Local Acetaldehyde—An Essential Role in Alcohol-Related Upper Gastrointestinal Tract Carcinogenesis

Abstract

The resident microbiome plays a key role in exposure of the upper gastrointestinal (GI) tract mucosa to acetaldehyde (ACH), a carcinogenic metabolite of ethanol. Poor oral health is a significant risk factor for oral and esophageal carcinogenesis and is characterized by a dysbiotic microbiome. Dysbiosis leads to increased growth of opportunistic pathogens (such as Candida yeasts) and may cause an up to 100% increase in the local ACH production, which is further modified by organ-specific expression and gene polymorphisms of ethanol-metabolizing and ACH-metabolizing enzymes. A point mutation in the aldehyde dehydrogenase 2 gene has randomized millions of alcohol consumers to markedly increased local ACH exposure via saliva and gastric juice, which is associated with a manifold risk for upper GI tract cancers. This human cancer model proves conclusively the causal relationship between ACH and upper GI tract carcinogenesis and provides novel possibilities for the quantitative assessment of ACH carcinogenicity in the human oropharynx. ACH formed from ethanol present in “non-alcoholic” beverages, fermented food, or added during food preparation forms a significant epidemiologic bias in cancer epidemiology. The same also concerns “free” ACH present in mutagenic concentrations in multiple beverages and foodstuffs. Local exposure to ACH is cumulative and can be reduced markedly both at the population and individual level. At best, a person would never consume tobacco, alcohol, or both. However, even smoking cessation and moderation of alcohol consumption are associated with a marked decrease in local ACH exposure and cancer risk, especially among established risk groups.

Alcohol and mouth cancer

“…Although, it has been noted that the drink that is most frequently consumed in a particular country is the one most strongly associated with oral cancer, there is evidence that fruit based spirits (example Grappa) can contain extremely high levels of ACH (up to 1850 mg per litre or 45 mmol). 8,14,15 . This high level of intake of such spirits especially prevalent in central European countries may help explain the high incidence of alcoholrelated upper aerodigestive tract cancers 8 In addition, there may be volatile and non-volatile flavour compounds entries and impurities that may be carcinogenic (example, polycyclic aromatic hydrocarbons) 16 .…”

“…8,14,15 . This high level of intake of such spirits especially prevalent in central European countries may help explain the high incidence of alcoholrelated upper aerodigestive tract cancers 8 In addition, there may be volatile and non-volatile flavour compounds entries and impurities that may be carcinogenic (example, polycyclic aromatic hydrocarbons) 16 . Wine also contains phytochemicals(polyphenols derived from plant phenylalanine) 3 .…”

“…For example, cancer warnings could be added to the labels attached to alcoholic beverage 7 although even then it is unclear how effective these are in countries where this has been attempted. It has been suggested that they should be mandatory labelling of acetaldehyde (ACH) as well as alcohol concentrations 8 . Taking an alcohol history can be problematic as it may fluctuate more frequently (binge drinking at weekends rather than regular daily intake) than a smoking history, which remains fairly stable each day.…”

Molecular docking explores heightened immunogenicity and structural dynamics of acetaldehyde human immunoglobulin G adduct

“…Acetaldehyde (AA) is associated with the consumption of alcoholic beverages and is classified as a Group 1 human carcinogen by the International Agency for Research on Cancer (IARC) . The most important exogenous sources for human AA exposure are alcoholic beverages, tobacco, and alcohol‐containing or AA‐containing (or both) “nonalcoholic” beverages and food . Acetaldehyde is highly toxic, carcinogenic, and mutagenic.…”

“…1 The most important exogenous sources for human AA exposure are alcoholic beverages, tobacco, and alcoholcontaining or AA-containing (or both) "nonalcoholic" beverages and food. 2 Acetaldehyde is highly toxic, carcinogenic, and mutagenic. It binds to DNA and proteins, destroys folate resulting in secondary hyperproliferation.…”