title: Deoxycholic acid at neutral and acid pH, is genotoxic to oesophageal cells through the induction of ROS: The potential role of anti-oxidants in Barrett's oesophagus.
abstract: Bile acids are often refluxed into the lower oesophagus and are candidate carcinogens in the development of oesophageal adenocarcinoma. We show here that the secondary bile acid, deoxycholic acid (DCA), is the only one of the commonly refluxed bile acids tested here, to show genotoxicity, in terms of chromosome damage and mutation induction in the human p53 gene. This genotoxicity was apparent at both neutral and acidic pH, whilst there was a considerable increase in bile-induced toxicity at acidic pH. The higher levels of cell death and low cell survival rates at acidic pH may imply that acid bile exposure is toxic rather than carcinogenic, as dead cells do not seed cancer development. We also show that DCA (at neutral and acid pH) induced the release of reactive oxygen species (ROS) within the cytoplasm of exposed cells. We further demonstrate that the genotoxicity of DCA is ROS mediated, as micronucleus induction was significantly reduced when cells were treated with DCA + the anti-oxidant vitamin C. In conclusion, we show that DCA, is an effective genotoxin at both neutral and acidic pH. As bile acids like DCA can induce DNA damage at neutral pH, suppressing the acidity of the refluxate will not completely remove its carcinogenic potential. The genotoxicity of DCA is however, ROS dependent, hence anti-oxidant supplementation, in addition to acid suppression may block DCA driven carcinogenesis in Barrett's patients.
authors.affiliation: Swansea School of Medicine, Swansea University, Swansea SA28PP, UK. g.j.jenkins@swansea.ac.uk
authors.forename: Gareth J S
authors.initials: GJ
authors.lastname: Jenkins
authors.forename: Francis R
authors.initials: FR
authors.lastname: D'Souza
authors.forename: Sinan H
authors.initials: SH
authors.lastname: Suzen
authors.forename: Zak S
authors.initials: ZS
authors.lastname: Eltahir
authors.forename: Sally A
authors.initials: SA
authors.lastname: James
authors.forename: James M
authors.initials: JM
authors.lastname: Parry
authors.forename: Paul A
authors.initials: PA
authors.lastname: Griffiths
authors.forename: John N
authors.initials: JN
authors.lastname: Baxter
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use; D001471:Barrett Esophagus / Q000188:drug therapy / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D003840:Deoxycholic Acid / Q000633:toxicity*; D003902:Detergents / Q000633:toxicity*; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015162:Micronucleus Tests; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53
chemical_list: D000975:Antioxidants; D003902:Detergents; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D003840:Deoxycholic Acid; D001205:Ascorbic Acid