Carcinogenesis Advance Access published online on March 14, 2007
Carcinogenesis, doi:10.1093/carcin/bgm057
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Increased formation of hepatic N2-ethylidene-2'-deoxyguanosine DNA adducts in aldehyde dehydrogenase 2 knockout mice treated with ethanol
1 Graduate School of Global Environmental Studies, Kyoto University, Kyoto 606-8501, Japan
2 Department of Social and Environmental Medicine, Saga Medical School, Saga 849-8501, Japan
3 Department of Environmental Biosciences, Yokohama City University, Yokohama, Kanagawa 236-0027, Japan
4 Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, USA
5 Department of Environmental Health, University of Occupational and Environmental Health, Kitakyusyu, Fukuoka 807-8555, Japan
6 1st Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
7 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyusyu University, Fukuoka 812-8582, Japan
* To whom correspondence should be addressed: Correspondence about DNA adduct analysis should be addressed to (T. M.) Department of Technology and Ecology, Graduate School of Global Environmental Studies, Kyoto University, Sakyo-ku Yoshida, Kyoto, 606-8501, Japan. Fax: +81-75-753-3335; E-mail: matsuda{at}eden.env.kyoto-u.ac.jp, and correspondence about animal experiments should be addressed to (M. I.) Department of Social and Environmental Medicine, Saga Medical School, Saga 849-8501, Japan. FAX: +81-952-34-2065; E-mail: ichiba{at}cc.saga-u.ac.jp
N2-ethylidene-2'-deoxyguanosine (N2-ethylidene-dG, 1) 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, 2), and 
-methyl-
-hydroxy-1,N2-propano-2'-deoxyguanosine (-Me--OH-PdG, 3) in the liver DNA of aldehyde dehydrogenase 2 (Aldh2)-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 -Me--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.
Key Words: Aldh2 knock-out mouse • acetaldehyde • DNA damage • LC/MS/MS • N2-ethylidene-2'-deoxyguanosine • N2-ethyl-2'-deoxyguanosine
Received November 13, 2006; revised February 22, 2007; accepted March 2, 2007.
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