Increased formation of hepatic N2-ethylidene-2'-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2-knockout mice treated with ethanol

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Abstract
N2 -ethylidene-2′-deoxyguanosine ( N2 -ethylidene-dG) is a major DNA adduct induced by acetaldehyde. Although it is unstable in the nucleoside form, it is relatively stable when present in DNA. In this study, we analyzed three acetaldehyde-derived DNA adducts, N2 -ethylidene-dG, N2 -ethyl-2′-deoxyguanosine ( N2 -Et-dG) and α-methyl-γ-hydroxy-1, N2 -propano-2′-deoxyguanosine (α-Me-γ-OH-PdG) in the liver DNA of aldehyde dehydrogenase ( Aldh )- 2 -knockout mice to determine the influence of alcohol consumption and the Aldh2 genotype on the levels of DNA damage. In control Aldh2 +/+ mice, the level of N2 -ethylidene-dG adduct in liver DNA was 1.9 ± 0.7 adducts per 10 7 bases and was not significantly different than that of Aldh2 +/− and −/− mice. In alcohol-fed mice (20% ethanol for 5 weeks), the adduct levels of Aldh2 +/+, +/− and −/− mice were 7.9 ± 1.8, 23.3 ± 4.0 and 79.9 ± 14.2 adducts per 10 7 bases, respectively, and indicated that adduct level was alcohol and Aldh2 genotype dependent. In contrast, an alcohol- or Aldh2 genotype-dependent increase was not observed for α-Me-γ-OH-PdG, and N2 -Et-dG was not detected in any of the analyzed samples. In conclusion, the risk of formation of N2 -ethylidene-dG in model animal liver in vivo is significantly higher in the Aldh2 -deficient population and these results may contribute to our understanding of in vivo adduct formation in humans.

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