CHOLINERGIC INSECTICIDE TOXICOLOGY

描述：(改编自《调查员摘要》)目标是 确定尼古丁的毒性作用和选择性的机制 杀虫剂，从而确保其有效使用，并将风险降至最低 人类和环境。合成尼古丁是唯一一种主要的新 过去40年的杀虫剂类别。最新吡虫啉(IMI) 已成为许多农作物的主要害虫防治剂和相关的 残留物现在是人类的一种饮食污染物。尼古丁 杀虫剂在结构和作用上与尼古丁有关。 烟碱型乙酰胆碱受体(NAChR)和至少一种IMI 代谢物和几种候选杀虫剂类似于 尼古丁毒性(小鼠半数致死量)。第一个假设是nAChR 尼古丁类杀虫剂的结合位点特异性与受体有关 亚型、功能、神经元区域和发育阶段。少校 重点介绍了α4β2亚型和含有α7的受体， 使用[H3]尼古丁类杀虫剂放射性配体与[H3]尼古丁和 [125I]α-银环蛇毒素在药理结合部位研究中的应用 从大脑和培养的细胞中分离出亚单位的抗体， 监测86Rb+外流、结合部位分布的功能分析 脑放射自显影及其在发育过程中的变化 海马神经元。第二个假设是新陈代谢的不稳定性 尼古丁类杀虫剂会导致生物活性毒物，如 哺乳动物中的去硝基-IMI。目标是确定在多大程度上 P450和含黄素的代谢活化与解毒作用 强调单加氧酶在尼古丁类化合物中的选择性毒性 在IMI上。第三个假设是尼古丁类杀虫剂的选择性 在很大程度上取决于神经元nAChR的主要结构差异 哺乳动物和昆虫的结合部位。优化的烟碱类杀虫剂 探针将允许分离(亲和层析)和光亲和 与毒理相关的nAChRs(哺乳动物和昆虫)的放射性标记。 目标是将结合部位定义为亚型、亚单位、多肽 序列和最终氨基酸衍生化。这些多个方法 将建立尼古丁对哺乳动物的选择性毒性机制，并 昆虫。

DESCRIPTION: (Adapted from the Investigator's Abstract) The objective is to define the mechanisms of toxic action and selectivity for nicotinoid insecticides and thereby insure their effective use with minimal risk to humans and the environment. Synthetic nicotinoids are the only major new class of insecticides of the past 4 decades. Recently imidacloprid (IMI) has become the main pest control agent for many crops and the associated residues are now a dietary contaminant for humans. The nicotinoid insecticides are related to nicotine in their structure and action at the nicotinic acetylcholine receptor (nAChR) and at least one of the IMI metabolites and several of the candidate insecticides are similar to nicotine in toxicity (LD50 in mice). The first hypothesis is that the nAChR binding-site specificity for nicotinoid insecticides is related to receptor subtype, function, neuronal region, and developmental stage. The major alpha4beta2 subtype and the alpha7-containing receptors are emphasized, using [H3]nicotinoid insecticide radioligands versus [H3]nicotine and [125I]alpha-bungarotoxin in studies of binding site pharmacological profiles, antibodies to isolate subunits from brain and cultured cells, functional assays monitoring 86Rb+ efflux, binding site distribution in brain by autoradiography and changes during development utilizing cultured hippocampal neurons. The second hypothesis is that the metabolic lability of the nicotinoid insecticides leads to bioactivated toxicants such as desnitro-IMI in mammals. The goal is to determine the extent to which metabolic activation and detoxification by P450s and flavin-containing monooxygenases confer selective toxicity among the nicotinoids with emphasis on IMI. The third hypothesis is that nicotinoid insecticide selectivity depends in large part on major structural differences in the neuronal nAChR binding sites of mammals and insects. Optimized nicotinoid insecticide probes will allow isolation (affinity chromatography) and photoaffinity radiolabeling of the toxicologically relevant nAChRs (mammal and insect). The goal will be to define the binding site as to subtype, subunit, peptide sequence and ultimately amino acid derivatized. These multiple approaches will establish mechanisms for nicotinoid selective toxicity in mammals and insects.