PROMOTION BY INDOLE-3-CARBINOL AND AH RECEPTOR AGONISTS

Indole-3-Carbinol 和 AH 受体激动剂的促进作用

• 批准号: 6106188
• 负责人: David Collin Williams
• 金额: $ 23.69万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6106188
• 关键词: aflatoxins; alternatives to animals in research; animal genetic material tag; antineoplastics; aromatic hydrocarbon receptor; dosage; drug screening /evaluation; gene expression; genetic library; halobiphenyl /halotriphenyl compound; immunocytochemistry; laboratory mouse; laboratory rabbit; mitogens; neoplastic process; nutrition related neoplasm /cancer; nutrition related tag; oncoprotein p21; plant extracts; receptor binding; stimulant /agonist; trout /salmon; tumor promoters

Indole 3-carbinol (I3C), a major constituent of cruciferous vegetables, has been shown to be an effective inhibitor of tumor initiation in a number of animal models, including trout. The potential for I3C to inhibit cancer in humans is currently under clinical trial. Potential concerns about I3C have been raised, however, by the finding (originally from our work in the trout model) that post-initiation exposure results in tumor promotion. To accurately predict efficacy and safety of I3C in humans, more knowledge about its potency and mechanism of action as a promoter are needed. In addition, it is important to understand the role of cell proliferation, oxidative stress and expression of oncogenes during promotion in the trout model. This study will address this issue by pursuing answers to the following questions: 1) How does dietary I3C shift the carcinogen dose-response curve and how does the potency of I3C as a promoter compare to its potency as an inhibitor? These studies will involve feeding 6 different levels of I3C to trout initiated with 4 different levels of aflatoxin B1; 2) Does I3C derive its promotional properties from the binding of acid condensation products to the Ah receptor? If so, the efficacy of Ah receptor binding of the various I3C derivatives should correlate with promotional potency, promotion should be subject to inhibition by Ah receptor antagonists, and sensitivity to I3C promotion should segregate with the Ah locus in congenic mice; 3) Does I3C and other promoters selectively alter the expression of cells containing different mutated p21 proteins?; 4) What are the properties of the Ah receptor in trout and what is the cellular localization of the Ah receptor in liver? Does the cellular localization of the receptor correlate with target cells for promotion and with precursors of transformed cells?; and 5) Does I3C have other mechanisms of promotion? We will examine the properties of I3C as a mitogen and compare the ability of various promoters including I3C to enhance cellular proliferation and/or oxidatively damage DNA. A knowledge of the mechanism(s) of action of I3C as a promoter are essential in order provide a foundation for predicting the risk versus benefits of this tumor modulator in humans.

吲哚3-甲醇（I3C），是十字花科蔬菜的主要成分， 已被证明是A中肿瘤起始的有效抑制剂 动物模型的数量，包括鳟鱼。 I3C的潜力 目前，人类抑制癌症正在接受临床试验。 潜在的 但是，该发现提出了对I3C的担忧（最初 从我们在鳟鱼模型中的工作），发出后的暴露结果 在肿瘤促进中。 准确预测I3C的功效和安全性 人类，更多关于其效力和行动机制的知识 需要发起人。 此外，重要的是要了解 细胞增殖，氧化应激和癌基因表达的作用 在鳟鱼模型中促销期间。 这项研究将解决这个问题 通过追求以下问题的答案：1）饮食I3C如何 移动致癌剂量响应曲线以及I3C的效力如何 作为启动子与抑制剂的效力相比？ 这些研究 将涉及将6个不同级别的I3C喂食到4 不同水平的黄曲霉毒素B1； 2）I3C是否获得促销 酸凝结产物与AH的结合的特性 受体？ 如果是这样，各种I3C的AH受体结合的功效 导数应与促销效力相关，促销应 受受体拮抗剂的抑制作用，并对 i3c促销应与同类小鼠的AH基因座分隔； 3） I3C和其他启动子是否有选择地改变细胞的表达 包含不同的突变P21蛋白？ 4）属性是什么 鳟鱼中的AH受体的细胞定位是什么 AH肝脏中的受体？ 受体的细胞定位是否 与目标细胞相关，以促进和 转化的细胞？ 5）I3C是否还有其他促进机制？ 我们将研究I3C作为有丝分裂原的特性，并比较 包括I3C在内的各种启动子的能力增强细胞 增殖和/或氧化损伤DNA。 对 I3C作为启动子的作用机制至关重要 为预测风险与利益提供了基础 人类的肿瘤调节剂。