NATURAL & SYNTHETIC COUMARINS AS ANTICARCINOGENIC AGENTS

自然的

• 批准号: 6350323
• 负责人: John DiGiovanni
• 金额: $ 21.19万
• 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/6350323
• 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范围和 天然香豆素衍生物调节机制(S) 多环芳烃(PAH)皮肤致癌。人类是 持续接触各种化学物质，包括：完全 致癌物质、引发剂、促进剂、致癌物质和抗癌物质。 目前的证据表明，饮食摄入各种不同的 物质可以抑制或增强人类的致癌作用。香豆素 物质是自然界中最大的一类 人类摄取的化合物尚未充分挖掘其潜力 (抗癌或致癌)对化学致癌的影响。 我们最近发现了几种天然的，以及新奇的合成 香豆素，有可能成为小鼠皮肤的有效抑制剂 多环芳烃的致癌作用。香豆素衍生物可通过以下方式起到抗癌作用 参与致癌的I相酶和II相酶的调控 新陈代谢。因此，我们将检验香豆素的假设 衍生物抑制多环芳烃小鼠皮肤肿瘤的启动和致癌 通过负责激活的新陈代谢途径的改变 和/或特定碳氢化合物的解毒。总体方法 这项提案中概述的内容将使我们能够评估香豆素类药物， 尤其是在人类饮食中摄入的那些，增加或降低风险 在特定的动物模型系统中的致癌作用。这样的信息将 在确定是否有任何自然产生的香豆素具有 潜在的化学预防特性或应被视为危险因素 在化学致癌方面。此外，拟议的研究将导致 更好地理解癌症的化学致癌过程 特定的目标组织，小鼠皮肤。具体目标是：(1) 确定自然产生的香豆素抑制 B[a]P与DMBA在小鼠表皮中形成共价DNA加合物的研究 活体；2)确定剂量-反应、时间进程和序列 部分天然药物抑制作用的暴露关系 香豆素类化合物对B[a]P和DMBA完全致癌的影响及测定 抑制效应是处于启动、促进还是 两者都有；3)详细研究最活跃的 香豆素类化合物抑制多环芳烃致癌作用如下：i)测定 所选香豆素对模型PAH整体代谢的影响(即， 氧化和非氧化)在培养和/或使用小鼠表皮细胞 活体小鼠表皮；ii)确定所选香豆素的作用 特异性细胞色素P-450同工酶活性和/或表达的研究 在小鼠表皮中；iii)确定抑制类似物是否失活 细胞色素P-450；以及iv)如有必要，确定 香豆素类药物对表皮尿苷-5‘-的水平和表达的影响 二磷酸葡萄糖醛酸基转移酶、谷胱甘肽S转移酶、 环氧化物水合酶(EH)和/或磺基转移酶(ST)；以及4)测定 部分天然香豆素对肝脏异种生物和蛋白质的调节能力 口服后的致癌物代谢酶。