基于PXR-UGT代谢网络研究炎性肠病-肿瘤演进中丹参酮IIA级联葡萄糖醛酸结合代谢与药效学调控机制

项目名称： 基于PXR-UGT代谢网络研究炎性肠病-肿瘤演进中丹参酮IIA级联葡萄糖醛酸结合代谢与药效学调控机制

项目编号： No.81202580

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 药物学、药理学

项目作者： 王琼

作者单位： 南京中医药大学

项目金额： 23万元

中文摘要： 文献研究表明PXR-UGT在肠炎癌症转化中起重要作用，激活PXR能抑制NF-κB，上调UGT能降低炎性损伤，肠癌中诱导UGT介导耐药；未见该病理进程中考察PXR/UGT动态变化的报道。丹参酮IIA(TSA)有PXR激动作用和确凿的抗炎抗肿瘤活性但深层药效机制未明。课题组研究表明级联葡萄糖醛酸代谢是TSA肠道代谢重要途径决定其药效，同时TSA能诱导UGT高表达。基于此提出假说：肠炎肿瘤转化中PXR/UGT的变化影响TSA级联代谢及药效；机制是TSA激活PXR抑制NF-κB通路同时上调UGT预防和治疗肠炎，肠癌发生后TSA激活PXR上调UGT介导耐药。研究采用人活检标本和小鼠模型明确肠炎癌症转化各病理阶段PXR/UGT变化及对TSA级联代谢的影响；应用siRNA和报告基因技术及代谢分析，从分子、细胞和整体水平结合药代药效多视角阐明TSA药效调控机制，为激活PXR中药的药效学机制研究提供新思路。

中文关键词： 丹参酮IIA；PXR；UGT1A9；肠炎相关结直肠癌；肠炎

英文摘要： There is ample evidence indicating that the pregnant X receptor (PXR)- UDP-glucuronosyltransferases (UGTs) signaling pathway play an important role in colitis-associated colorectal carcinogenesis, whereby the activation of PXR could inhibit the NF-κB signaling pathways and the induction of UGT could lead to multi-drug resistance. Up to now no report is available concerning the dynamic expression of the PXR-UGT pathway.PXR could be activated by tanshinone IIa (TSA), an important lipophilic Danshen component possessing well proven anti-inflammation and anticancer effects. However, in-depth regulatory mechanism has not been explored. Our previous studies strongly indicated that the quinone reduction and the following glucuronidation play an important role in the intestinal elimination of TSA and the realization of its anti-tumor effects. Moreover, the expression of UGT could be induced by TSA. Based on this background, we hypothesize that the dynamic change of the PXR-UGT pathway during the colitis-colorectal carcinogenesis could influence the glucuronidation of TSA, thereby affecting its anti-tumor efficacy. The mechanism for the pharmacodynamic profile involves two aspects: Firstly,TSA could inhibit the NF-κB signaling pathways through activation of PXR during colitis and induce the expression of UGT to reduce th

英文关键词： tanshinone IIA；PXR；UGT1A9；colitis-associated carcinogenesis；colitis