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

基本信息

批准号：
9207754
负责人：
Claus Schneider
金额：
$ 40.99万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207754
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 Isotope Labeling Isotopes Lead Liver Microsomes Malignant Neoplasms Mediator of activation protein Metabolism Methodology Molecular Molecular Mechanisms of Action Mus Neurodegenerative Disorders Oral Administration Outcome Oxidation-Reduction Oxidative Stress Oxides Oxygen Pharmaceutical Chemistry Pharmacology Phase Physiological Plants Plasma Poisoning Prevention trial Proteins Randomized Clinical Trials Reaction Signal Transduction Structure Sulfenic Acids Testing Therapeutic Therapeutic Effect Time Tissues Topoisomerase II Tumeric Tumorigenicity adduct base clinical application cysteinesulfenic acid delta protein dietary supplements disorder prevention experimental study improved in vitro Assay in vivo insight novel oxidation parathyroid hormone-related protein polyphenol public health relevance quinone methide success tumorigenic

项目摘要

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 IKKß 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（由申请人提供）：姜黄素是一种从植物姜黄中分离出来的多酚，因其抗氧化、抗炎和抗肿瘤生物活性而被认可，目前正在多项临床试验中评估其预防或治疗炎症和神经退行性疾病的作用。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确定。我们发现了一种新的、以前未被认识的姜黄素氧化转化，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大量的氧化代谢产物。通过反应中间体产生新的代谢物，包括醌甲基化物和螺环氧化物中间体，主要的最终产物是双氧化的。姜黄素的环戊二酮衍生物。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，我们将分析还原姜黄素的抑制机制。并通过亲电和亲核姜黄素代谢物氧化 IKKß，拓扑异构酶诱导 DNA 切割的机制II，醌甲基化物中间体形成蛋白质和DNA加合物。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，并确定它们的形成机制。在具体目标3中，我们将确定体内代谢、组织分布。以及姜黄素及其代谢物的药代动力学，使用新型 LC-MS 方法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产生一种新的理解范式。姜黄素的结构和功能对其作为治疗性 CAM 药物的临床应用具有重要意义。