Matsuda Tomonari, Yabushita Hisatoshi, Kanaly Robert A, Shibutani Shinya, Yokoyama Akira
Department of Technology and Ecology, Graduate School of Global Environmental Studies, Kyoto University, Kyoto, Japan.
Chem Res Toxicol. 2006 Oct;19(10):1374-8. doi: 10.1021/tx060113h.
Drinking alcohol is a risk factor for cancers of the oral cavity, pharynx, larynx, and esophagus. Although many studies suggest that acetaldehyde, a major metabolite of orally ingested alcohol, plays a crucial role in cancer initiation, the link between the aldehyde dehydrogenase-2 (ALDH2) genotype and acetaldehyde-derived DNA damage has not yet been explored. We have developed a sensitive and quantitative method for detecting the acetaldehyde-derived DNA adducts, N(2)-ethyl-2'-deoxyguanosine (N(2)-Et-dG), alpha-S- and alpha-R-methyl-gamma-hydroxy-1,N(2)-propano-2'-deoxyguanosine (alpha-S-Me-gamma-OH-PdG and alpha-R-Me-gamma-OH-PdG), and N(2)-(2,6-dimethyl-1,3-dioxan-4-yl)-deoxyguanosine (N(2)-Dio-dG), by using liquid chromatography electrospray tandem mass spectrometry (LC/ESI-MS/MS) and stable-isotope internal standards. We determined the DNA adducts in 44 blood DNA samples from Japanese alcoholic patients. The levels of three acetaldehyde-derived DNA adducts, N(2)-Et-dG, alpha-S-Me-gamma-OH-PdG, and alpha-R-Me-gamma-OH-PdG, were significantly higher in alcoholics with the ALDH2 1/2 2 genotype compared to those with the ALDH2 1/2 1 genotype. N(2)-Dio-dG was not detected in any of the DNA samples analyzed. These results provide molecular evidence that the ALDH2 genotype affects the genotoxic damage caused by acetaldehyde.
饮酒是口腔癌、咽癌、喉癌和食道癌的一个风险因素。尽管许多研究表明，经口摄入酒精的主要代谢产物乙醛在癌症发生过程中起关键作用，但醛脱氢酶2（ALDH2）基因型与乙醛衍生的DNA损伤之间的联系尚未得到探索。我们开发了一种灵敏且定量的方法，通过液相色谱电喷雾串联质谱法（LC/ESI-MS/MS）和稳定同位素内标来检测乙醛衍生的DNA加合物，即N(2)-乙基-2'-脱氧鸟苷（N(2)-Et-dG）、α-S-和α-R-甲基-γ-羟基-1,N(2)-丙烷-2'-脱氧鸟苷（α-S-Me-γ-OH-PdG和α-R-Me-γ-OH-PdG）以及N(2)-(2,6-二甲基-1,3-二氧杂环己烷-4-基)-脱氧鸟苷（N(2)-Dio-dG）。我们测定了44例日本酗酒患者血液DNA样本中的DNA加合物。与携带ALDH2 1/2 1基因型的酗酒者相比，携带ALDH2 1/2 2基因型的酗酒者体内三种乙醛衍生的DNA加合物，即N(2)-Et-dG、α-S-Me-γ-OH-PdG和α-R-Me-γ-OH-PdG的水平显著更高。在所分析的任何DNA样本中均未检测到N(2)-Dio-dG。这些结果提供了分子证据，表明ALDH2基因型会影响乙醛所致的基因毒性损伤。
