PRODUCTION AND FATE OF HYDROXAMIC ACIDS IN HEPATOCYTES

本节目的目的是阐明某些生化过程。 与芳香胺和亚硝基芳香族化合物的毒性有关 化合物。作为一个基团，芳香胺构成了人类最多的 重要的工业化学品。它们被广泛用作杀虫剂 现代农业实践继续增加，但对 它们在生物体中的生物学命运和影响是非常不完整的。 由于许多芳香胺和相关化学物质是已知的致癌物质，它 有必要对这些化学物质的新陈代谢有详细的了解 在高等动物中是可以达到的。该计划将研究在多大程度上 模型芳香胺被代谢成异羟肟酸，因为异羟肟酸 众所周知，芳香胺的毒性很大程度上是由酸引起的。 该计划将研究转化亚硝基的生化过程。 芳香族化合物到具有不寻常N-酰基的异羟肟酸。 产生这种异羟肟酸的特定生化途径 由亚硝基芳香化合物与一种 依赖硫胺素的酶。另一种简单但非酶促的反应 引起N-甲酰型异羟肟酸的生成是反应 亚硝基芳香族化合物与乙醛酸的反应。原代肝细胞培养 从老鼠准备的将是这些研究将在其中的主要系统 进行原代肝细胞培养，尽管出于比较目的 叙利亚仓鼠也将被使用。这一计划的结果将是 提供有价值的数据，以帮助设计措施，将人类的 暴露在潜在的遗传毒性化学物质中或受到其损害。

The purpose of this program is to elucidate certain biochemical processes that are involved in the toxicity of aromatic amines and nitroso aromatic compounds. As a group the aromatic amines comprise some of mankind's most important industrial chemicals. Their extensive use as pesticides in modern agricultural practice continues to increase, yet a knowledge of their biological fate and effects in living organisms is very incomplete. Since many aromatic amines and related chemicals are known carcinogens, it is necessary that a detailed knowledge of the metabolism of these chemicals in higher animals be attained. This program will study the extent to which model aromatic amines are metabolized to hydroxamic acids, since hydroxamic acids are known to account for much of the toxicity of aromatic amines. The program will examine the biochemical processes that convert nitroso aromatic compounds to hydroxamic acids possessing unusual N-acyl groups. The specific biochemical pathways responsible for such hydroxamic acids arise from the interaction of a nitroso aromatic compound with a thiamine-dependent enzyme. Another facile, but non-enzymatic reaction that causes the production of the N-formyl type hydroxamic acids is the reaction of a nitroso aromatic with glyoxylic acid. Primary hepatocyte cultures prepared from rats will be the principal system in which these studies will be conducted, although for comparative purposes primary hepatocyte cultures for syrian hamsters will also be used. The results of this program will provide valuable data to help design measures to minimize mankind's exposure to or damage from potentially genotoxic chemicals.