Metabolism and Age-Related Organophosphate Toxicity

描述（由申请人提供）：有机磷（OP）杀虫剂，广泛用于农业和住宅，具有多种化学性质。有机磷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。青少年通常比成年人更容易受到OP杀虫剂的毒性影响。幼鱼对未成熟的生物外源性物质的解毒能力较低，导致其更易受到伤害。合乎逻辑的结论是，在成年人中容易解毒的化合物在青少年中的毒性水平将比不易解毒的化合物相对更高;换句话说，所谓“较安全”的杀虫剂（基于对成年人的低毒性水平）对婴儿和儿童的危险性相对大于“不安全”的杀虫剂。本申请的目的是确定幼年和成年大鼠暴露于一组代表性OP化合物后对毒性作用的相对脆弱程度，并描述解毒在这些脆弱性中的作用。假设是：在高接触水平下观察到的成年人对有机磷杀虫剂毒性的脆弱性较低，主要是由于其成熟的解毒系统更有效;对于对成年人毒性较小的化合物，传统上被认为“较安全”的那些这一假设来自我们的初步发现，即成人和青少年的急性毒性水平与几种保护性酯酶的水平和效率密切相关。我们计划通过调查以下两个具体目标来测试我们的假设：1。确定12个选择的OP化合物的关键解毒机制和目标酶的敏感性在开发过程中的体外效率;和2。确定这12种OP化合物的解毒机制对不同年龄段体内OP毒性水平的贡献。该项目将利用我们实验室合成的新型OP化合物，这些化合物具有独特的抑制效力和解毒潜力。该项目将研究肝脏和血液解毒机制（保护性酯酶：羧酸酯酶、非目标乙酰胆碱酯酶、丁酰胆碱酯酶、A-酯酶）的效率和目标酶（脑和外周乙酰胆碱酯酶）对每种试验化合物的敏感性。实验将在2个幼龄（1天和12天）和成年大鼠中进行。我们预期解毒效率将是化合物特异性的，这些保护性酯酶解毒OP的效率的测定将允许预测青少年毒性水平与成年人毒性水平的差异有多大，并且在更容易解毒的化合物中将存在更显著的年龄相关差异。这些结果将表明解毒对毒性水平的贡献，并将允许更准确地预测与年龄相关的毒性差异。

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.