MAJOR ROLE OF ACETALDEHYDE IN UPPER GI TRACT CANCER

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Salaspuro M

Research Unit on Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland

A key factor in acetaldehyde associated carcinogenesis is its local accumulation after alcohol drinking in the upper digestive tract. A dose of alcohol results in mutagenic salivary acetaldehyde concentrations, and the enhanced local acetaldehyde exposure continues for as long as ethanol stays in the water phase of human body. Acetaldehyde accumulates in the upper digestive tract because of the local oxidation of ethanol to acetaldehyde by the normal upper digestive tract microbial flora, parotid glands and mucosal cells. However, unlike the liver these structures are not sufficiently capable for the detoxification of acetaldehyde.
A single point mutation in ALDH2-gene provides conclusive evidence for a causal relationship between acetaldehyde and upper GI tract cancer. Mutation results in deficient activity of the main acetaldehyde metabolizing enzyme mitochondrial aldehyde dehydrogenase (ALDH2). When drinking alcohol, ALDH2-deficients are exposed via saliva to 2-3 times and via gastric juice to 5-6 times higher acetaldehyde concentrations than individuals with active ALDH2-enzyme. Parallel to increased local acetaldehyde exposure, the risk of ALDH2-deficient alcohol drinkers for oral, pharyngeal, esophageal and gastric cancer is many fold compared to alcohol drinking ALDH2-actives. Based on strong gene-epidemiological and gene-biochemical evidence, the International Agency for Research on Cancer (IARC) has reclassified acetaldehyde associated with the consumption of alcoholic beverages as a group 1 human carcinogen. Equal gene mutation based human cancer model is not available for any other of the 118 group 1 human carcinogens.
Acetaldehyde presumably is the most common human carcinogen. In addition to acetaldehyde formed from ethanol, high concentrations of ‘free’ acetaldehyde are present in many alcoholic beverages and as well in some foodstuffs produced by fermentation. Acetaldehyde is widely used as aroma agent and food additive. It is the most abundant carcinogen of tobacco smoke that dissolves in saliva during smoking and is by that means distributed to the mucosal surfaces of the whole upper GI tract. Knowledge of the mechanisms regulating local acetaldehyde levels in the upper digestive tract provides a variety of methods for the reduction of local acetaldehyde exposure both at a population and individual level.

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