PROMOTION BY INDOLE-3-CARBINOL AND AH RECEPTOR AGONISTS

吲哚-3-甲醇（I3 C）是十字花科蔬菜的主要成分， 已经显示出是一种有效的肿瘤起始抑制剂， 一些动物模型，包括鳟鱼。 I3 C的潜力， 目前正在进行临床试验。 潜在 然而，这一发现（最初是）引起了人们对I3 C的担忧。 从我们在鳟鱼模型中的工作）， 在肿瘤促进中。 准确预测I3 C在以下患者中的疗效和安全性： 人类，更多地了解其效力和作用机制， 促进者是必要的。 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 在鳟鱼模型中进行推广。 本研究将解决这一问题 通过寻求以下问题的答案：1）饮食中的I3 C如何 改变致癌物剂量反应曲线，I3 C的效力如何 作为一种促进剂和作为一种抑制剂的效力相比呢？ 这些研究 将涉及喂养6个不同水平的I3 C鳟鱼开始与4 不同水平的黄曲霉毒素B1; 2）I3 C是否源于其促进 酸缩合产物与Ah的结合性质 受体？ 如果是这样的话，各种I3 C的Ah受体结合的功效 衍生物应与促销效力相关，促销应 受到Ah受体拮抗剂的抑制，并且对 在同种小鼠中，I3 C的促进作用应与Ah位点分离; 3） I3 C和其他启动子是否选择性地改变细胞的表达 含有不同的突变p21蛋白？4)有哪些属性 的Ah受体在鳟鱼和什么是细胞定位的 肝脏中的AH受体？ 受体的细胞定位 与促进的靶细胞和与 转化细胞？5）I3 C是否有其他促进机制？ 我们将研究I3 C作为有丝分裂原的性质，并比较I3 C与细胞分裂原的差异。 包括I3 C在内的各种启动子增强细胞增殖的能力 增殖和/或氧化损伤DNA。 的知识 I3 C作为启动子的作用机制是必要的 为预测这一风险与收益提供了基础 肿瘤调节剂。

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.