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：
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
项目类别：
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

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 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（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，以其抗氧化剂，抗炎和抗肿瘤生物活性率而被认可。目前正在多个临床试验中评估T，以预防或治疗炎症和神经退行性疾病以及肠癌。尽管已经确定了大量的姜黄素体外靶标，但尚未阐明其生物学活性的精确化学分子机制。我们发现了姜黄素的一种新颖的，以前未识别的氧化转化，并且在口服姜黄素向小鼠口服后，我们发现了血浆和肠粘膜中的大量氧化代谢产物。姜黄素的氧化转化是快速，突出的，并通过反应性中间体（包括奎因酮甲基和螺旋氧化物中间体）引起新的代谢产物。主要的最终产物是姜黄素的二氧化环体衍生物。我们将检验以下假设：氧化转化的产物是姜黄素药理作用的介体。在特定目标1中，我们将确定姜黄素氧化转化的生物学后果。具体而言，我们将分析抑制减少和氧化IKK的机制？通过亲电和亲核姜黄素代谢产物，拓扑异构酶II诱导DNA裂解的机理，以及奎因酮甲基化中间体的蛋白质和DNA加合物形成。在特定目标2中，我们将确定姜黄素氧化转化的产物和中间体，并确定其形成机理。在特定目标3中，我们将使用新型的LC-MS方法来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，并通过同位素标记的标准进行定量。氧化激活的概念可能导致一种新的了解姜黄素的结构和功能的范式，对其作为治疗性凸轮剂的临床应用具有重要意义。