Acetaldehyde-DNA Adducts: Implications for the Molecular Mechanism of Alcohol-Related CarcinogenesisBrooks P. · Theruvathu J.
Section on Molecular Neurobiology, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Md., USA
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Alcoholic beverage consumption is classified as a known human carcinogen, causally related to an increased risk of cancer of the upper aerodigestive tract. The formation of acetaldehyde from ethanol metabolism appears to be the major mechanism underlying this effect. Acetaldehyde has been shown to cause cancer in animals, and is classified as a suspected human carcinogen. In human cells, acetaldehyde causes sister chromatid exchanges and chromosomal aberrations. In this chapter, we focus on the mechanisms by which a specific DNA adduct, α-methyl-γ-hydroxy-1, N2-propano-2´-deoxyguanosine (Cr-PdG), is formed from the reaction of acetaldehyde and DNA. We compare the mechanism of formation and biological properties of this adduct with another, well known acetaldehyde-DNA adduct, N2-ethyl-dG, and describe how the genotoxic properties of the Cr-PdG adduct can explain many of the known genotoxic effects of acetaldehyde. We propose that while N2-ethyl-dG is a good marker for acetaldehyde reaction with DNA, the Cr-PdG adduct is likely to play a central role in the mechanism of alcoholic beverage related carcinogenesis. We also discuss the DNA repair pathways responsible for protecting the human genome from this adduct, with the goal of identifying candidate DNA repair genes in which variation may affect the risk of cancer.
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