Increased DNA Damage in ALDH2-Deficient Alcoholics

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Abstract
Drinking alcohol is a risk factor for cancers of the oral cavity, pharynx, larynx, and esophagus. Although many studies suggest that acetaldehyde, a major metabolite of orally ingested alcohol, plays a crucial role in cancer initiation, the link between the aldehyde dehydrogenase-2 (ALDH2) genotype and acetaldehyde-derived DNA damage has not yet been explored. We have developed a sensitive and quantitative method for detecting the acetaldehyde-derived DNA adducts, N2-ethyl-2‘-deoxyguanosine (N2-Et-dG), α-S- and α-R-methyl-γ-hydroxy-1,N2-propano-2‘-deoxyguanosine (α-S-Me-γ-OH-PdG and α-R-Me-γ-OH-PdG), and N2-(2,6-dimethyl-1,3-dioxan-4-yl)-deoxyguanosine (N2-Dio-dG), by using liquid chromatography electrospray tandem mass spectrometry (LC/ESI-MS/MS) and stable-isotope internal standards. We determined the DNA adducts in 44 blood DNA samples from Japanese alcoholic patients. The levels of three acetaldehyde-derived DNA adducts, N2-Et-dG, α-S-Me-γ-OH-PdG, and α-R-Me-γ-OH-PdG, were significantly higher in alcoholics with the ALDH2*1/2*2 genotype compared to those with the ALDH2*1/2*1 genotype. N2-Dio-dG was not detected in any of the DNA samples analyzed. These results provide molecular evidence that the ALDH2 genotype affects the genotoxic damage caused by acetaldehyde.
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