Ethanol-induced oxidative DNA damage and CYP2E1 expression in liver tissue of Aldh2 knockout mice.
Excessive alcohol consumption is associated with increased risks of many diseases including cancer. We evaluated oxidative DNA damage in Aldh2 +/+ and Aldh2 -/- mice after they had been subjected to acute ethanol exposure. Olive tail moment, which was measured using a comet assay, was not increased by ethanol treatment in both Aldh2 +/+ and Aldh2 -/- mice. However, after controlling for the effect of ethanol exposure, the Aldh2 genotype was a significant determinant for Olive tail moments. Although the ethanol treatment significantly increased the hepatic 8-OHdG generation in only Aldh2 +/+ mice, the level of 8-OHdG was the highest in Aldh2 -/- ethanol treated mice. The increase in the level of 8-OHdG was associated with hepatic expression of cytochrome P450 2E1 (CYP2E1). The levels of Olive tail moment and the hepatic 8-OHdG in the Aldh2 -/- control group were significantly higher than those of the Aldh2 +/+ control group. The level of CYP2E1 in liver tissue showed a similar pattern to those of the oxidative DNA damage markers. This study shows that acute ethanol consumption increases oxidative DNA damage and that expression of CYP2E1 protein may play a pivotal role in the induction of oxidative DNA damage. The finding that oxidative DNA damage was more intense in Aldh2 -/- mice than in Aldh2 +/+ mice suggests that ALDH2-deficient individuals may be more susceptible than wild-type ALDH2 individuals to ethanol-mediated liver disease, including cancer.
Kim
Yong-Dae
YD
Department of Preventive Medicine and Medical Research Institute, College of Medicine, Chungbuk National University, Republic of Korea.
Eom
Sang-Yong
SY
Ogawa
Masanori
M
Oyama
Tsunehiro
T
Isse
Toyohi
T
Kang
Jong-Won
JW
Zhang
Yan Wei
YW
Kawamoto
Toshihiro
T
Kim
Heon
H
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000444:Aldehyde Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury; D020552:Comet Assay; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis / Q000235:genetics; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D020022:Genetic Predisposition to Disease; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008107:Liver Diseases / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic
D000431:Ethanol; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019392:Cytochrome P-450 CYP2E1; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D003849:Deoxyguanosine