Insecticide Interactions With Acetylcholinesterase

杀虫剂与乙酰胆碱酯酶的相互作用

基本信息

批准号：
7276733
负责人：
LESTER G SULTATOS
金额：
$ 28.01万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-06 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7276733
关键词：
Acetylcholine Acetylcholinesterase Acetylthiocholine Active Sites Acute Agriculture Binding Binding Sites Chlorpyrifos Cholinergic Agents Chromosome Pairing Class Condition Data Dose Enzyme Inhibition Enzyme Interaction Enzymes Event Exposure to Health Human Hydrolysis Insecticides Kinetics Laboratories Ligands Malathion Mediating Methyl Parathion Neuromuscular Junction O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate Occupations Organophosphates Paraoxon Parathion Parents Peripheral Phosphorylation Principal Investigator Protein Dephosphorylation Publishing Range Rate Reaction Recombinants Research Research Personnel Risk Site Spectrophotometry Synapses Testing Time Toxic effect Triad Acrylic Resin United States base chlorpyrifos-methyl cholinergic enzyme activity enzyme substrate inhibitor/antagonist malaoxon methylparaoxon mutant neurotoxic organophosphorus insecticide response time interval

Acetylcholine Acetylcholinesterase Acetylthiocholine Active Sites Acute Agriculture Binding Binding Sites Chlorpyrifos Cholinergic Agents Chromosome Pairing Class Condition Data Dose Enzyme Inhibition Enzyme Interaction Enzymes Event Exposure to Health Human Hydrolysis Insecticides Kinetics Laboratories Ligands Malathion Mediating Methyl Parathion Neuromuscular Junction O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate Occupations Organophosphates Paraoxon Parathion Parents Peripheral Phosphorylation Principal Investigator Protein Dephosphorylation Publishing Range Rate Reaction Recombinants Research Research Personnel Risk Site Spectrophotometry Synapses Testing Time Toxic effect Triad Acrylic Resin United States base chlorpyrifos-methyl cholinergic enzyme activity enzyme substrate inhibitor/antagonist malaoxon methylparaoxon mutant neurotoxic organophosphorus insecticide response time interval

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项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this project is to provide information that will be useful in assessing the risks posed to human health by the neurotoxic organophosphorus insecticides. It seeks to accomplish this objective by investigating preliminary observations that suggest the current view of how these toxic insecticides inhibit acetylcholinesterase is inadequate to describe the insecticide-enzyme interactions over a wide range of insecticide concentrations. Preliminary data indicates that the capacity of certain organophosphates to inhibit acetylcholinesterase changes as a function of inhibitor concentration. Moreover, evidence presented indicates that the organophosphate paraoxon causes a transient activation of acetylcholinesterase prior to inhibition. Collectively, these data suggest the presence of a secondary binding site on human recombinant acetylcholinesterase for certain organophosphates. Therefore, the overall hypothesis of this application is that organophosphates and their parent insecticides bind to a site on human recombinant acetylcholinesterase distinct from the catalytic triad, and that occupation of this site alters events at the active site. As a consequence of such binding, low exposures to certain organophosphorus insecticides could pose a greater health risk than is currently estimated based on dose-response relationships using higher exposure levels. The specific aims of this application are as follows: 1) To determine the bimolecular inhibition rate constant &,, for the inhibition of human recombinant acetylcholinesterase by the test organophosphates over a wide range of inhibitor concentrations; 2) To determine if the test organophosphates and their parent compounds can transiently enhance the hydrolysis of the substrate acetylthiocholine by human recombinant acetylcholinesterase prior to inhibition of the enzyme through phosphorylation; 3) To determine if the test organophosphates and their corresponding parent insecticides bind to the peripheral anionic site on human recombinant acetylcholinesterase; and 4) To determine if the rate of dephosphorylation of organophosphate- inhibited human recombinant acetylcholinesterase (reactivation) is altered by the occupation of the peripheral anionic site or some other secondary site for organophosphates.

描述（由申请人提供）：该项目的长期目标是提供信息，这些信息将有助于评估神经毒性有机磷杀虫剂对人类健康带来的风险。它试图通过研究初步观察来实现这一目标，这些观察表明，这些毒性杀虫剂如何抑制乙酰胆碱酯酶的当前观点不足以描述多种杀虫剂浓度的杀虫剂 - 酶相互作用。初步数据表明，某些有机磷酸盐抑制乙酰胆碱酯酶的能力随抑制剂浓度的函数而变化。此外，提出的证据表明，有机磷酸二氧氧气在抑制前会导致乙酰胆碱酯酶的短暂激活。总的来说，这些数据表明在人重组乙酰胆碱酯酶中存在二次结合位点，以用于某些有机磷酸盐。因此，该应用的总体假设是，有机磷酸盐及其母杀虫剂与人类重组乙酰胆碱酯酶在不同于催化三合会的地方结合，并且该部位的占用在活性部位改变了事件。由于这种结合，低暴露于某些有机磷杀虫剂可能会带来更大的健康风险，而使用较高的暴露水平基于剂量 - 反应关系估计的估计。本应用的具体目的如下：1）确定双分子抑制速率常数，以通过测试有机磷酸盐在较大范围的抑制剂浓度上抑制人重组乙酰胆碱酯酶的抑制； 2）确定测试有机磷酸盐及其母体是否可以通过人重组乙酰胆碱酯酶在抑制酶通过磷酸化之前通过人重组乙酰胆碱酯酶瞬时增强底物乙酰硫胆碱的水解； 3）确定测试有机磷酸盐及其相应的母杀虫剂是否与人重组乙酰胆碱酯酶上的外周阴离子位点结合； 4）确定有机磷酸盐抑制的人重组乙酰胆碱酯酶（重新激活）的去磷酸化速率是否会因占用外周阴离子位点还是其他一些有机磷酸盐的次要部位的变化。