Pharmacokinetics and Metabolism of Oxidized Curcumin

氧化姜黄素的药代动力学和代谢

基本信息

批准号：
8301157
负责人：
Claus Schneider
金额：
$ 7.8万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-05 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301157
关键词：
Accounting Address Animals Anti-Inflammatory Agents Anti-inflammatory Antineoplastic Agents Antioxidants Applications Grants Biochemical Biochemistry Biological Biological Availability Cell Respiration Chemical Structure Chemopreventive Agent Clinical Clinical Trials Colon Carcinoma Cultured Cells Curcumin DNA Adducts DNA Damage Development Diet Disease Drug Kinetics Drug or chemical Tissue Distribution Etoposide Goals Human Hydrogen Hydroxyl Radical In Vitro Individual Differences Inflammatory Intestinal Mucosa Isotopes Lead Liver Microsomes Malignant Neoplasms Mediating Mediator of activation protein Metabolism Methods Mitomycins Molecular Multiple Myeloma Mus Neurodegenerative Disorders Oral Oral Administration Oxidation-Reduction Oxygen Pancreas Parents Pharmacology Phenols Plants Plasma Preparation Prevention Proteins Publishing Reaction Rectum Research Role Signal Pathway Site Sulfhydryl Compounds Testing Therapeutic Therapeutic Effect Tissues Tumeric United States National Institutes of Health Validation adduct base cancer prevention cancer therapy cell growth regulation defense response design dietary supplements ds-DNA efficacy testing improved in vivo novel polyphenol quinone methide research study response sensor stable isotope tumorigenic web site

项目摘要

DESCRIPTION (provided by applicant): Curcumin, a polyphenol isolated from the plant turmeric, is recognized for its anti-inflammatory and anti- tumorigenic bioactivities. It is currenly being evaluated in multiple clinical trials for the prevention or treatment of cancers of the colon rectum, pancreas, multiple myeloma, and also for neurodegenerative diseases. Although a plethora of in vitro targets of curcumin have been identified, the precise molecular mechanism(s) of its biological activities have not been uncovered. Low oral bioavailability and rapid reductive metabolism and conjugation limit the clinical use of curcumin. We have recently discovered a novel, previously unrecognized oxidative transformation of curcumin. In preliminary experiments we have detected the major oxidative metabolite of curcumin in plasma and intestinal mucosa after oral administration of curcumin to mice. The reaction of curcumin with molecular oxygen is rapid, prominent, and gives rise to novel and reactive metabolites that could potentially explain some of the pharmacological effects of curcumin. In preliminary studies we have shown that these metabolites contribute to the regulation of cellular antioxidant response and form covalent DNA adducts. The goal of this grant application is to characterize pharmacokinetics, tissue distribution, and metabolism of the oxidative metabolites of curcumin in the mouse and in human liver microsomes. The following specific aims will be performed: (1) To develop a specific and accurate isotope- dilution based LC-MS quantification method for curcumin and its oxididative and reductive metabolites; (2) To identify and quantify oxidative metabolites of curcumin in cultured cells and in human liver microsomes; (3) To perform a pharmacokinetic and tissue distribution analysis of curcumin and its oxidative and reductive metabolites in the mouse. Our research plan is designed to define the in vivo formation, abundance, and distribution of oxidative metabolites of curcumin. The transformation of curcumin into reactive and oxygenated metabolites could be mediating some of the biological effects of curcumin, and could ultimately lead to a novel understanding of the biochemistry and pharmacology of curcumin. PUBLIC HEALTH RELEVANCE: Increasing biochemical and clinical evidence supports the use of the dietary supplement curcumin for the prevention of cancer. The goal of this application is to characterize the in vivo formation and abundance of novel metabolites of curcumin that could be involved in its biological activity.

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结肠直肠癌、胰腺癌、多发性骨髓瘤以及神经退行性疾病进行评估。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分子机制尚未被发现。较低的口服生物利用度以及快速的还原代谢和结合限制了姜黄素的临床使用。我们最近发现了一种新颖的、以前未被识别的姜黄素氧化转化。在初步实验中，我们在给小鼠口服姜黄素后，在血浆和肠粘膜中检测到了姜黄素的主要氧化代谢产物。姜黄素与分子氧的反应快速、显着，并产生新颖的反应性代谢物，这可能解释姜黄素的一些药理作用。在初步研究中，我们表明这些代谢物有助于调节细胞抗氧化反应并形成共价 DNA 加合物。该拨款申请的目标是表征姜黄素氧化代谢物在小鼠和人肝微粒体中的药代动力学、组织分布和代谢。将实现以下具体目标：（1）开发基于同位素稀释的姜黄素及其氧化和还原代谢物的特异且准确的LC-MS定量方法； (2) 鉴定和定量培养细胞和人肝微粒体中姜黄素的氧化代谢物； (3)对姜黄素及其氧化还原代谢物在小鼠体内的药动学和组织分布进行分析。我们的研究计划旨在确定姜黄素氧化代谢物的体内形成、丰度和分布。姜黄素转化为活性和含氧代谢物可能会介导姜黄素的一些生物效应，并最终可能导致对姜黄素的生物化学和药理学的新理解。公共健康相关性：越来越多的生化和临床证据支持使用膳食补充剂姜黄素来预防癌症。该应用的目的是表征姜黄素新型代谢物的体内形成和丰度，这些代谢物可能参与其生物活性。