In Barrett's esophagus patients and Barrett's cell lines, ursodeoxycholic acid increases antioxidant expression and prevents DNA damage by bile acids.
Hydrophobic bile acids like deoxycholic acid (DCA), which cause oxidative DNA damage and activate NF-κB in Barrett's metaplasia, might contribute to carcinogenesis in Barrett's esophagus. We have explored mechanisms whereby ursodeoxycholic acid (UDCA, a hydrophilic bile acid) protects against DCA-induced injury in vivo in patients and in vitro using nonneoplastic, telomerase-immortalized Barrett's cell lines. We took biopsies of Barrett's esophagus from 21 patients before and after esophageal perfusion with DCA (250 μM) at baseline and after 8 wk of oral UDCA treatment. DNA damage was assessed by phospho-H2AX expression, neutral CometAssay, and phospho-H2AX nuclear foci formation. Quantitative PCR was performed for antioxidants including catalase and GPX1. Nrf2, catalase, and GPX1 were knocked down with siRNAs. Reporter assays were performed using a plasmid construct containing antioxidant responsive element. In patients, baseline esophageal perfusion with DCA significantly increased phospho-H2AX and phospho-p65 in Barrett's metaplasia. Oral UDCA increased GPX1 and catalase levels in Barrett's metaplasia and prevented DCA perfusion from inducing DNA damage and NF-κB activation. In cells, DCA-induced DNA damage and NF-κB activation was prevented by 24-h pretreatment with UDCA, but not by mixing UDCA with DCA. UDCA activated Nrf2 signaling to increase GPX1 and catalase expression, and protective effects of UDCA pretreatment were blocked by siRNA knockdown of these antioxidants. UDCA increases expression of antioxidants that prevent toxic bile acids from causing DNA damage and NF-κB activation in Barrett's metaplasia. Elucidation of this molecular pathway for UDCA protection provides rationale for clinical trials on UDCA for chemoprevention in Barrett's esophagus.
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas; Division of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Sui
S
Peng
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas;
Xiaofang
X
Huo
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Research and Development, VA North Texas Heath Care System, Dallas, Texas;
Davood
D
Rezaei
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas;
Qiuyang
Q
Zhang
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas;
Xi
X
Zhang
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas;
Chunhua
C
Yu
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas;
Kiyotaka
K
Asanuma
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Pediatrics, Children's Medical Center and the University of Texas Southwestern Medical Center, Dallas, Texas;
Edaire
E
Cheng
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas;
Thai H
TH
Pham
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas;
David H
DH
Wang
Division of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Minhu
M
Chen
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas; rhonda.souza@utsouthwestern.edu.
Rhonda F
RF
Souza
Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas, Department of Internal Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, Texas;
Stuart Jon
SJ
Spechler
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D001471:Barrett Esophagus / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects*; D003840:Deoxycholic Acid / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004947:Esophagus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome; D015854:Up-Regulation; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*; D000094765:Glutathione Peroxidase GPX1
D016588:Anticarcinogenic Agents; D000975:Antioxidants; C468783:H2AX protein, human; D006657:Histones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C498143:RELA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D002374:Catalase; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human
GPX1; bile acids; catalase; chemoprevention; esophageal adenocarcinoma