title: Mechanism study of goldenseal-associated DNA damage.
abstract: 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.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. FDA, Jefferson, AR 72079, USA.
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.forename: Liqing
authors.initials: L
authors.lastname: Wan
authors.forename: Letha
authors.initials: L
authors.lastname: Couch
authors.forename: Haixia
authors.initials: H
authors.lastname: Lin
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Vasily N
authors.initials: VN
authors.lastname: Dobrovolsky
authors.forename: Nan
authors.initials: N
authors.lastname: Mei
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
mesh_terms: D000470:Alkaloids / Q000633:toxicity*; D001599:Berberine / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D001600:Berberine Alkaloids / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D020552:Comet Assay; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020868:Gene Silencing; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D039321:Hydrastis / Q000737:chemistry / Q000378:metabolism*; D009153:Mutagens / Q000633:toxicity*; D010936:Plant Extracts / Q000737:chemistry / Q000633:toxicity; D034741:RNA, Small Interfering / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D001600:Berberine Alkaloids; C468783:H2AX protein, human; D006657:Histones; D009153:Mutagens; D010936:Plant Extracts; D034741:RNA, Small Interfering; D001599:Berberine; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; C005413:palmatine
keywords: Berberine; Comet assay; DNA damage; Goldenseal; Topoisomerase; γ-H2A.X