TOXICOLOGICAL SIGNIFICANCE OF PESTICIDE METABOLISM

本建议的总体目标是提供信息， 这将有助于确定 个体可能异常敏感（或抵抗） 农药的毒性作用。 该项目将侧重于 有机磷杀虫剂，因为它们代表了 作为杀虫剂使用的化学物质，因为它们具有潜在的 对人体有严重的毒性作用。 研究将被导向 来描述那些影响哺乳动物 有机磷杀虫剂的生物转化反应，如 以及这些反应的后果。 预计在 这些研究将提供有用的信息， 有机磷杀虫剂对健康的危害， 可能与某些其他外来物质发生毒性相互作用 化学品 此外，这项研究将有助于 这些代谢系统的基本知识， 这些杀虫剂的生物转化 具体目标是 本研究的主要内容如下：1）继续调查 肝外激活的毒理学意义 有机硫磷杀虫剂2)调查为什么 谷胱甘肽依赖的解毒许多 二甲基取代的有机磷杀虫剂在体外 但不是在体内。3)确定和描述 影响肝脏和血清A-酯酶活性。 纳入本 目的将是动力学和物理化学的研究 “高活性”和“低活性”形式之间的差异 人血清A-酯酶。4)从生物化学的角度来描述 从小鼠肝微粒体中纯化的A-酯酶的形式， 实验室5)为了表征影响分泌的因素， 来自肝脏的A-酯酶。 这些研究还将侧重于 A-酯酶的分泌形式与那些 在肝微粒体中发现的形式。

The overall objective of this proposal is to provide information which will aid in the identification of conditions in which individuals might be unusually susceptible (or resistant) to the toxic actions of pesticides. The project will focus on the organophosphorus insecticides since they represent the major class of chemicals used as insecticides, and since they have potential for serious toxic effects in humans. Research will be directed towards characterizing those factors which affect the mammalian biotransformation reactions of organophosphorus insecticides, as well as the consequences of such reactions. It is expected that these studies will provide information useful in assessing the health hazards of organophosphorus insecticides, as well as their potential for toxic interactions with certain other foreign chemicals. Additionally this proposed research will contribute to the fundamental knowledge of those metabolic systems involved in the biotransformation of these insecticides. The specific aims in this research are as follows: 1) To continue to investigate the toxicological significance of extrahepatic activation of certain organothiophosphorus insecticides. 2) To investigate why glutathione-dependent detoxification of numerous dimethyl-substituted organophosphorus insecticides occurs in vitro but not in vivo. 3) To identify and characterize factors which affect hepatic and serum A-esterase activities. Included in this aim will be the investigation of kinetic and physiochemical differences between "high activity" and "low activity" forms of human serum A-esterase. 4) To characterize biochemically the two forms of A-esterase purified from mouse hepatic microsomes in this laboratory. 5) To characterize the factors affecting secretion of A-esterase(s) from liver. These studies will also focus on comparisons of the secreted form(s) of A-esterase(s) with those forms found in hepatic microsomes.