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：（改编自研究者摘要）目的是 确定烟碱类的毒性作用和选择性机制 杀虫剂，从而确保其有效使用， 人类和环境。 合成类尼古丁是唯一的主要新的 这是过去40年来的第一批杀虫剂。 最近，吡虫啉（IMI） 已成为许多作物的主要害虫控制剂， 残留物现在是人类的饮食污染物。 尼古丁 杀虫剂的结构和作用与尼古丁有关， 烟碱乙酰胆碱受体（nAChR）和IMI中的至少一种 代谢物和几种候选杀虫剂类似于 尼古丁毒性（小鼠LD 50）。 第一个假设是nAChR 烟碱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。 主要 α 4 β 2亚型和含α 7的受体被强调， 使用[H3]烟碱类杀虫剂放射性配体对比[H3]烟碱， [125 I] α-银环蛇毒素结合位点药理学研究 从大脑和培养细胞中分离亚基的抗体， 功能测定监测86 Rb+外排，结合位点分布， 脑放射自显影和发育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性 烟碱类杀虫剂导致生物活化毒物， 哺乳动物中的去硝基-IMI。 我们的目标是确定 P450和含黄素的代谢活化和解毒 单加氧酶在类烟碱中赋予选择性毒性， 关于IMI 第三个假设是烟碱类杀虫剂的选择性 这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位点。 优化的烟碱类杀虫剂 探针将允许分离（亲和层析）和光亲和 毒理学相关nAChR（哺乳动物和昆虫）的放射性标记。 我们的目标将是确定结合位点的亚型，亚基，肽 测序并最终进行氨基酸衍生。 这些多重方法 将建立类尼古丁在哺乳动物中的选择性毒性机制， 昆虫