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

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 10⁷ 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 10⁷ 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.