Antiproliferation of berberine is mediated by epigenetic modification of constitutive androstane receptor (CAR) metabolic pathway in hepatoma cells

Sci Rep. 2016 Jun 17;6:28116. doi: 10.1038/srep28116.


Constitutive androstane receptor (CAR) regulates hepatic xenobiotic and energy metabolism, as well as promotes cell growth and hepatocarcinogenesis. Berberine is an ancient multipotent alkaloid drug which derived from Coptis chinensis plants. Here we report that berberine is able to be cellular uptake and accessible to chromatin in human hepatoma HepG2 cells. Berberine induces more apoptosis, cell cycle arrest, but less ROS production in CAR overexpressed mCAR-HepG2 cells. Moreover, berberine inhibits expressions of CAR and its target genes CYP2B6 and CYP3A4. Furthermore, berberine enhances DNA methylation level in whole genome but reduces that in promoter regions CpG sites of CYP2B6 and CYP3A4 genes under the presence of CAR condition. These results indicated that the antiproliferation of berberine might be mediated by the unique epigenetic modifying mechanism of CAR metabolic pathway, suggesting that berberine is a promising candidate in anticancer adjuvant chemotherapy, due to its distinct pharmacological properties in clinic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Berberine / pharmacology*
  • Carcinoma, Hepatocellular / drug therapy*
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Cytochrome P-450 CYP2B6 / biosynthesis
  • Cytochrome P-450 CYP2B6 / genetics
  • Cytochrome P-450 CYP3A / biosynthesis
  • Cytochrome P-450 CYP3A / genetics
  • DNA Methylation / drug effects*
  • DNA Methylation / genetics
  • Epigenesis, Genetic
  • Hep G2 Cells
  • Hepatocytes / metabolism
  • Humans
  • Liver Neoplasms / drug therapy*
  • Promoter Regions, Genetic / genetics
  • Reactive Oxygen Species / metabolism
  • Receptors, Cytoplasmic and Nuclear / biosynthesis*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism


  • Antineoplastic Agents
  • Reactive Oxygen Species
  • Receptors, Cytoplasmic and Nuclear
  • Berberine
  • constitutive androstane receptor
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human