Unique human cancer model for acetaldehyde based on Mendelian randomization
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LETTER TO THE EDITOR, NEWS AND VIEWS
Unique human cancer model for acetaldehyde based on Mendelian randomization Mikko Salaspuro1 · Dirk W. Lachenmeier2 Received: 13 July 2020 / Accepted: 13 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
In their extensive review on the mode of action-based risk assessment of genotoxic carcinogens, the authors conclude that local concentrations of ethanol and acetaldehyde in the digestive tract seem to play a major role in the development of cancer (Hartwig et al. 2020). We strongly agree with this statement for four major reasons. (1) Congruent mechanistic and epidemiological evidence, based on Mendelian randomization, highlights the crucial role of local acetaldehyde in alcohol-related upper digestive tract cancer. (2) Updated knowledge of the biochemical mechanisms regulating salivary acetaldehyde concentrations during and after alcohol drinking emphasizes the key role of oral microbes and aldehyde dehydrogenase 2 (ALDH2) enzyme in the local exposure to carcinogenic acetaldehyde via saliva. (3) The unique human cancer model based on ALDH2 deficiency offers entirely new possibilities for the quantitative assessment of the excess acetaldehyde exposure via saliva in relation to increased alcohol-related oropharyngeal cancer risk. (4) Identifying a specific carcinogenic agent is a key factor in cancer prevention. 1. A single point mutation in the ALDH2 gene conclusively proves the causal role of local acetaldehyde in alcohol-related upper digestive tract and particularly in oropharyngeal and oesophageal cancers (Lachenmeier and Salaspuro 2017). Mutation results in deficient activity of mitochondrial ALDH2 enzyme, which leads to markedly increased local acetaldehyde exposure via saliva following alcohol drinking and concomitantly to dose-dependently increased risk for oropharyngeal and oesophageal cancer. The worldwide carrier frequency of * Mikko Salaspuro [email protected] 1
Research Unit On Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland
Chemisches Und Vetrinäruntersuchungsamt (CVUA) Karlsruhe, Karlsruhe, Germany
2
the mutation is about 600 million people of East-Asian descent. Because the mutation is randomized by nature, it lacks the bias caused by confounding factors typically reducing the informativeness of epidemiological studies on alcohol-related cancer. Smoking, under-reporting of alcohol consumption, diet, drinking habits, use of different types of alcoholic beverages, oral hygiene, human papillomavirus infection and body mass index can be assumed to be evenly distributed among ALDH2deficient and ALDH2-active alcohol drinkers. No other genotoxic carcinogen has equally strong gene–epidemiological and gene–biochemical evidence for its carcinogenicity in humans. 2. The free acetaldehyde molecule is mutagenic and carcinogenic due to its highly reactive –CHO group. After a dose of alcohol, mutagenic (> 100 µM) concentrations of free acetaldehyde are found in saliva and gastric juice of humans and in colonic con
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