经毒剂）的供应，突出了有效医疗的必要性。急性OP毒性主要由乙酰胆碱酯酶（AChE，EC 3.1.1.7）抑制引起。抑制AChE的再活化剂（肟）是治疗的主要手段，然而，市售化合物双肟和解磷定被认为对各种神经毒剂相当无效。新肟的解毒功效主要是出于伦理原因在动物中进行测试。然而，AChE，OP和肟之间的各种相互作用可以与人类AChE，使肟的效力直接评估，从而排除物种差异进行了研究。用人红细胞AChE、各种结构不同的OP（有机磷酸酯、-膦酸酯和氨基磷酸酯）和肟（双肟、解磷定、HI 6、HLo 7）研究了抑制、再活化和老化的动力学。OPs的抑制效力，肟和自发再激活和老化的再激活效力的OPs和磷酸-乙酰胆碱酯酶复合物的结构特征的强烈影响。动力学数据强调了有机膦酸酯的上级抑制效力。AChE被各种氨基磷酸酯抑制主要是抵抗肟的再激活，而磷酸化的AChE很容易再激活。HLo 7对磷酸化AChE和双肟的作用最强，而AChE被有机磷酸酯和氨基磷酸酯抑制。除梭曼外，OP抑制的AChE老化相当缓慢（t（1/2）3-231 h），并与一些化合物自发地重新激活。这些结果表明，人AChE、OPs和肟的各种相互作用显然没有直接的构效关系。(C)2004爱思唯尔公司All rights reserved.
The wide-spread use of organophosphorus compounds (OP) as pesticides and the availability of highly toxic OP-type chemical warfare agents (nerve agents) underlines the necessity for an effective medical treatment. Acute OP toxicity is primarily caused by inhibition of acetylcholinesterase (AChE, EC 3.1.1.7). Reactivators (oximes) of inhibited AChE are a mainstay of treatment, however, the commercially available compounds, obidoxime and pralidoxime, are considered to be rather ineffective against various nerve agents. The antidotal efficacy of new oximes is primarily tested in animals for ethical reasons. However, the various interactions between AChE, OP and oximes can be investigated with human AChE which enables the direct assessment of oxime potency, thus excluding species differences. The kinetics of inhibition, reactivation and aging were investigated with human erythrocyte AChE, various structurally different OP (organophosphates, -phosphonates and phosphoramidates) and oximes (obidoxime, pralidoxime, HI 6, HLo 7). The inhibitory potency of OPs, reactivating potency of oximes and spontaneous reactivation and aging were strongly affected by the structural characteristics of the OPs and of the phosphyl-AChE-complex. The kinetic data emphasize the superior inhibitory potency of organophosphonates. AChE inhibited by various phosphoramidates was mostly resistant towards reactivation by oximes while phosphonylated AChE was easily reactivated. HLo 7 was most potent with phosphonylated AChE and obidoxime with AChE inhibited by organophosphates and phosphoramidates. With the exception of soman, OP-inhibited AChE aged rather slowly (t(1/2) 3-231 h) and reactivated spontaneously with some compounds. These results indicate that there is obviously no direct structure-activity relationship for the various interactions of human AChE, OPs and oximes. (C) 2004 Elsevier Inc. All rights reserved.