3,4-DICHLOROANILINE NEPHROTOXICITY

描述：(改编自《调查者摘要》) 3，4-二氯苯胺是一种芳香胺，是生产中的一种成分 在美国广泛使用的几种除草剂中，3，4-二氯苯胺是 在世界各地的土壤、地下水和淡水湖中都可以检测到。 本项目的目标是研究黄曲霉毒素的肾脏毒性。 3，4-二氯苯胺。拟议的研究将检验以下假设： A)3，4-二氯苯胺肾毒性也是由母体化合物引起的 作为其代谢物，b)3，4二氯苯胺及其主要代谢物为 对肾皮质有直接毒性，c)3，4二氯苯胺可降低肾脏 谷胱甘肽水平和d)谷胱甘肽在毒性顺序中是必需的。 这个项目将确定两个主要的潜在的肾脏毒性 3，4-二氯苯胺的代谢物：3，4-二氯苯羟胺 (3，4CPHA)和2-氨基-4，5-二氯酚(2A4，5CP)。毒性将是 F344大鼠体内给药后的肾脏监测 体重、尿素氮、尿液剖面与肾皮质积聚的关系 离子。体外毒性将通过直接接触肾脏来确定。 大脑皮层切片到母体化合物和主要代谢物。中的毒性 将通过直接或间接测量细胞酶来监测体外培养 活动。肾组织谷胱甘肽水平将在体内和 3，4-二氯苯胺和3，4-二氯苯胺的体外暴露 二氯苯羟胺和2-氨基-4，5-二氯苯酚。数据 由这一领域提供的赠款将提供一个知识基础，将 3，4-二氯苯胺和2，4-二氯苯胺的潜在肾毒性首次表征 主要代谢物。这些结果将开始为 关于3，4-二氯苯胺细胞机理的信息 毒性。这些发现还将评估谷胱甘肽是否参与其中 作为生成反应性成分的解毒途径。

DESCRIPTION: (Adapted from the Investigator's Abstract) 3,4-Dichloroaniline, an aromatic amine, is an ingredient in the production of several herbicides widely used in the U.S. 3, 4-Dichloroaniline is detectable in soil, groundwater and fresh water lakes throughout the world. The goal of this project is to investigate the renal toxicity of 3,4-dichloroaniline. The proposed studies will test the hypothesis that: a) 3,4-dichloroaniline nephrotoxicity is due to the parent compound as well as its metabolites, b) 3,4 dichloroaniline and its major metabolites are directly toxic to the renal cortex, c) 3,4 dichloroaniline decreases renal glutathione levels and d) glutathione is needed in the sequence of toxicity. This project will establish the potential renal toxicity for two major metabolites of 3,4-dichloroaniline: 3,4-dichlorophenylhydroxylamine (3,4CPHA) and 2-amino-4,5-dichlorophenol (2A4,5CP). Toxicity will be evaluated following in vivo administration to F344 rats by monitoring kidney weight, BUN, urine profile and renal cortical slice accumulation of organic ions. In vitro toxicity will be determined by direct exposure of renal cortical slices to the parent compound and major metabolites. Toxicity in vitro will be monitored by direct or indirect measurement of cellular enzyme activity. Renal glutathione levels will be measured following in vivo and in vitro exposure to 3,4-dichloroaniline as well as 3,4 dichlorophenylhydroxylamine and 2-amino-4,5-dichlorophenol. The data provided by this AREA grant will provide a foundation of knowledge that will first characterize the potential nephrotoxicity of 3,4-dichloroaniline and 2 major metabolites. These results will then begin a foundation of information regarding the cellular mechanism of 3,4 dichloroaniline toxicity. These findings will also evaluate whether glutathione is involved as a detoxification pathway of in generation of a reactive component.