NATURAL & SYNTHETIC COUMARINS AS ANTICARCINOGENIC AGENTS

自然的

• 批准号: 2719572
• 负责人: John DiGiovanni
• 金额: $ 19.39万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2719572
• 关键词: adduct; alpha benzopyrone; antineoplastics; benzopyrenes; cancer risk; carbopolycyclic compound; carcinogenesis; chemoprevention; cytochrome P450; dietary constituent; drug carcinogenesis; drug metabolism; enzyme activity; isozymes; laboratory mouse; liver metabolism; neoplastic growth; nutrition related tag; skin neoplasms; tissue /cell culture

The primary aim of the proposed research is to determine the extent and mechanism(s) whereby naturally occurring coumarin derivatives modulate polycyclic aromatic hydrocarbon (PAH) skin carcinogenesis. Humans are continually exposed to a wide variety of chemicals, including: complete carcinogens, initiators, promoters, cocarcinogens, and anticarcinogens. Current evidence indicates that dietary ingestion of a variety of substances may either inhibit or enhance carcinogenesis in man. Coumarin substances represent one of the largest naturally occurring classes of compounds, ingested by man, yet to be fully explored for their potential effects (anticarcinogenic or cocarcinogenic) on chemical carcinogenesis. We have recently found that several natural, as well as novel synthetic coumarins, have the potential to be effective inhibitors of mouse skin carcinogenesis by PAHs. Coumarin derivatives may act as anticarcinogens by modulating both Phase I and Phase II enzymes involved in carcinogen metabolism. Therefore, we will test the hypothesis that the coumarin derivatives inhibit PAH mouse skin tumor initiation and carcinogenesis through alterations in metabolic pathways responsible for the activation and/or detoxification of specific hydrocarbons. The overall approach outlined in this proposal will allow us to evaluate whether coumarins, especially those consumed in the diet of man, increase or decrease the risk of carcinogenesis in a specific animal model system. Such information will be useful in defining whether any naturally occurring coumarins have potential chemopreventive properties or should be considered a risk factor in chemical carcinogenesis. In addition, the proposed studies will lead to a better understanding of the process of chemical carcinogenesis in a specific target tissue, mouse skin. The specific aims are: (1) to determine the ability of naturally occurring coumarins to inhibit the formation of covalent DNA-adducts from B[a]P and DMBA in mouse epidermis in vivo; 2) to determine the dose-response, time course, and sequence of exposure relationships for the inhibitory effects of selected natural coumarins on complete carcinogenesis by B[a]P and DMBA and to determine whether the inhibitory effect is at the level of initiation, promotion, or both; 3) to examine in detail the overall mechanism whereby the most active coumarins inhibit carcinogenesis by PAH as follows: i) to determine the effects of selected coumarin on the overall metabolism of model PAH (i.e., oxidative and non-oxidative) using mouse epidermal cells in culture and/or mouse epidermis in vivo; ii) to determine the effects of selected coumarins on the activities and/or expression of specific cytochrome P-450 isozymes in mouse epidermis; iii) to determine whether inhibitory analogs inactivate cytochrome P-450s; and iv) to determine, if warranted, the effects of coumarins on the levels and expression of epidermal uridine-5'- diphosphoglucuronyltransferase (UDPGT), glutathione-S-transferase (GST), epoxide hydrase (EH), and/or sulfotransferase (ST); and 4) to determine the ability of selected natural coumarins to modulate hepatic xenobiotic and carcinogen metabolizing enzymes following oral administration.

拟议研究的主要目的是确定 天然存在的香豆素衍生物调节 多环芳烃（PAH）皮肤致癌作用。 人类是 持续接触各种化学品，包括： 致癌物、引发剂、促进剂、辅致癌物和抗癌物。 目前的证据表明，饮食摄入的各种 这些物质可能抑制或增强人类的致癌作用。 物质代表了最大的自然发生的类别之一， 化合物，人类摄入，尚未充分开发其潜力 对化学致癌作用的影响（抗癌或助致癌）。 我们最近发现，一些天然的，以及新的合成的， 香豆素类，有可能成为有效的小鼠皮肤抑制剂 多环芳烃致癌作用 香豆素衍生物可作为抗癌剂， 调节I相和II相酶参与致癌物质 新陈代谢. 因此，我们将检验香豆素 衍生物抑制PAH小鼠皮肤肿瘤引发和致癌作用 通过改变负责激活的代谢途径 和/或特定烃的解毒。 的总方针 该提案中概述的内容将使我们能够评估香豆素， 特别是那些在男性饮食中消耗的，增加或减少风险 在特定的动物模型系统中的致癌作用。 这些信息将 可用于确定任何天然存在的香豆素是否具有 潜在的化学预防特性或应被视为风险因素 化学致癌作用。 此外，拟议的研究将导致 更好地了解化学致癌的过程， 特定目标组织老鼠皮肤 具体目标是：（1） 确定天然存在的香豆素抑制 小鼠表皮中B[a]P和DMBA的共价DNA加合物的形成 体内; 2）确定剂量反应，时间过程和顺序 选择的天然药物的抑制作用的暴露关系 香豆素对B[a]P和DMBA完全致癌作用的影响，并确定 抑制作用是否处于起始、促进或 （3）详细研究最活跃的 香豆素抑制PAH致癌作用如下：i）确定 选择的香豆素对模型PAH的总体代谢的影响（即， 氧化的和非氧化的），和/或 小鼠体内表皮; ii）确定所选香豆素的作用 对特定细胞色素P-450同工酶的活性和/或表达的影响 在小鼠表皮中; iii）确定抑制性类似物是否在小鼠表皮中表达。 细胞色素P-450 s;和iv）如果需要，确定 香豆素类药物对表皮尿苷-5 '- 二磷酸葡糖醛酸转移酶（UDPGT），谷胱甘肽-S-转移酶（GST）， 环氧化物水化酶（EH）和/或磺基转移酶（ST）;和4）确定 选择的天然香豆素调节肝脏异生物质的能力， 致癌物代谢酶。