Molecular Mechanisms of Acetaldehyde-Mediated Carcinogenesis in Squamous Epithelium

Abstract

Acetaldehyde is a highly reactive compound that causes various forms of damage to DNA, including DNA adducts, single- and/or double-strand breaks (DSBs), point mutations, sister chromatid exchanges (SCEs), and DNA–DNA cross-links. Among these, DNA adducts such as N2-ethylidene-2′-deoxyguanosine, N2-ethyl-2′-deoxyguanosine, N2-propano-2′-deoxyguanosine, and N2-etheno-2′-deoxyguanosine are central to acetaldehyde-mediated DNA damage because they are associated with the induction of DNA mutations, DNA–DNA cross-links, DSBs, and SCEs. Acetaldehyde is produced endogenously by alcohol metabolism and is catalyzed by aldehyde dehydrogenase 2 (ALDH2). Alcohol consumption increases blood and salivary acetaldehyde levels, especially in individuals with ALDH2 polymorphisms, which are highly associated with the risk of squamous cell carcinomas in the upper aerodigestive tract. Based on extensive epidemiological evidence, the International Agency for Research on Cancer defined acetaldehyde associated with the consumption of alcoholic beverages as a “group 1 carcinogen” (definite carcinogen) for the esophagus and/or head and neck. In this article, we review recent advances from studies of acetaldehyde-mediated carcinogenesis in the squamous epithelium, focusing especially on acetaldehyde-mediated DNA adducts. We also give attention to research on acetaldehyde-mediated DNA repair pathways such as the Fanconi anemia pathway and refer to our studies on the prevention of acetaldehyde-mediated DNA damage.

Identification of novel mutational signatures in Asian oral squamous cell carcinomas associated with bacterial infections

“…There have been several reports of conversion of ethanol into acetaldehyde by oral bacteria (Yokoi et al 2015;Tagaino et al 2019). Acetaldehyde is a known mutagen, forming DNA adducts mainly on guanines (Brooks and Zakhari 2014;Mizumoto et al 2017). Due to acetaldehyde's propensity to form adducts on guanines, it is unlikely to be the causal agent of SBS_A n T which primarily involves adenines and thymines.…”

Mutational impact of chronic alcohol use on stem cells in cirrhotic liver

“…In spite of the clear link between alcohol intake and tumorigenesis, the underlying mechanism remains debated and mainly revolves around two hypotheses. The first hypothesis suggests that alcohol consumption may contribute to the development of cancer through an increased mutation accumulation in the genome 4 . Consistently, the first metabolite of ethanol, acetaldehyde, is highly carcinogenic 5–7 and can also contribute to the formation of mutagenic reactive oxygen species (ROS) 8–11 .…”

Protective effects of N-acetylcysteine and taurine on oxidative stress induced by chronic acetaldehyde administration in rat liver and brain tissues

“…Although the liver is the primary site of ethanol oxidation, other organs in gastrointestinal system, heart and brain may also participate in the formation of AA from ethanol [1]. Therefore, many of the toxic effects of ethanol consumption is suggested to be related to AA formation in the liver and other tissues [2,3].…”

“…In addition, significant extrahepatic formation of AA takes place in the gastrointestinal system via alcohol dehydrogenase during ethanol oxidation. Therefore, marked amounts of AA may be supplied from dietary sources and generated through extrahepatic metabolism of ethanol [2,3].…”

“…Lipid peroxidation, together with the covalent binding of AA to lipids and proteins, is considered a critical process underlying AAinduced toxicity. AA may react with amino, hydroxyl and sulfhydryl groups and modify the structure and function of macromolecules such as DNA, proteins and enzymes [1][2][3]. In addition, AA induces apoptosis and increases the formation of inflammatory mediators [1,5,6].…”