Acetaldehyde (ACH) associated with alcoholic beverages is Group 1 carcinogen to 
humans (IARC/WHO). Aldehyde dehydrogenase (ALDH2), a major ACH eliminating 
enzyme, is genetically deficient in 30-50% of Eastern Asians. In alcohol 
drinkers, ALDH2-deficiency is a well-known risk factor for upper aerodigestive 
tract cancers, i.e., head and neck cancer and esophageal cancer. However, there 
is only a limited evidence for stomach cancer. In this study we demonstrated for 
the first time that ALDH2 deficiency results in markedly increased exposure of 
the gastric mucosa to acetaldehyde after intragastric administration of alcohol. 
Our finding provides concrete evidence for a causal relationship between 
acetaldehyde and gastric carcinogenesis. A plausible explanation is the gastric 
first pass metabolism of ethanol. The gastric mucosa expresses alcohol 
dehydrogenase (ADH) enzymes catalyzing the oxidation of ethanol to acetaldehyde, 
especially at the high ethanol concentrations prevailing in the stomach after 
the consumption of alcoholic beverages. The gastric mucosa also possesses the 
acetaldehyde-eliminating ALDH2 enzyme. Due to decreased mucosal ALDH2 activity, 
the elimination of ethanol-derived acetaldehyde is decreased, which results in 
its accumulation in the gastric juice. We also demonstrate that ALDH2 
deficiency, proton pump inhibitor (PPI) treatment, and L-cysteine cause 
independent changes in gastric juice and salivary acetaldehyde levels, 
indicating that intragastric acetaldehyde is locally regulated by gastric 
mucosal ADH and ALDH2 enzymes, and by oral microbes colonizing an achlorhydric 
stomach. Markedly elevated acetaldehyde levels were also found at low 
intragastric ethanol concentrations corresponding to the ethanol levels of many 
foodstuffs, beverages, and dairy products produced by fermentation. A capsule 
that slowly releases L-cysteine effectively eliminated acetaldehyde from the 
gastric juice of PPI-treated ALDH2-active and ALDH2-deficient subjects. These 
results provide entirely novel perspectives for the prevention of gastric 
cancer, especially in established risk groups.