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：
8540399
负责人：
Claus Schneider
金额：
$ 7.33万
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8540399
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.

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，以其抗炎和抗肿瘤生物活性而被认可。在多个临床试验中，对此进行了弯曲，以预防或治疗结肠直肠，胰腺，多发性骨髓瘤以及神经退行性疾病的癌症。尽管已经确定了大量姜黄素的体外靶标，但尚未发现其生物学活性的精确分子机制。低口服生物利用度和快速还原代谢和共轭限制了姜黄素的临床使用。我们最近发现了姜黄素的一种新颖的，未被认可的氧化转化。在初步实验中，我们已经检测到口服姜黄素向小鼠口服后血浆和肠粘膜中姜黄素的主要氧化代谢产物。姜黄素与分子氧的反应是快速，突出的，并引起新颖和反应性的代谢产物，这些代谢物可能有可能解释姜黄素的某些药理作用。在初步研究中，我们表明这些代谢产物有助于调节细胞抗氧化剂反应并形成共价DNA加合物。该赠款应用的目的是表征小鼠和人肝微粒体中姜黄素氧化代谢产物的药代动力学，组织分布和代谢。将执行以下特定目的：（1）开发一种基于姜黄素及其氧化和还原代谢物的基于同位素稀释的LC-MS定量方法；（2）鉴定和量化培养细胞和人肝微粒体中姜黄素的氧化代谢物；（3）对姜黄素及其在小鼠中的氧化和还原代谢产物进行药代动力学和组织分布分析。我们的研究计划旨在定义姜黄素氧化代谢产物的体内形成，丰度和分布。姜黄素转化为反应性和氧化代谢产物可能正在介导姜黄素的某些生物学作用，并最终可能导致对姜黄素生物化学和药理学的新了解。