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Increased DNA damage in ALDH2-deficient alcoholics
Tomonari Matsuda1, Hisatoshi Yabushita, Robert A Kanaly
1Department of Technology and Ecology, Graduate School of Global Environmental Studies, Kyoto University, Kyoto, Japan. matsuda@eden.env.kyoto-u.ac.jp
Chemical Research in Toxicology
|October 17, 2006
Summary
Alcohol consumption increases cancer risk. The aldehyde dehydrogenase-2 (ALDH2) genotype influences acetaldehyde-induced DNA damage in alcoholics, with higher adducts found in the ALDH2 1/2 2 genotype.
Area of Science:
- Biochemistry
- Genetics
- Cancer Research
Background:
- Alcohol consumption is a known risk factor for several cancers, including oral cavity, pharynx, larynx, and esophagus.
- Acetaldehyde, a major alcohol metabolite, is implicated in cancer initiation, but its link to specific genetic variations and DNA damage is not fully understood.
Purpose of the Study:
- To investigate the relationship between aldehyde dehydrogenase-2 (ALDH2) genotype and acetaldehyde-derived DNA damage.
- To develop and apply a sensitive method for quantifying specific acetaldehyde DNA adducts.
Main Methods:
- Development of a liquid chromatography electrospray tandem mass spectrometry (LC/ESI-MS/MS) method for detecting N(2)-ethyl-2'-deoxyguanosine (N(2)-Et-dG), alpha-S- and alpha-R-methyl-gamma-hydroxy-1,N(2)-propano-2'-deoxyguanosine (alpha-S-Me-gamma-OH-PdG and alpha-R-Me-gamma-OH-PdG), and N(2)-(2,6-dimethyl-1,3-dioxan-4-yl)-deoxyguanosine (N(2)-Dio-dG).
- Analysis of DNA adducts in blood samples from 44 Japanese alcoholic patients using stable-isotope internal standards.
Main Results:
- Significantly higher levels of N(2)-Et-dG, alpha-S-Me-gamma-OH-PdG, and alpha-R-Me-gamma-OH-PdG were observed in alcoholics with the ALDH2 1/2 2 genotype compared to those with the ALDH2 1/2 1 genotype.
- The DNA adduct N(2)-Dio-dG was not detected in any of the analyzed samples.
Conclusions:
- The ALDH2 genotype significantly impacts the level of genotoxic DNA damage induced by acetaldehyde.
- These findings provide molecular evidence linking alcohol metabolism, genetic predisposition (ALDH2 genotype), and cancer risk through DNA adduct formation.
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