Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: Relevance to the pathogenesis of Barrett’s Oesophagus

Katerina Dvorak ^1*, Claire M Payne ¹, Melissa Chavarria ¹, Lois Ramsey ², Barbora Dvorakova ¹, Harris Bernstein ¹, Hana Holubec ¹, Richard E Sampliner ², Naihsuan Guy ¹, Amanda Condon ¹, Carol Bernstein ¹, Sylvan B Green ¹, Anil Prasad ² and Harinder S Garewal ¹

¹ University of Arizona, United States
² Southern Arizona VA Health Care System, United States

^* To whom correspondence should be addressed. E-mail: kdvorak{at}email.arizona.edu.

Accepted 30 October 2006

Abstract

Objectives: Barrett's oesophagus (BO) is a premalignant condition associated with elevated risk for the development of oesophageal adenocarcinoma (ADCA). Previous studies indicated that oxidative damage contributes to the development of ADCA. Here we tested the hypothesis that bile acids and gastric acid, two components of refluxate, can induce oxidative stress and oxidative DNA damage.

Methods: Oxidative stress was evaluated by staining with 8-hydroxy-deoxyguanosine (8-OH-dG) antibody in BO tissues with different degrees of dysplasia. The levels of 8-OH-dG were also evaluated ex vivo in BO tissues incubated for 10 minutes with control medium and medium acidified to pH 4 and supplemented with 0.5 mM bile acid cocktail. Furthermore, three oesophageal cell lines (Seg-1 cells, BO cells and HET-1A cells) were exposed to control media, media containing bile acid cocktail, media acidified to pH 4, and media at pH 4 supplemented with bile acid cocktail and evaluated for induction of reactive oxygen species (ROS).

Results: Immunohistochemical analysis showed that 8-OH-dG is formed mainly in the epithelial cells in dysplastic BO. Importantly, incubation of BO tissues with the combination of bile acid cocktail and acid leads to increased formation of 8-OH-dG. An increase in ROS in oesophageal cells was detected after exposure to pH 4 and bile acid cocktail.

Conclusions: Oxidative stress and oxidative DNA damage can be induced in oesophageal tissues and cells by short exposures to bile acids and low pH. These alterations may underlie the development of BO and tumor progression.

Keywords: Barrett's esophagus, bile acids, oxidative DNA damage, oxidative stress

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