Oxidative activation of the dietary cancer chemopreventive agent curcumin

膳食癌症化学预防剂姜黄素的氧化活化

• 批准号: 8601172
• 负责人: Claus Schneider
• 金额: $ 43.18万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601172
• 关键词: Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Biochemical; Biological; Biological Assay; Breast Cancer Cell; Cells; Chemicals; Chemopreventive Agent; Clinical; Clinical Trials; Clinical Trials Design; Complement; Curcumin; Cysteine; DNA; DNA Adduction; DNA Adducts; Diet; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Epoxy Compounds; Fractionation; Glucuronides; Glutathione; Goals; In Vitro; Inflammatory; Intestinal Cancer; Intestinal Mucosa; Intestines; Isotopes; Label; Lead; Liver Microsomes; Malignant Neoplasms; Mediator of activation protein; Metabolism; Methodology; Molecular; Molecular Mechanisms of Action; Mus; Neurodegenerative Disorders; Oral Administration; Outcome Study; Oxidation-Reduction; Oxidative Stress; Oxygen; Pharmaceutical Chemistry; Phase; Physiological; Plants; Plasma; Poisoning; Prevention; Proteins; Randomized Clinical Trials; Reaction; Signal Transduction; Structure; Sulfenic Acids; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Topoisomerase II; Tumeric; adduct; base; clinical application; cysteinesulfenic acid; dietary supplements; disorder prevention; improved; in vitro Assay; in vivo; insight; novel; oxidation; parathyroid hormone-related protein; polyphenol; public health relevance; quinone methide; research study; success; tumorigenic

DESCRIPTION (provided by applicant): Curcumin, a polyphenol isolated from the plant turmeric, is recognized for its antioxidant, anti-inflammatory and anti-tumorigenic bioactivities. t is currently being evaluated in multiple clinical trials for the prevention or treatment of inflammatory and neurodegenerative diseases, and also for intestinal cancers. Although a large number of in vitro targets of curcumin have been identified, the precise chemical-molecular mechanism(s) of its biological activities have not been elucidated. We have discovered a novel, previously unrecognized oxidative transformation of curcumin, and we have detected abundant levels of the oxidative metabolites in plasma and intestinal mucosa after oral administration of curcumin to mice. The oxidative transformation of curcumin is rapid, prominent, and gives rise to novel metabolites via reactive intermediates, including a quinone methide and a spiro-epoxide intermediate. The major final product is a dioxygenated cyclopentadione derivative of curcumin. We will test the hypothesis that the products of oxidative transformation are mediators of pharmacological effects of curcumin. In Specific Aim 1 we will determine biological consequences of oxidative transformation of curcumin. Specifically, we will analyze the mechanism of inhibition of reduced and oxidized IKK? by electrophilic and nucleophilic curcumin metabolites, the mechanism of induction of DNA cleavage by topoisomerase II, and protein and DNA adduct formation by the quinone methide intermediate. In Specific Aim 2 we will identify the products and intermediates of oxidative transformation of curcumin and determine their mechanism of formation. In Specific Aim 3 we will determine in vivo metabolism, tissue distribution, and pharmacokinetics of curcumin and its metabolites using a novel LC-MS methodology with quantification by isotopically labeled standards. The concept of oxidative activation could result in a new paradigm of understanding the structure and function of curcumin with important implications for its clinical application as a therapeutic CAM agent.

描述（申请人提供）： 姜黄素是从植物姜黄中分离出来的一种多酚，因其抗氧化、抗炎和抗肿瘤生物活性而闻名。目前正在多项临床试验中对其用于预防或治疗炎症和神经退行性疾病以及肠癌进行评估。尽管姜黄素的大量体外靶标已被确定，但其生物活性的精确化学分子机制尚未阐明。我们发现了一种新的、以前未被识别的姜黄素氧化转化，并且在给小鼠口服姜黄素后，我们在血浆和肠粘膜中检测到了丰富水平的氧化代谢产物。姜黄素的氧化转化快速、显着，并通过活性中间体（包括醌甲基化物和螺环氧化物中间体）产生新的代谢物。主要最终产品是姜黄素的双氧化环戊二酮衍生物。我们将检验氧化转化产物是姜黄素药理作用介质的假设。在具体目标 1 中，我们将确定姜黄素氧化转化的生物学后果。具体来说，我们来分析一下还原型和氧化型IKK的抑制机制？亲电和亲核姜黄素代谢物、拓扑异构酶 II 诱导 DNA 切割的机制以及醌甲基化物中间体形成蛋白质和 DNA 加合物的机制。在具体目标 2 中，我们将鉴定姜黄素氧化转化的产物和中间体，并确定其形成机制。在具体目标 3 中，我们将使用新型 LC-MS 方法确定姜黄素及其代谢物的体内代谢、组织分布和药代动力学，并通过同位素标记标准品进行定量。氧化活化的概念可能会带来理解姜黄素结构和功能的新范式，对其作为治疗性 CAM 药物的临床应用具有重要意义。