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Title: Protective effects of Alda-1, an ALDH2 activator, on alcohol-derived DNA damage in the esophagus of human ALDH2*2 (Glu504Lys) knock-in mice
Authors: Hirohashi, Kenshiro
Ohashi, Shinya
Amanuma, Yusuke
Nakai, Yukie
Ida, Tomomi
Baba, Kiichiro
Mitani, Yosuke
Mizumoto, Ayaka
Yamamoto, Yoshihiro
Kikuchi, Osamu
Matsubara, Junichi
Yamada, Atsushi
Miyamoto, Shin’ichi
Seno, Hiroshi
Matsuda, Tomonari
Muto, Manabu
Author's alias: 廣橋, 研志郎
大橋, 真也
天沼, 裕介
中井, 由起恵
井田, 有美
三谷, 洋介
水本, 綾佳
山本, 佳宏
菊池, 理
松原, 淳一
山田, 敦
宮本, 心一
妹尾, 浩
松田, 知成
武藤, 学
Issue Date: 10-May-2019
Publisher: Oxford University Press (OUP)
Journal title: Carcinogenesis
Thesis number: bgz091
Abstract: Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2′-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.
Rights: © The Author(s) 2019. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
URI: http://hdl.handle.net/2433/242864
DOI(Published Version): 10.1093/carcin/bgz091
PubMed ID: 31074772
Appears in Collections:Journal Articles

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