DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis
DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis
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DOI：
10.1016/j.alcohol.2005.03.009
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发表时间：
2005-04-01
期刊：
影响因子：
2.3
通讯作者：
Theruvathu, JA
中科院分区：
文献类型：
--
作者：
Brooks, PJ;Theruvathu, JA
酒精饮料消费被归类为已知的人类致癌物，与上消化道癌症风险增加有因果关系。乙醇代谢形成乙醛似乎是这种效应的主要机制。乙醛在啮齿类动物中具有致癌性，并导致人类细胞中的姐妹染色单体交换和染色体畸变。研究得最多的乙醛DNA加合物是N-2-乙基-2 '-脱氧鸟苷，其在从乙醇处理的啮齿动物获得的肝DNA和从人类酒精滥用者获得的白色血细胞中增加。然而，由于缺乏证据表明该加合物在哺乳动物细胞中具有致突变性，因此该加合物的致癌相关性尚不清楚。一种不同的DNA加合物，1，N-2-丙-2 '-脱氧鸟苷（PdG），也可以在组蛋白和其他碱性分子存在下由乙醛形成。PdG已被证明是巴豆醛的遗传毒性和致突变作用的原因。PdG加合物可以以两种形式中的任一种存在：闭环形式或开环醛形式。尽管闭环形式具有致突变性，但醛形式可参与继发性损伤的形成，包括DNA-蛋白质交联和DNA链间交联。PdG导致的这些类型的复杂继发性DNA损伤的形成可以解释上述乙醛的许多观察到的遗传毒性作用。PdG及其相关加合物的修复是复杂的，涉及多个途径。编码参与PdG及其次级加合物修复的蛋白质的基因的遗传变异可能有助于对酒精饮料相关致癌作用的易感性。(c)2005年爱思唯尔公司All rights reserved.
Alcoholic beverage consumption is classified as a known human carcinogen, causally related to an increased risk of cancer of the upper gastrointestinal tract. The formation of acetaldehyde from ethanol metabolism seems to be the major mechanism underlying this effect. Acetaldehyde is carcinogenic in rodents and causes sister chromatid exchanges and chromosomal aberrations in human cells. The best-studied DNA adduct from acetaldehyde is N-2-ethyl-2'-deoxyguanosine, which is increased in liver DNA obtained from ethanol-treated rodents and in white blood cells obtained from human alcohol abusers. However, the carcinogenic relevance of this adduct is unclear in view of the lack of evidence that it is mutagenic in mammalian cells. A different DNA adduct, 1,N-2-propano-2'-deoxyguanosine (PdG), can also be formed from acetaldehyde in the presence of histones and other basic molecules. PdG has been shown to be responsible for the genotoxic and mutagenic effects of crotonaldehyde. The PdG adduct can exist in either of two forms: a ring-closed form or a ring-opened aldehyde form. Whereas the ring-closed form is mutagenic, the aldehyde form can participate in the formation of secondary lesions, including DNA-protein cross-links and DNA interstrand cross-links. The formation of these types of complex secondary DNA lesions resulting from PdG may explain many of the observed genotoxic effects of acetaldehyde described above. Repair of PdG and its associated adducts is complex, involving multiple pathways. Inherited variation in the genes encoding the proteins involved in the repair of PdG and its secondary adducts may contribute to susceptibility to alcoholic beverage-related carcinogenesis. (c) 2005 Elsevier Inc. All rights reserved.