Tanshinone IIA exerts protective effects in a LCA-induced cholestatic liver model associated with participation of pregnane X receptor.
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.
['Zhang|Xianxie|X|', 'Ma|Zengchun|Z|', 'Liang|Qiande|Q|', 'Tang|Xianglin|X|', 'Hu|Donghua|D|', 'Liu|Canglong|C|', 'Tan|Hongling|H|', 'Xiao|Chengrong|C|', 'Zhang|Boli|B|', 'Wang|Yuguang|Y|', 'Gao|Yue|Y|']
D045784:Abietanes D000818:Animals D002779:Cholestasis D051544:Cytochrome P-450 CYP3A 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 D012333:RNA, Messenger D011987:Receptors, Steroid
Pregnane X receptor Hepatotoxicity and cholestasis Lithocholic acid (PubChem CID: 434-13-9) Tanshinone IIA (PubChem CID: 568-72-9)