Document Detail


A novel mechanism of acid and bile acid-induced DNA damage involving Na+/H+ exchanger: implication for Barrett's oesophagus.
MedLine Citation:
PMID:  20876775     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: Barrett's oesophagus is a premalignant disease associated with oesophageal adenocarcinoma. The major goal of this study was to determine the mechanism responsible for bile acid-induced alteration in intracellular pH (pH(i)) and its effect on DNA damage in cells derived from normal oesophagus (HET1A) or Barrett's oesophagus (CP-A).
DESIGN: Cells were exposed to bile acid cocktail (BA) and/or acid in the presence/absence of inhibitors of nitric oxide synthase (NOS) or sodium-hydrogen exchanger (NHE). Nitric oxide (NO), pH(i) and DNA damage were measured by fluorescent imaging and comet assay. Expression of NHE1 and NOS in cultured cells and biopsies from Barrett's oesophagus or normal squamous epithelium was determined by RT-PCR, immunoblotting or immunohistochemistry.
RESULTS: A dose dependent decrease in pH(i) was observed in CP-A cells exposed to BA. This effect of BA is the consequence of NOS activation and increased NO production, which leads to NHE inhibition. Exposure of oesophageal cells to acid in combination with BA synergistically decreased pH(i). The decrease was more pronounced in CP-A cells and resulted in >2-fold increase in DNA damage compared to acid treatment alone. Examination of biopsies and cell lines revealed robust expression of NHE1 in Barrett's oesophagus but an absence of NHE1 in normal epithelium.
CONCLUSIONS: The results of this study identify a new mechanism of bile acid-induced DNA damage. We found that bile acids present in the refluxate activate immediately all three isoforms of NOS, which leads to an increased NO production and NHE inhibition. This consequently results in increased intracellular acidification and DNA damage, which may lead to mutations and cancer progression. Therefore, we propose that in addition to gastric reflux, bile reflux should be controlled in patients with Barrett's oesophagus.
Authors:
Aaron Goldman; Mohammad Shahidullah; David Goldman; Ludmila Khailova; George Watts; Nicholas Delamere; Katerina Dvorak
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-09-28
Journal Detail:
Title:  Gut     Volume:  59     ISSN:  1468-3288     ISO Abbreviation:  Gut     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-12     Completed Date:  2010-12-10     Revised Date:  2014-09-15    
Medline Journal Info:
Nlm Unique ID:  2985108R     Medline TA:  Gut     Country:  England    
Other Details:
Languages:  eng     Pagination:  1606-16     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Barrett Esophagus / genetics*,  metabolism,  pathology
Bile Acids and Salts / pharmacology*
Cation Transport Proteins / biosynthesis,  genetics
Cell Line
DNA Damage*
Dose-Response Relationship, Drug
Drug Synergism
Enzyme Activation / drug effects
Esophagus / drug effects*,  metabolism
Humans
Hydrochloric Acid / pharmacology
Hydrogen-Ion Concentration / drug effects
Nitric Oxide / physiology
Nitric Oxide Synthase / metabolism
RNA, Messenger / genetics
Reverse Transcriptase Polymerase Chain Reaction / methods
Sodium-Hydrogen Antiporter / biosynthesis,  genetics*,  physiology
Grant Support
ID/Acronym/Agency:
CA023074-26/CA/NCI NIH HHS; CA95060/CA/NCI NIH HHS; EY06951/EY/NEI NIH HHS; P30 CA023074/CA/NCI NIH HHS; P30 ES006694/ES/NIEHS NIH HHS; P50 CA095060/CA/NCI NIH HHS; P50 CA095060-09/CA/NCI NIH HHS; R01 EY006915/EY/NEI NIH HHS; R01 EY006915-22/EY/NEI NIH HHS; T32 CA009213/CA/NCI NIH HHS; T32 CA009213-33/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Cation Transport Proteins; 0/RNA, Messenger; 0/SLC9A1 protein, human; 0/Sodium-Hydrogen Antiporter; 31C4KY9ESH/Nitric Oxide; EC 1.14.13.39/Nitric Oxide Synthase; QTT17582CB/Hydrochloric Acid
Comments/Corrections

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