CONJUGATES OF ISOTHIOCYANATES AS CHEMOPREVENTIVE AGENTS

作为化学预防剂的异硫氰酸酯缀合物

• 批准号: 6295912
• 负责人: FUNG-LUNG CHUNG
• 金额: $ 24.34万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-05 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6295912
• 关键词: benzopyrenes; biotransformation; blood chemistry; cancer prevention; carcinogenesis inhibitor; chemical carcinogen; chemical conjugate; chemoprevention; clinical research; cytochrome P450; drug metabolism; enzyme inhibitors; high performance liquid chromatography; human subject; isothiocyanates; laboratory mouse; laboratory rat; lung neoplasms; nitrosamines; pharmacokinetics; statistics /biometry; tobacco abuse; toxin metabolism; transferase; urinalysis

Isothiocyanates are effective and versatile chemopreventative agents in many animal models due to their ability to inhibit metabolic activation of carcinogens and/or induce phase II enzymes for detoxification. Studies have recently shown that, like the parent compounds, the thiol conjugates of isothiocyanates inhibited cytochrome P450 enzymes and induced glutathione transferases, and are inhibitory against the A/J mouse lung tumorigenesis induced by tobacco nitrosamine 4-(methylnitrosamino)-1(3- pyridyl)-1 butanone. These findings are interesting because thiol conjugation constitutes a major metabolic route to detoxify isothiocyanates via the mercapturic acid pathway. These results not only reveal how isothiocyanates may work as inhibitors in vivo, they also suggest that the less toxic conjugates may be promising candidates to place isothiocyanates as chemopreventative agents. Our main hypothesis is that the thiol conjugates, as a transport form, serves as a depot of isothiocyanate which slowly releases the parent compound and thiol via a dissociation mechanism. The purpose of this application is to explore the potential of the thiol conjugates as chemopreventative agents in lung tumorigenesis by carrying out the following studies: Aim 1, we will study the role of conjugate dissociation in cytochrome P450 enzyme inhibition; Aim 2, we will determine the tissue distribution, in vivo metabolism, and toxicity of the conjugates; Aim 3, we will examine the effects of isothiocyanates and conjugates on lung tumorigenesis induced by tobacco carcinogens; Aim 4, we will compare the metabolism of the conjugates and their parent compounds in rodents and humans.

异硫氰酸盐是有效且通用的化学预防剂 许多动物模型由于它们能够抑制代谢激活 致癌物和/或诱导 II 相酶进行解毒。研究 最近表明，与母体化合物一样，硫醇缀合物 异硫氰酸盐抑制细胞色素 P450 酶并诱导 谷胱甘肽转移酶，对 A/J 小鼠肺有抑制作用 烟草亚硝胺4-(甲基亚硝胺)-1(3-)诱导肿瘤发生 吡啶基)-1丁酮。这些发现很有趣，因为硫醇 结合构成解毒的主要代谢途径 通过硫醇酸途径产生异硫氰酸盐。这些成果不仅 揭示异硫氰酸盐如何在体内作为抑制剂发挥作用，它们还 表明毒性较小的缀合物可能是有前途的候选物 将异硫氰酸盐作为化学预防剂。我们的主要假设是 硫醇结合物作为一种运输形式，充当 异硫氰酸酯通过缓慢释放母体化合物和硫醇 解离机制。该应用程序的目的是探索 硫醇缀合物作为肺部化学预防剂的潜力 通过进行以下研究来确定肿瘤发生：目标1，我们将研究 缀合物解离在细胞色素 P450 酶抑制中的作用； 目标 2，我们将确定组织分布、体内代谢以及 缀合物的毒性；目标 3，我们将检查以下效果： 异硫氰酸盐及其结合物对烟草诱导的肺肿瘤发生的影响 致癌物质；目标 4，我们将比较缀合物的代谢和 它们的母体化合物存在于啮齿动物和人类体内。