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Hepatoprotective Effects of Schisandra sphenanthera Extract against Lithocholic Acid-Induced Cholestasis in Male Mice Are Associated with Activation of the Pregnane X Receptor Pathway and Promotion of Liver Regeneration.

Abstract
We previously reported that the ethanol extract of Schisandra sphenanthera [Wuzhi (WZ) tablet] significantly protects against acetaminophen-induced hepatoxicity. However, whether WZ exerts a protective effect against cholestasis remains unclear. In this study, the protective effect of WZ on lithocholic acid (LCA)-induced intrahepatic cholestasis in mice was characterized and the involved mechanisms were investigated. WZ pretreatment (350 mg/kg) with LCA significantly reversed liver necrosis and decreased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase activity. More importantly, serum total bile acids and total bilirubin were also remarkably reduced. Quantitative reverse-transcription polymerase chain reaction and Western blot analysis showed that hepatic expression of pregnane X receptor (PXR) target genes such as CYP3A11 and UDP-glucuronosyltransferase (UGT) 1A1 were significantly increased by WZ treatment. Luciferase assays performed in LS174T cells illustrated that WZ extract and its six bioactive lignans could all activate human PXR. In addition, WZ treatment significantly promoted liver regeneration via inhibition of p53/p21 to induce cell proliferation-associated proteins such as cyclin D1 and proliferating cell nuclear antigen. In conclusion, WZ has a protective effect against LCA-induced intrahepatic cholestasis, partially owing to activation of the PXR pathway and promotion of liver regeneration.
AuthorsHang 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, Huichang Bi
JournalDrug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 44 Issue 3 Pg. 337-42 (Mar 2016) ISSN: 1521-009X [Electronic] United States
PMID26658429 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
Chemical References
  • Drugs, Chinese Herbal
  • Lignans
  • Plant Extracts
  • Pregnane X Receptor
  • Protective Agents
  • Receptors, Steroid
  • wuzhi
  • Acetaminophen
  • Lithocholic Acid
  • Cytochrome P-450 CYP3A
  • UGT1A1 enzyme
  • Glucuronosyltransferase
Topics
  • Acetaminophen (pharmacology)
  • Animals
  • Chemical and Drug Induced Liver Injury (drug therapy, metabolism)
  • Cholestasis (chemically induced, drug therapy, metabolism)
  • Cytochrome P-450 CYP3A (metabolism)
  • Drugs, Chinese Herbal (chemistry, pharmacology)
  • Glucuronosyltransferase (metabolism)
  • Lignans (pharmacology)
  • Lithocholic Acid (adverse effects)
  • Liver (drug effects, metabolism)
  • Liver Regeneration (drug effects)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Plant Extracts (chemistry, pharmacology)
  • Pregnane X Receptor
  • Protective Agents (chemistry, pharmacology)
  • Receptors, Steroid (metabolism)
  • Schisandra (chemistry)
  • Signal Transduction (drug effects)

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