Sodium deoxycholate causes nitric oxide mediated DNA damage in oesophageal cells.
Patients with chronic gastro-oesophageal reflux disease experience the reflux of acid and bile into the distal oesophagus. The secondary bile salt sodium deoxycholate (NDC) is implicated in the induction of mucosal injury during reflux episodes. This study hypothesized that NDC damages DNA in oesophageal cells by an oxidative mechanism. In the oesophageal cell line HET1-A, increased production of nitric oxide (NO) was measured in NDC-treated cells. Protection from DNA strand breaks induced by NDC (10 microm) was observed in cells coincubated with the nitric oxide scavenger C-PTIO (p<0.012) or pre-incubated with the NO synthase inhibitor L-NAME (p<0.009) or the NFkappaB inhibitor, TPCK (p<0.036). Collectively these data implicate the involvement of NFkappaB and nitric oxide synthase in the DNA damage induced by NDC in oesophageal cells. In conclusion, NDC-driven NO production may play an important role in inducing DNA damage during episodes of gastro-oesophageal reflux and thereby contribute to reflux-related carcinogenesis.
Jolly
Arthur J
AJ
Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, UK.
Wild
Christopher P
CP
Hardie
Laura J
LJ
D000943:Antigens, Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004249:DNA Damage; D003840:Deoxycholic Acid / Q000378:metabolism*; D004947:Esophagus / Q000187:drug effects* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology
D000943:Antigens, Differentiation; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; D016328:NF-kappa B; D009573:Nitrites; D003840:Deoxycholic Acid; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D014108:Tosylphenylalanyl Chloromethyl Ketone; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester