Concentration-dependent kinetics of acetylcholinesterase inhibition by the organophosphate paraoxon.
Concentration-dependent kinetics of acetylcholinesterase inhibition by the organophosphate paraoxon.
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有机磷对氧磷抑制乙酰胆碱酯酶的浓度依赖性动力学。
DOI：
10.1093/toxsci/kfj094
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Sultatos,LesterG
中科院分区：
文献类型：
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作者：
Rosenfeld,ClintA;Sultatos,LesterG
几十年来，抗胆碱酯酶有机磷化合物与乙酰胆碱酯酶的相互作用的特征在于活性位点丝氨酸（Ser-203）的直接磷酸化，其可以通过抑制率constantki动力学描述。然而，最近某些动力学的复杂性，抑制乙酰胆碱酯酶的有机磷，如对氧磷（O，O-二乙基O-（对硝基苯基）磷酸盐）和毒死蜱氧磷（O，O-二乙基O-（3，5，6-三氯-2-吡啶基）磷酸盐）提出了问题的动力学方案的适当性，kii是基于。本文记录了对氧磷对人类重组乙酰胆碱酯酶的抑制能力似乎随着氧磷浓度的变化而变化的条件（如changingki所证明的），单个氧磷分子的抑制能力在较低的氧磷浓度下增加。优化的计算机模型的基础上有序单双动力学机制磷酸化乙酰胆碱酯酶测定k1为0.5 nM−1h−1，和k − 1为169.5 h−1。这些值被用于有序Uni Bi模型与Aki模型的比较，以评估Ki准确描述对氧磷抑制乙酰胆碱酯酶的能力。有趣的是，该模型仅在平衡（或接近平衡）时是准确的，当抑制剂浓度远低于其Kd（伪一级条件）。有序Uni Bi和ki模型的比较表明，作为抑制剂浓度的函数的变化不是由不适当的抑制剂浓度引起的伪影。
For decades the interaction of the anticholinesterase organophosphorus compounds with acetylcholinesterase has been characterized as a straightforward phosphylation of the active site serine (Ser-203) which can be described kinetically by the inhibitory rate constantki. However, more recently certain kinetic complexities in the inhibition of acetylcholinesterase by organophosphates such as paraoxon (O,O-diethylO-(p-nitrophenyl) phosphate) and chlorpyrifos oxon (O,O-diethylO-(3,5,6-trichloro-2-pyridyl) phosphate) have raised questions regarding the adequacy of the kinetic scheme on whichkiis based. The present article documents conditions in which the inhibitory capacity of paraoxon towards human recombinant acetylcholinesterase appears to change as a function of oxon concentration (as evidenced by a changingki), with the inhibitory capacity of individual oxon molecules increasing at lower oxon concentrations. Optimization of a computer model based on an Ordered Uni Bi kinetic mechanism for phosphylation of acetylcholinesterse determinedk1to be 0.5 nM−1h−1, andk−1to be 169.5 h−1. These values were used in a comparison of the Ordered Uni Bi model versus akimodel in order to assess the capacity ofkito describe accurately the inhibition of acetylcholinesterase by paraoxon. Interestingly, thekimodel was accurate only at equilibrium (or near equilibrium), and when the inhibitor concentration was well below itsKd(pseudo first order conditions). Comparisons of the Ordered Uni Bi andkimodels demonstrate the changingkias a function of inhibitor concentrations is not an artifact resulting from inappropriate inhibitor concentrations.