title: Impairment of aldehyde dehydrogenase 2 increases accumulation of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion.
abstract: Ethanol and its metabolite, acetaldehyde, are the definite carcinogens for esophageal squamous cell carcinoma (ESCC), and reduced catalytic activity of aldehyde dehydrogenase 2 (ALDH2), which detoxifies acetaldehyde, increases the risk for ESCC. However, it remains unknown whether the ALDH2 genotype influences the level of acetaldehyde-derived DNA damage in the esophagus after ethanol ingestion. In the present study, we administered ethanol orally or intraperitoneally to Aldh2-knockout and control mice, and we quantified the level of acetaldehyde-derived DNA damage, especially N(2) -ethylidene-2'-deoxyguanosine (N(2) -ethylidene-dG), in the esophagus. In the model of oral ethanol administration, the esophageal N(2) -ethylidene-dG level was significantly higher in Aldh2-knockout mice compared with control mice. Similarly, in the model of intraperitoneal ethanol administration, in which the esophagus is not exposed directly to the alcohol solution, the esophageal N(2) -ethylidene-dG level was also elevated in Aldh2-knockout mice. This result indicates that circulating ethanol-derived acetaldehyde causes esophageal DNA damage, and that the extent of damage is influenced by knockout of Aldh2. Taken together, our findings strongly suggest the importance of acetaldehyde-derived DNA damage which is induced in the esophagus of individuals with ALDH2 gene impairment. This provides a physiological basis for understanding alcohol-related esophageal carcinogenesis.
authors: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto, Japan.
authors: Yoshiyuki
authors: Y
authors: Yukawa
authors: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto, Japan ; Institute for Advancement of Clinical and Translational Science (iACT), Kyoto University Hospital Kyoto, Japan.
authors: Shinya
authors: S
authors: Ohashi
authors: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto, Japan.
authors: Yusuke
authors: Y
authors: Amanuma
authors: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto, Japan.
authors: Yukie
authors: Y
authors: Nakai
authors: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto, Japan.
authors: Mihoko
authors: M
authors: Tsurumaki
authors: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto, Japan.
authors: Osamu
authors: O
authors: Kikuchi
authors: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto, Japan.
authors: Shin'ichi
authors: S
authors: Miyamoto
authors: Department of Environmental Health, School of Medicine, University of Occupational and Environmental Health Fukuoka, Japan.
authors: Tsunehiro
authors: T
authors: Oyama
authors: Department of Environmental Health, School of Medicine, University of Occupational and Environmental Health Fukuoka, Japan.
authors: Toshihiro
authors: T
authors: Kawamoto
authors: Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine Kyoto, Japan.
authors: Tsutomu
authors: T
authors: Chiba
authors: Research Center for Environmental Quality Management, Kyoto University Otsu, Japan.
authors: Tomonari
authors: T
authors: Matsuda
authors: Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine Kyoto, Japan.
authors: Manabu
authors: M
authors: Muto
keywords: Carcinogenesis; DNA adduct; acetaldehyde; acetaldehyde-derived DNA damage; esophageal squamous cell carcinoma