In Barrett's Epithelial Cells, Weakly Acidic Bile Salt Solutions Cause Oxidative DNA Damage with Response and Repair Mediated by p38.

In Barrett's Epithelial Cells, Weakly Acidic Bile Salt Solutions Cause Oxidative DNA Damage with Response and Repair Mediated by p38. Am J Physiol Gastrointest Liver Physiol. 2020 Jan 27;: Authors: Huo X, Dunbar KB, Zhang X, Zhang Q, Spechler SJ, Souza RF Abstract The frequency of esophageal adenocarcinoma is rising despite widespread use of PPIs, which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett's esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett's cells. Since p53 is inactivated frequently in Barrett's esophagus and p38 can assume p53 functions, we explored p38's role in DNA damage response and repair. We exposed Barrett's cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38-dependent. We also measured phospho-p38 in biopsies of Barrett's metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced BrdU incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with Ref-1/APE1. Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All these effects were...
Source: Am J Physiol Gastroi... - Category: Gastroenterology Authors: Tags: Am J Physiol Gastrointest Liver Physiol Source Type: research