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.
Highlights
Alcohol is a major risk factor for upper gastrointestinal (GI) tract cancer and exhibits a dose-dependent effect on the incidence of oropharyngeal and esophageal squamous cell cancers [1].A similar but weaker dose-risk relationship exists with alcohol-related gastric cancer [1,2]
According to benchmark dose values (BMDL) modeling, aldehyde dehydrogenase 2 (ALDH2)-deficient heavy drinkers can be calculated to be exposed to a mean of 6.7 μg/kg bw/day of additional ACH via saliva compared to ALDH2-active individuals [7]
There is no evidence that ACH derived from ethanol present sometimes in percentage concentrations in “non-alcoholic” beverages or food is less carcinogenic to the upper GI tract mucosa than ACH formed metabolically from the ethanol of official alcoholic beverages
Summary
Alcohol is a major risk factor for upper gastrointestinal (GI) tract cancer and exhibits a dose-dependent effect on the incidence of oropharyngeal and esophageal squamous cell cancers [1]. Its first metabolite, acetaldehyde (ACH), is a group 1 carcinogen to humans when associated with consumption of alcoholic beverages [5]. A point mutation in the aldehyde dehydrogenase 2 (ALDH2) gene results in deficient activity of the main ACH-metabolizing mitochondrial enzyme (ALDH2) and proves conclusively the causal relationship between local ACH exposure and upper GI tract cancers (Table 1; [7,8]). Bacteria and yeasts present in the normal upper GI tract microbiome play a major role in local ACH formation from ethanol present either in alcoholic beverages or food. Adequate data on salivary ACH in ALDH2-deficient subjects vs ALDH2-active subjects; equivalent data on ACH of the mucosal surface of the esophagus is still unavailable Adequate epidemiological data on the role of ALDH2 polymorphisms on the risk for oropharyngeal cancer among never, moderate, and heavy drinkers. Diet, consumption of different beverages, varying drinking habits, underreporting, oral hygiene levels, human papilloma virus (HPV), body mass index (BMI)
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