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的多酚，被认为具有抗炎和抗肿瘤生物活性。它目前正在多项临床试验中进行评估，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。尽管已经鉴定了过多的姜黄素体外靶点，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还原代谢和缀合限制了姜黄素的临床使用。我们最近发现了一种新的，以前未被认识的姜黄素氧化转化。在初步的实验中，我们检测了姜黄素口服给药后，小鼠血浆和肠粘膜中的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的，突出的，并产生新的和反应性的代谢产物，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，这些代谢产物有助于调节细胞的抗氧化反应，并形成共价DNA加合物。这项资助申请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。本研究的主要目的是：（1）建立一种特异、准确的姜黄素及其氧化和还原代谢产物的同位素稀释LC-MS定量方法;（2）鉴定和定量姜黄素在培养细胞和人肝微粒体中的氧化代谢产物;（3）研究姜黄素及其氧化还原代谢产物在小鼠体内的药代动力学和组织分布。我们的研究计划旨在确定姜黄素的氧化代谢产物在体内的形成，丰度和分布。姜黄素转化为活性和含氧代谢产物可能介导姜黄素的一些生物学效应，并可能最终导致对姜黄素的生物化学和药理学的新理解。

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.