Kinetics of DNA Adduct Formation in the Oral Cavity after Drinking Alcohol

Abstract

Background Alcohol consumption is one of the top-10 risks for the worldwide burden of disease and an established cause of head and neck cancer as well as cancer at other sites. Acetaldehyde, the major metabolite of ethanol, reacts with DNA to produce adducts, which are critical in the carcinogenic process and can serve as biomarkers of exposure and possibly of disease risk. Acetaldehyde associated with alcohol consumption is considered “carcinogenic to humans”. We have previously developed the technology to quantify acetaldehyde-DNA adducts in human tissues, but there are no studies in the literature defining the formation and removal of acetaldehyde-DNA adducts in people who consumed alcohol. Methods We investigated levels of N2-ethylidene-dGuo, the major DNA adduct of acetaldehyde, in DNA from human oral cells at several time points after consumption of increasing alcohol doses. Ten healthy non-smokers were dosed once a week for three weeks. Mouthwash samples were collected before and at several time points after the dose. N2-Ethylidene-dGuo was measured as its NaBH3CN reduction product N2-ethyl-dGuo by LC-ESI-MS/MS. Results N2-ethylidene-dGuo levels increased as much as 100-fold from baseline within 4h after each dose for all subjects and in a dose responsive manner (p = 0.001). Conclusion These results demonstrate an effect of alcohol on oral cell DNA adduct formation, strongly supporting the key role of acetaldehyde in head and neck cancer caused by alcohol drinking. Impact Our results provide some of the first conclusive evidence linking exposure to a lifestyle carcinogen and kinetics of DNA adduct formation in humans.

Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

“…As the most abundant DNA adduct, N 2 -ethylidene-2′-deoxyguanosine (N 2 -EtidG), impairs the DNA repair system and apoptosis [26]. The level of N 2 -EtidG is increased in oro-esophageal epithelial cells after alcohol drinking in mice [76] and humans [77]. Moreover, the N 2 -EtidG level is dependent on ALDH2 and ADH genotypes.…”

Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo

“…Further, an elevated risk of hepatocarcinoma and its recurrence occurs among hepatitis C-infected patients with the ALDH2*2 mutation (17). Acetaldehyde levels are particularly high in the saliva after ethanol ingestion (18), leading to a significant increase in acetaldehyde-DNA adduct levels in ALDH2*1/*2 heterozygotes, even after moderate ethanol consumption (19). Because acetaldehyde is a carcinogen, and the duration and extent of exposure influences its toxicity, increasing the rate of acetaldehyde elimination, especially in ALDH2*1/*2 heterozygotes, may reduce important health risks.…”

A Perspective on Chemoprevention by Resveratrol in Head and Neck Squamous Cell Carcinoma

“…There are ample evidences showing that exposure to acetaldehyde produce mucosal lesions and adenocarcinomas in the nasal mucosa in rats [ 32 , 70 ]. A study by Balbo and colleague have reported that N 2 -ethyl-2′-deoxyguanosine, a major acetaldehyde derived-DNA adduct was increased by several-fold from baseline after alcohol use in humans [ 2 ]. Genetic evidence suggests that individuals having fast metabolites alleles variants for ADHs [ADH1B*2, ADH1C*1] and the null allele for ALDH 2 [ALDH2*2] have increased acetaldehyde levels and inefficient alcohol metabolism, thereby increasing susceptibility to cancer after alcohol consumption [ 9 , 57 , 7 ].…”