title: Tanshinone IIA exerts protective effects in a LCA-induced cholestatic liver model associated with participation of pregnane X receptor.
abstract: 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.
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Xianxie
authors: X
authors: Zhang
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Zengchun
authors: Z
authors: Ma
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Qiande
authors: Q
authors: Liang
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Xianglin
authors: X
authors: Tang
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Donghua
authors: D
authors: Hu
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Canglong
authors: C
authors: Liu
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Hongling
authors: H
authors: Tan
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
authors: Chengrong
authors: C
authors: Xiao
authors: Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
authors: Boli
authors: B
authors: Zhang
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address: wangyg@bmi.ac.cn.
authors: Yuguang
authors: Y
authors: Wang
authors: Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China. Electronic address: gaoyue@bmi.ac.cn.
authors: Yue
authors: Y
authors: Gao
mesh_terms: D045784:Abietanes / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008095:Lithocholic Acid; D008297:Male; D008807:Mice, Inbred BALB C; D008517:Phytotherapy; D000077297:Pregnane X Receptor; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism
chemical_list: D045784:Abietanes; D000077297:Pregnane X Receptor; D020011:Protective Agents; D012333:RNA, Messenger; D011987:Receptors, Steroid; C021751:tanshinone; D008095:Lithocholic Acid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Hepatotoxicity and cholestasis; Lithocholic acid (PubChem CID: 434-13-9); Pregnane X receptor; Tanshinone IIA (PubChem CID: 568-72-9);