Pharmacokinetics and Metabolism of Oxidized Curcumin

描述(申请人提供)：姜黄素是从植物姜黄中分离出来的一种多酚，被公认为具有抗炎和抗肿瘤生物活性。目前正在进行多项临床试验，以预防或治疗结肠癌、胰腺癌、多发性骨髓瘤以及神经退行性疾病。虽然姜黄素的体外靶点已经确定，但其生物学活性的确切分子机制(S)尚未被揭示。姜黄素口服生物利用度低，还原代谢和结合速度快，限制了其临床应用。我们最近发现了一种新的、以前未被发现的姜黄素氧化转化。在初步实验中，我们检测到小鼠口服姜黄素后，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迅速、显著，并产生新的反应性代谢物，这可能解释姜黄素的一些药理作用。在初步研究中，我们已经证明这些代谢物有助于调节细胞的抗氧化反应，并形成共价DNA加合物。这项赠款申请的目的是研究姜黄素在小鼠和人肝微粒体中的药代动力学、组织分布和代谢。本研究的具体目标如下：(1)建立基于同位素稀释的LC-MS定量测定姜黄素及其氧化和还原代谢物的方法；(2)鉴定和定量姜黄素在培养细胞和人肝微粒体内的氧化代谢物；(3)对姜黄素及其氧化和还原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物的体内形成、丰度和分布。姜黄素转化为活性代谢物和氧化代谢物可能介导了姜黄素的一些生物学效应，并最终可能导致对姜黄素的生物化学和药理学的新的理解。

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.