Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
J Ethnopharmacol. 2015 Apr 22;164:357-67. doi: 10.1016/j.jep.2015.01.047. Epub 2015 Feb 7.
Tanshinone IIA (Tan IIA) is one of the main natural active ingredients purified from Salvia miltiorrhiza radix, which has long been used in clinical practice in China to treat diseases including liver fibrosis, Alzheimer׳s disease, and cardiovascular diseases. Tan IIA has hepatoprotective properties, and is an efficacious PXR agonist. Our study was designed to observe the function and mechanism of the hepatoprotective properties of Tan IIA. HepG2 cells were used to investigate the vitrol effects of Tan IIA on PXR and CYP3A4. Gut-formed LCA is hepatotoxic, and has been implicated in the pathogenesis of cholestatic diseases. To further investigate the hepatoprotective mechanisms of Tan IIA against LCA-induced cholestasis in vivo, we choose the normal mice and siRNA-treated mice. The in vitro study demonstrated that the effect of Tan IIA on CYP3A4 was mediated by transactivation of PXR in a dose- and time-dependent manner. The in vivo experiments using PXR siRNA revealed that Tan IIA could protect against LCA-induced hepatotoxicity and cholestasis in a dose-dependent manner. These effects were partially caused by the upregulation of PXR, as well as Cyp3a11, Cyp3a13, and Mdr1, which are the enzymes responsible for LCA metabolism. This is the first report showing that the hepatoprotective effects of Tan IIA are partly mediated by PXR.
丹参酮 IIA（Tan IIA）是从丹参根中提取的主要天然活性成分之一，在中国临床上长期用于治疗肝纤维化、阿尔茨海默病和心血管疾病等疾病。Tan IIA 具有保肝作用，是有效的 PXR 激动剂。我们的研究旨在观察 Tan IIA 保肝作用的功能和机制。使用 HepG2 细胞研究 Tan IIA 对 PXR 和 CYP3A4 的体外作用。肠道形成的 LCA 具有肝毒性，并与胆汁淤积性疾病的发病机制有关。为了进一步研究 Tan IIA 对 LCA 诱导的体内胆汁淤积的保肝机制，我们选择了正常小鼠和 siRNA 处理的小鼠。体外研究表明，Tan IIA 对 CYP3A4 的作用是通过 PXR 的剂量和时间依赖性转激活介导的。使用 PXR siRNA 的体内实验表明，Tan IIA 可以剂量依赖性地保护 LCA 诱导的肝毒性和胆汁淤积。这些作用部分是由于 PXR 的上调以及负责 LCA 代谢的酶 Cyp3a11、Cyp3a13 和 Mdr1 的上调所致。这是首次报道 Tan IIA 的保肝作用部分是通过 PXR 介导的。
