Mechanism study of goldenseal-associated DNA damage

Toxicol Lett. 2013 Jul 31;221(1):64-72. doi: 10.1016/j.toxlet.2013.05.641. Epub 2013 Jun 5.


Goldenseal has been used for the treatment of a wide variety of ailments including gastrointestinal disturbances, urinary tract disorders, and inflammation. The five major alkaloid constituents in goldenseal are berberine, palmatine, hydrastine, hydrastinine, and canadine. When goldenseal was evaluated by the National Toxicology Program (NTP) in the standard 2-year bioassay, goldenseal induced an increase in liver tumors in rats and mice; however, the mechanism of goldenseal-associated liver carcinogenicity remains unknown. In this study, the toxicity of the five goldenseal alkaloid constituents was characterized, and their toxic potencies were compared. As measured by the Comet assay and the expression of γ-H2A.X, berberine, followed by palmatine, appeared to be the most potent DNA damage inducer in human hepatoma HepG2 cells. Berberine and palmatine suppressed the activities of both topoisomerase (Topo) I and II. In berberine-treated cells, DNA damage was shown to be directly associated with the inhibitory effect of Topo II, but not Topo I by silencing gene of Topo I or Topo II. In addition, DNA damage was also observed when cells were treated with commercially available goldenseal extracts and the extent of DNA damage was positively correlated to the berberine content. Our findings suggest that the Topo II inhibitory effect may contribute to berberine- and goldenseal-induced genotoxicity and tumorigenicity.

Keywords: Berberine; Comet assay; DNA damage; Goldenseal; Topoisomerase; γ-H2A.X.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkaloids / toxicity*
  • Berberine / chemistry
  • Berberine / metabolism
  • Berberine / toxicity
  • Berberine Alkaloids / chemistry
  • Berberine Alkaloids / metabolism
  • Berberine Alkaloids / toxicity
  • Comet Assay
  • DNA / drug effects*
  • DNA Damage
  • DNA Topoisomerases, Type I / genetics
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II / genetics
  • DNA Topoisomerases, Type II / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Silencing
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Histones / metabolism
  • Humans
  • Hydrastis / chemistry
  • Hydrastis / metabolism*
  • Mutagens / toxicity*
  • Plant Extracts / chemistry
  • Plant Extracts / toxicity
  • RNA, Small Interfering / genetics
  • Structure-Activity Relationship


  • Alkaloids
  • Berberine Alkaloids
  • H2AX protein, human
  • Histones
  • Mutagens
  • Plant Extracts
  • RNA, Small Interfering
  • Berberine
  • DNA
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II
  • palmatine