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.

Keywords: ADH; ALDH; ALDH2; acetaldehyde; alcohol; cancer; ethanol; fermented food; tobacco; upper gastrointestinal tract.

Figure 1

Schematic overview of the major factors contributing to salivary acetaldehyde (ACH) levels and therefore the local ACH exposure of oropharyngeal mucosa. ACH exposure leads to molecular changes and mutagenesis, including DNA-adduct formation, DNA-protein crosslinks, DNA strand breaks and chromosomal aberrations. Locally, these changes may lead to dysplasia and further into oropharyngeal cancer. Microbial and host metabolism share the ability to convert ethanol to ACH by the alcohol dehydrogenase enzyme (ADH). There is plethora of microbes that possess highly-active ADH enzymes. However, the subsequent conversion of ACH to less harmful substances seems to be very limited due to the lack of active aldehyde dehydrogenase (ALDH) enzymes in both microbial and oropharyngeal mucosal cells. In contrast to the human host, ethanol fermentation is a specific trait for microbes. In low oxygen tension, sugars derived from dietary sources, such as glucose and fructose, are converted into ethanol and ACH is formed as a byproduct. The possible contribution of fermentative pathways from glucose to local ACH production and further to ethanol has not been explored thus far in vivo. In addition to alcoholic beverages and spirits, multiple dietary constituents can contain ethanol, ACH, or both. There are also other sources of ethanol, such as hygiene products, including daily oral mouthwash use. In addition to alcohol, tobacco is the major contributor to salivary ACH.