Pharmacokinetics and Metabolism of Oxidized 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，具有抗炎和抗肿瘤的生物活性。目前，它正在多个临床试验中进行评估，用于预防或治疗结肠癌、直肠癌、胰腺癌、多发性骨髓瘤以及神经退行性疾病。虽然大量的姜黄素体外靶点已被确定，但其生物活性的精确分子机制尚未被揭示。低口服生物利用度和快速的还原代谢和结合限制了姜黄素的临床应用。我们最近发现了一种新的，以前未被认识到的姜黄素氧化转化。在初步实验中，我们检测了小鼠口服姜黄素后血浆和肠黏膜中姜黄素的主要氧化代谢物。姜黄素与分子氧的反应是快速的，显著的，并产生新的和反应性代谢产物，这可能解释姜黄素的一些药理作用。在初步研究中，我们已经表明这些代谢物有助于细胞抗氧化反应的调节，并形成共价DNA加合物。本基金申请的目的是表征姜黄素在小鼠和人肝微粒体中的药代动力学、组织分布和氧化代谢物的代谢。以下具体目标将实现：(1)建立一种基于同位素稀释的姜黄素及其氧化和还原性代谢产物的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性代谢物在小鼠体内的药代动力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产物的体内形成，丰度和分布。姜黄素转化为活性氧代谢物可能介导了姜黄素的一些生物学效应，并可能最终导致对姜黄素生物化学和药理学的新认识。

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.