Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers
The key issue in cancer prevention is the identification of specific aetiologic factors. Acetaldehyde, the first metabolite of ethanol oxidation, is carcinogenic in animals. ADH and ALDH2 gene mutations provide an exceptional human model to estimate the long-term effects of acetaldehyde exposure in man. These models provide strong evidence for the local carcinogenic potential of acetaldehyde also in humans. Ethanol is metabolized to acetaldehyde by both mucosal and microbial enzymes. Many microbes produce acetaldehyde from ethanol, but their capacity to eliminate acetaldehyde is low, which leads to the accumulation of acetaldehyde in saliva during an alcohol challenge. Acetaldehyde is the most abundant carcinogen in tobacco smoke, and it readily dissolves into saliva during smoking. Fermented food and many alcoholic beverages can also contain significant amounts of acetaldehyde. Thus acetaldehyde, derived from mucosal or microbial oxidation of ethanol, tobacco smoke, and/or diet, appears to act as a cumulative carcinogen in the upper digestive tract of humans. The evidence strongly suggests the importance of world-wide screening of acetaldehyde and ethanol levels in many beverages and foodstuffs, as well as an urgent need for regulatory measures and consumer guidance. Screening of the risk groups with enhanced acetaldehyde exposure, e.g. people with ADH and ALDH2 gene polymorphisms and hypochlorhydric atrophic gastritis, should also be seriously considered. Most importantly, the GRAS (generally regarded as safe) status of acetaldehyde, which allows it to be used as a food additive, should be re-evaluated, and the classification of acetaldehyde as a carcinogen should be upgraded.
...
Contribution of alcohol and tobacco use in gastrointestinal cancer development.
Tobacco smoke and alcohol are major risk factors for a variety of cancer sites, including those of the gastrointestinal tract. Tobacco smoke contains a great number of mutagenic and carcinogenic compounds, including polycyclic carbohydrates, nitrosamines, and nicotine, while ethanol per se has only weak carcinogenic potential, but its first metabolite, acetaldehyde, is a mutagen and carcinogen, since it forms stable adducts with DNA. The possibility of proto-oncogene mutation in gastrointestinal mucosa cells may be associated with tobacco smoking-induced cancers through the formation of unfavorable DNA adducts. Individuals with defective DNA repair mechanisms and unfavorable genetic make-up for carcinogen metabolism may be at increased risk for gastrointestinal cancers. Individuals with a high production rate of acetaldehyde from ethanol also have an increased cancer risk when they drink chronically. These include individuals with a genetically determined increased acetaldehyde production due to alcohol dehydrogenase polymorphism and those with a decreased detoxification of acetaldehyde due to acetaldehyde dehydrogenase mutation. In addition, oral bacterial overgrowth due to poor oral hygiene also increases salivary acetaldehyde. Dietary deficiencies such as a lack of folate, riboflavine, and zinc may also contribute to the increase cancer risk in the alcoholic patient. It is of considerable importance that smoking and drinking act synergistically. Smoking increases the acetaldehyde burden following alcohol consumption and drinking enhances the activation of various procarcinogens present in tobacco smoke due to increased metabolic activation by an induced cytochrome P450-2E1-dependent microsomal biotransformation system in the mucosa of the upper digestive tract and the liver.
