Enhancing Bioavailability of Resveratrol

描述(申请人提供)：研究表明，白藜芦醇(反式-3，5，4‘-三羟基二苯乙烯)是一种在葡萄、红酒、浆果和花生中发现的植物保健素抗氧化剂，可以预防几种疾病。大量的临床前研究表明，白藜芦醇对几种癌症具有化学预防和治疗作用。此外，白藜芦醇正被广泛用作一种补充剂以及一种补充和替代医学(CAM)方法，用于管理几种疾病/状况。然而，一个重要的问题是 使用白藜芦醇，特别是在预防环境中(通过饮食或补充剂)，被认为是其最低点 由于其在哺乳动物中的快速新陈代谢，其生物利用度。已知，在代谢过程中，白藜芦醇的大部分经历了葡萄糖醛酸化和硫酸盐化。研究还表明，胡椒碱，一种从黑胡椒(Piper spp.)中提取的生物碱，在体内可以抑制葡萄糖醛酸化反应。我们认为，胡椒碱可以抑制白藜芦醇的葡萄糖醛酸化反应，从而提高其生物利用度，从而产生更好的化学预防反应。这一假设得到了我们最近令人兴奋的初步数据的支持，这些数据表明，胡椒碱(20 mg/kg；口服)使白藜芦醇(500 mg/kg；口服)在血清中的生物利用度提高了约175%。在这一应用中，我们建议检验胡椒碱将提高白藜芦醇的生物利用度的假设，从而产生更好的化学预防和治疗反应。在这项应用中，我们建议进行临床研究(在人类志愿者中)以及临床前试验(在前列腺癌的小鼠模型中)。在我们的临床前试验中，我们将在前列腺癌(PCA)的小鼠模型上进行原理证明研究。我们选择PCA是基于以下几点。前列腺癌仅次于肺癌，是美国男性癌症相关死亡的第二大原因，由于其进展缓慢和潜伏期长，被认为是化学预防的理想候选疾病。此外，我们还证明了白藜芦醇具有抗增殖作用。 对人前列腺癌细胞的作用，可能是通过调节磷脂酰肌醇3‘-激酶 (PI3K)/Akt通路和Bcl2蛋白家族。此外，最近的研究表明， 白藜芦醇可抑制TRAMP(转基因小鼠前列腺癌)和TRAP(转基因前列腺癌大鼠)模型中前列腺癌的进展，提示该药具有预防和治疗前列腺癌的潜力。提出了以下两个具体目标：1)确定胡椒碱对白藜芦醇在人类志愿者体内的生物利用度的影响；2)确定胡椒碱联合给药是否增强了白藜芦醇的生物利用度和对前列腺癌发生的化学预防作用。我们相信，这一提议的成功完成可能会为开发新的战略来提高白藜芦醇的生物利用度铺平道路。 与公共健康相关：研究表明，白藜芦醇，一种在葡萄、红酒、浆果和花生中发现的抗氧化剂，对包括某些癌症在内的许多疾病具有保护作用。此外，白藜芦醇正被广泛用作一种补充剂以及一种补充和替代医学(CAM)方法，用于管理几种疾病/状况。然而，白藜芦醇的一个重要问题，特别是在预防环境中(通过饮食或补充剂)，被认为是由于其在哺乳动物中的快速新陈代谢而生物利用度低。在这项应用中，我们将进行一项临床研究和临床前研究，以检验胡椒碱(黑胡椒中的一种化学物质)将提高白藜芦醇的生物利用度(通过抑制其代谢)的假设，从而产生更好的化学预防和治疗反应。我们相信，如果成功完成这项工作， 该提案可能为开发新的战略，以提高白藜芦醇的生物利用度，从而预防和/或治疗反应铺平道路。

DESCRIPTION (provided by applicant): Studies have shown that resveratrol (trans-3,5,4'-trihydroxystilbene), a phytoalexin antioxidant found in grapes, red wines, berries and peanuts, imparts protection against several diseases. A plethora of pre-clinical studies have shown that resveratrol imparts chemopreventive as well as therapeutic response against several cancers. Further, resveratrol is being widely used as a supplement as well as a complementary and alternative medicine (CAM) approach for the management of several diseases/conditions. However, an important issue with resveratrol, especially in prevention settings (through diet or supplements), is believed to be its low bioavailability due to its rapid metabolism in mammals. It is known that during metabolism, the majority of resveratrol undergoes glucuronidation and sulfation. Studies have also shown that piperine, an alkaloid derived from black pepper (Piper spp.), inhibits glucuronidation in vivo. We believe that piperine will inhibit glucuronidation of resveratrol thereby enhancing its bioavailability leading to a superior chemopreventive response. This assumption is supported by our recent exciting preliminary data showing that piperine (20 mg/kg; oral gavage) enhances the bioavailability of resveratrol (500 mg/kg; oral gavage) in serum by ~175%. In this application, we propose to test the hypothesis that piperine will enhance the bioavailability of resveratrol leading to a superior chemopreventive and therapeutic response. In this application, we propose to conduct a clinical study (in human volunteers) as well as a preclinical trial (in a mouse model of prostate cancer. For our preclinical trial, we will conduct proof of principle study in a mouse model of prostate cancer (PCa). Our choice of PCa is based on the following point. PCa, next only to lung cancer, is the second leading cause of cancer related deaths in American males and because of its slow progression and long latency, is believed to be an ideal candidate disease for chemoprevention. Further, we have demonstrated that resveratrol imparts antiproliferative effects against human PCa cells, possibly via modulation of phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and Bcl-2 family of proteins. Furthermore, recent studies have demonstrated that resveratrol suppresses PCa progression in TRAMP (transgenic adenocarcinoma of mouse prostate) and TRAP (Transgenic Rat for Adenocarcinoma of Prostate) models suggesting the potential of this agent for the prevention and treatment of PCa. The following two specific aims are proposed: 1) To determine the influence of piperine on the bioavailability of resveratrol in human volunteers; and 2) To determine if piperine coadministration enhances the bioavailability and chemopreventive effects of resveratrol on PCa development in TRAMP mice. We believe that a successful completion of this proposal may pave the way for the development of novel strategies to enhance the bioavailability of resveratrol. PUBLIC HEALTH RELEVANCE: Studies have shown that resveratrol, an antioxidant found in grapes, red wines, berries and peanuts, imparts protection against many diseases including certain cancers. Further, resveratrol is being widely used as a supplement as well as a complementary and alternative medicine (CAM) approach for the management of several diseases/conditions. However, an important issue with resveratrol, especially in prevention settings (through diet or supplements), is believed to be its low bioavailability due to its rapid metabolism in mammals. In this application, we will conduct a clinical study and a preclinical study to test the hypothesis that piperine (a chemical in black pepper) will enhance the bioavailability of resveratrol (via inhibiting its metabolism) leading to a superior chemopreventive and therapeutic response. We believe that a successful completion of this proposal may pave the way for the development of novel strategies to enhance the bioavailability and therefore preventive and/or therapeutic response of resveratrol.