MECHANISMS OF FURAN-INDUCED TOXICITY AND CARCINOGENICITY

描述：呋喃是一类化合物的母体化合物， 有毒或致癌。它是一种重要的工业化合物， 存在于环境中。呋喃的广泛存在和意义重大 人体接触的可能性需要进行毒理学研究 这种化合物的性质。呋喃本身是有毒和致癌的， 小鼠和大鼠。它被归类为非遗传毒性致癌物。呋喃 被认为被活化为反应性中间体顺式-2-丁烯-1，4-二醛， 烷基化蛋白质导致毒性反应。由此产生的慢性毒性 刺激细胞复制，增加肿瘤的可能性 生产而顺-2-丁烯-1，4-二醛已被鉴定为微粒体 呋喃代谢物，顺式-2-丁烯-1，4-二醛在毒性中的确切作用 呋喃的致癌特性尚不清楚。的机械作用 呋喃介导的毒性和/或致癌性中的蛋白质烷基化也 仍有待确定。此外，虽然人们普遍认为， 呋喃是一种非遗传毒性致癌物，有数据支持至少一个 小鼠遗传毒性机制的部分作用。DNA损伤在 尚未对呋喃诱发的癌症进行研究。这些知识差距是 重要的问题，因为他们阻止了更好地了解呋喃和 相关化合物诱导它们的毒性和致癌作用。 长期目标是了解含呋喃的 化合物导致其毒性和致癌作用。的目的 具体的应用是确定顺式-2-丁烯-1，4-二醛在 呋喃的毒性和致癌活性。核心假设是， 顺式-2-丁烯-1，4-二醛是代谢过程中形成的最终活性物质 呋喃的活化以及该代谢产物与蛋白质和DNA的反应 目标启动呋喃的毒性和致癌作用。PI计划 测试中心假设，并实现这一总体目标 通过追求以下具体目标来实施。1)描述 呋喃的体内代谢物，2）表征由以下产生的蛋白质加合物： 呋喃暴露; 3）表征由呋喃暴露引起的DNA损伤。 拟议的研究预计将产生以下成果：首先， PI将确定顺式-2-丁烯-1，4-二醛对整体的重要性， 呋喃的体内代谢。其次，PI将对呋喃进行化学表征 蛋白质加合物。这些研究将揭示的化学结构的 最终的蛋白质烷基化代谢物。第三，PI将识别类型 呋喃暴露引起的DNA损伤，这样他们就可以评估 的DNA反应与呋喃观察到的不良反应。统称 拟议的研究将确定最终的反应物种形成的过程中， 呋喃代谢这些研究将为确定 引发毒性和致癌效应的关键事件 的呋喃。他们还将帮助了解“非基因毒性”化合物如何发挥作用， 对DNA功能的影响

DESCRIPTION: Furan is the parent compound for a class of compounds that are toxic or carcinogenic. It is an important industrial compound that is also present in the environment. The widespread occurrence of furan and significant potential for human exposure warrant investigation into the toxicological properties of this compound. Furan, itself, is both toxic and carcinogenic in mice and rats. It has been classified as a nongenotoxic carcinogen. Furan is thought to be activated to a reactive intermediate, cis-2-butene-1,4-dial that alkylates proteins leading to a toxic response. The resulting chronic toxicity stimulates cell replication, which increases the likelihood of tumor production. While cis-2-butene-1,4-dial has been identified as a microsomal metabolite for furan, the precise role of cis-2-butene-1,4-dial in the toxic and carcinogenic properties of furan is not known. The mechanistic role of protein alkylation in furan-mediated toxicity and/or carcinogenicity also remains to be determined. Furthermore, while it is generally accepted that furan is a nongenotoxic carcinogen, there are data that support at least a partial role for a genotoxic mechanism in mice. The role of DNA damage in furan-induced cancer has not been investigated. These knowledge gaps are important problems because they prevent a better understanding of how furan and related compounds induce their toxic and carcinogenic effects. The long range goal is to understand the mechanism by which furan-containing compounds cause their toxic and carcinogenic effects. The objective of this particular application is to determine the role of cis-2-butene-1,4-dial in the toxic and carcinogenic activities of furan. The central hypothesis is that cis-2-butene-1,4-dial is the ultimate reactive species formed during metabolic activation of furan and the reaction of this metabolite with protein and DNA targets initiates the toxic and carcinogenic effects of furan. The PI plans to test the central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims. 1) Characterize the in vivo metabolites of furan, 2) Characterize the protein adducts resulting from furan exposure; 3) Characterize the DNA damage resulting from furan exposure. The proposed studies are expected to yield the following outcomes: first, the PI will determine the importance of cis-2-butene-1,4-dial to the overall in vivo metabolism of furan. Second, the PI will chemically characterize furan protein adducts. These studies will reveal the chemical structure of the ultimate protein alkylating metabolite. Third, the PI will identify the types of DNA damage caused by furan exposure so that they can evaluate the importance of DNA reactions to the adverse effects observed with furan. Collectively, the proposed studies will identify the ultimate reactive species formed during furan metabolism. These studies will set the stage for the determination of the critical events responsible for triggering the toxic and carcinogenic effects of furan. They will also help understand how "nongenotoxic" compounds exert their effects on DNA function.