Metabolism and Age-Related Organophosphate Toxicity

代谢和与年龄相关的有机磷毒性

• 批准号: 6768811
• 负责人: Janice Elaine Chambers
• 金额: $ 25.03万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6768811
• 关键词: acetylcholinesterase; active sites; age difference; blood brain barrier; blood chemistry; carboxylic ester hydrolases; cholinesterases; cytochrome P450; detoxification; drug metabolism; environmental toxicology; enzyme inhibitors; esterase; juvenile animal; laboratory rat; liver metabolism; mature animal; organophosphorus insecticide; phenothiazines; tissue /cell culture

DESCRIPTION (provided by applicant): Organophosphorus (OP) insecticides, extensively used agriculturally and residentially, display a variety of chemistries. OP insecticides demonstrate a wide range of acute toxicity levels, which are largely dependent on the compound-specific efficiencies of detoxication. Juveniles are typically more vulnerable than adults to the toxic effects of OP insecticides. The low immature xenobiotic detoxication capacity of juveniles contributes to their enhanced vulnerability. It is logical to conclude that compounds, which are readily detoxified in adults, will display relatively higher toxicity levels in juveniles than compounds, which are not readily detoxified; in other words, the so-called "safer" insecticides (based on low toxicity levels in adults) are of relatively more danger to infants and children than are the "unsafe" insecticides. The objective of this application is to determine the relative degree of vulnerability to toxic effects following exposures to a representative group of OP compounds in juvenile and adult rats, and to characterize the role of detoxication in these vulnerabilities. The hypothesis is: The lower vulnerability of adults to the toxicity of OP insecticides observed at high exposure levels is primarily the result of (he greater effectiveness of their mature detoxication systems; the age-related differences in vulnerability to individual OP compounds will be greater for the compounds which are less toxic to adults, i.e., those traditionally viewed as "safer" This hypothesis was derived from our preliminary findings that acute toxicity levels in both adults and juveniles are strongly related to the levels and the efficiency of several protective esterases. We plan to test our hypothesis by investigating the following two specific aims: 1. Determine for 12 select OP compounds the in vitro efficiency of critical detoxication mechanisms and of target enzyme sensitivity during development; and 2. Determine for these 12 OP compounds the contribution of detoxication mechanisms to the in vivo OP toxicity levels among ages. The project will utilize novel OP compounds synthesized in our laboratories, which demonstrate unique characteristics 0 inhibitory potency plus detoxication potential. The project will investigate the efficiency of hepatic and blood detoxication mechanisms (the protective esterases: carboxylesterases, non-target acetylcholinesterase, butyrylcholinesterase, A-esterase) and target enzyme (brain and peripheral acetylcholinesterase) sensitivity for each test compound. Experiments will be conducted in rats of 2 juvenile ages (1 and 12 days) and adults. We expect that detoxication efficiencies will be compound-specific, that the determination of the efficiencies of these protective esterases to detoxify the OP's will allow a prediction of how greatly the juvenile toxicity levels will differ from those of adults, and that there will be more dramatic age-related differences in compounds which are more readily detoxified. These results will indicate the contribution of detoxication to toxicity level, and will allow more accurate predictions of age-related differences in toxicity.

描述（由申请人提供）：在农业和生活中广泛使用的有机磷（OP）杀虫剂显示各种化学物质。 OP杀虫剂表现出广泛的急性毒性水平，这在很大程度上取决于化合物的解毒效率。少年通常比成年人更容易受到OP杀虫剂的毒性作用。未成熟的少年未成熟的异种解毒能力有助于增强其脆弱性。可以得出结论，在成年人中很容易排毒的化合物在少年中的毒性水平比不容易被解毒的化合物表现出相对较高的毒性水平。换句话说，所谓的“更安全”杀虫剂（基于成年人的毒性水平低）对婴儿和儿童的危险性比“不安全”的杀虫剂的危险相对较大。该应用的目的是确定在少年和成年大鼠中向代表性的OP化合物群体暴露后对毒性作用的相对程度，并表征解毒在这些脆弱性中的作用。假设是：成年人对在高暴露水平下观察到的OP杀虫剂毒性的较低脆弱性主要是（他成熟的解毒系统的更大有效性；与年龄相关的单个OP化合物的年龄相关差异将更大对成年人的毒性较小的化合物，即传统上被视为“更安全”的假设，是我们的初步发现，即成人和少年的急性毒性水平与几种保护性酯的水平和效率密切相关计划通过研究以下两个特定目的来检验我们的假设：1。确定12种OP化合物的体外临界解毒机制的体外效率和开发过程中的靶酶敏感性。年龄之间的体内OP毒性水平的机制将利用我们实验室中合成的新型OP化合物，该化合物表现出独特的特征0抑制效力和解毒潜力。该项目将研究肝和血液解毒机制（保护性酯酶：羧酸酯酶，非目标乙酰胆碱酯酶，丁乙酸酯酶，A-酯酶）和靶酶（脑和外围乙酰胆碱酯酶）对每种测试化合物的敏感性。实验将在2个少年年龄（1和12天）和成人的大鼠中进行。我们预计解毒效率将是特定于复合的，确定这些保护性酯酶对OP的排毒效率的确定将允许预测少年毒性水平与成年人的毒性水平有多大不同，并且会有更大的戏剧性。更容易排毒的化合物中与年龄相关的差异。这些结果将表明解毒对毒性水平的贡献，并可以更准确地预测与年龄相关的毒性差异。