Hepato-Protective Effects of Schisandra Sphenanthera Extract against Lithocholic Acid-Induced Cholestasis in Mice are Associated With the Activation of PXR Pathway and Promotion of Liver Regeneration

Hang Zeng, Dongshun Li, Xiaoling Qin, Pan Chen, Huasen Tan, Xuezhen Zeng, Xi Li, Xiaomei Fan, Yiming Jiang, Yawen Zhou, Yixin Chen, Ying Wang, min huang and Huichang Bi

Drug Metabolism and Disposition December 10, 2015, dmd.115.066969; DOI: https://doi.org/10.1124/dmd.115.066969

Abstract

We previously reported the ethanol extract of Schisandra sphenanthera (Wuzhi tablet, WZ) significantly protects against acetaminophen-induced hepatoxicity. However, whether it exerts protecitve effect against cholestasis remains unclear. In this study, the protection effect of WZ on lithocholic acid (LCA)-induced intraphepatic cholestasis in mice was characterized and the involved mechanisms were investigated. WZ pre-treatment (350 mg/kg) with LCA significantly reversed liver necrosis and decreased activity of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). More importantly, serum total bile acids (TBA) and total bilirubin (Tbili) were also remarkably reduced. RT-qPCR and Western blot analysis showed that hepatic expression of PXR target genes such as CYP3A11 and UGT1A1 were significantly increased by WZ treatment. Luciferase assays performed in LS174T cells illustrated that WZ extract and its six bioactive lignans could all activate hPXR. Additionally, WZ treatment significantly promoted liver regeneration via inhibition of p53/p21 to induce cell proliferation-associated proteins such as CCND1 and PCNA. In conclusion, WZ performs protective effect against LCA-induced intrahepatic cholestasis, partially due to the activation of PXR pathway and promotion of liver regeneration.