CHOLINERGIC INSECTICIDE TOXICOLOGY

胆碱能杀虫剂毒理学

• 批准号: 6382209
• 负责人: JOHN E CASIDA
• 金额: $ 16万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6382209
• 关键词: affinity chromatography; analog; bungarotoxins; environmental toxicology; immunologic assay /test; insecticide biological effect; insecticides; laboratory mouse; laboratory rat; nicotine; nicotinic receptors; pharmacokinetics; plant insecticide; protein structure function; radiotracer; receptor binding; tissue /cell culture; toxicant screening

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.

描述：（根据调查人员的摘要进行了改编）目的是 定义有毒作用的机制和烟素的选择性 杀虫剂，从而确保其有效使用，并以最小的风险 人类和环境。 合成烟酸素是唯一主要的新的 过去40年的杀虫剂类别。 近来伊替夫拉普利（IMI） 已成为许多农作物的主要害虫防治剂和相关的 现在，残留物是人类的饮食污染物。 烟素 杀虫剂与尼古丁在其结构和作用中有关 烟碱乙酰胆碱受体（NACHR）和至少一个IMI 代谢物和几种候选杀虫剂类似于 毒性中的尼古丁（小鼠的LD50）。 第一个假设是NACHR 烟碱杀虫剂的结合位点特异性与受体有关 亚型，功能，神经元区和发育阶段。 专业 强调α4Beta2亚型和含α7的受体， 使用[H3]烟酸杀虫剂放射性物质与[H3]尼古丁和 [125i]在结合位点药理研究中的α-核毒素 剖面，抗体与大脑和培养细胞分离的抗体， 功能分析监视86RB+外排，结合位点分布 大脑通过放射自显影和开发过程中的变化利用培养 海马神经元。 第二个假设是代谢不稳定 烟素杀虫剂的生物活化有毒物质，例如 哺乳动物中的Desnitro-IMI。 目标是确定多大程度上 P450和含黄素的代谢激活和排毒 单加氧酶赋予烟素的选择性毒性，重点 在IMI上。 第三个假设是烟素杀虫剂的选择性 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。 优化了烟碱杀虫剂 探针将允许隔离（亲和力色谱）和光性 毒理学相关的NACHR（哺乳动物和昆虫）的放射性标记。 目标是定义绑定位点，以亚型，亚基，肽 序列并最终衍生化氨基酸。 这些多种方法 将建立哺乳动物中烟素选择性毒性的机制 昆虫。