MECHANISMS OF FURAN-INDUCED TOXICITY AND CARCINOGENICITY

描述：呋喃是一类化合物的母体化合物， 有毒的或致癌的。它是一种重要的工业大院，也是 存在于环境中。呋喃的广泛存在和重大意义 对人类接触的可能性进行毒理学调查 这种化合物的性质。呋喃本身就是有毒和致癌的 老鼠和老鼠。它已被归类为非遗传毒性致癌物。呋喃是 被认为被激活为活性中间体，顺-2-丁烯-1，4-拨号 使蛋白质烷基化，导致毒性反应。由此产生的慢性毒性 刺激细胞复制，从而增加患肿瘤的可能性 制作。而顺-2-丁烯-1，4-Dial已被鉴定为微生物体 代谢产物呋喃、顺-2-丁烯-1，4-二烯的确切毒性作用 呋喃的致癌特性尚不清楚。的机械性作用 呋喃介导的毒性和/或致癌性中的蛋白质烷基化 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质，有数据支持至少 对小鼠的遗传毒性机制的部分作用。DNA损伤在人类免疫缺陷中的作用 呋喃诱发的癌症尚未得到研究。这些知识差距是 重要的问题，因为它们阻碍了人们更好地理解呋喃和 相关化合物具有毒性和致癌作用。 长期目标是了解含有呋喃的 化合物具有毒性和致癌作用。这样做的目的是 具体的应用是确定顺-2-丁烯-1，4-Dial在 呋喃的毒性和致癌活性。中心假设是 顺式-2-丁烯-1，4-二烯是代谢过程中形成的终极活性物种 呋喃的活化及其代谢产物与蛋白质和DNA的反应 靶标引发呋喃的毒性和致癌作用。私家侦探计划 检验中心假设并实现总体目标 通过追求以下具体目标来申请。1)描述In 呋喃的体内代谢物，2)表征由呋喃产生的蛋白质加合物 呋喃暴露；3)表征呋喃暴露造成的DNA损伤。 预计拟议的研究将产生以下结果：第一， PI将决定顺式-2-丁烯-1，4-拨号在整体中的重要性 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。这些研究将揭示该化合物的化学结构 最终的蛋白质烷基化代谢物。第三，PI将确定类型 呋喃接触造成的DNA损伤，这样他们就可以评估 对观察到的呋喃不良反应的DNA反应。总体而言， 拟议的研究将确定最终形成的反应物种 呋喃新陈代谢。这些研究将为确定 引发毒性和致癌效应的关键事件 呋喃。他们还将帮助理解“非遗传毒性”化合物如何发挥作用。 它们对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.