Departamento de Bioquímica, Instituto de Química, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo SP, Brazil.
J Am Chem Soc. 2011 Jun 22;133(24):9140-3. doi: 10.1021/ja2004686. Epub 2011 May 27.
Acetaldehyde is an environmentally widespread genotoxic aldehyde present in tobacco smoke, vehicle exhaust and several food products. Endogenously, acetaldehyde is produced by the metabolic oxidation of ethanol by hepatic NAD-dependent alcohol dehydrogenase and during threonine catabolism. The formation of DNA adducts has been regarded as a critical factor in the mechanisms of acetaldehyde mutagenicity and carcinogenesis. Acetaldehyde reacts with 2'-deoxyguanosine in DNA to form primarily N(2)-ethylidene-2'-deoxyguanosine. The subsequent reaction of N(2)-ethylidenedGuo with another molecule of acetaldehyde gives rise to 1,N(2)-propano-2'-deoxyguanosine (1,N(2)-propanodGuo), an adduct also found as a product of the crotonaldehyde reaction with dGuo. However, adducts resulting from the reaction of more than one molecule of acetaldehyde in vivo are still controversial. In this study, the unequivocal formation of 1,N(2)-propanodGuo by acetaldehyde was assessed in human cells via treatment with [(13)C(2)]-acetaldehyde. Detection of labeled 1,N(2)-propanodGuo was performed by HPLC/MS/MS. Upon acetaldehyde exposure (703 μM), increased levels of both 1,N(2)-etheno-2'-deoxyguanosine (1,N(2)-εdGuo), which is produced from α,β-unsaturated aldehydes formed during the lipid peroxidation process, and 1,N(2)-propanodGuo were observed. The unequivocal formation of 1,N(2)-propanodGuo in cells exposed to this aldehyde can be used to elucidate the mechanisms associated with acetaldehyde exposure and cancer risk.
乙醛是一种环境中广泛存在的遗传毒性醛，存在于烟草烟雾、汽车尾气和几种食品中。内源性的乙醛是由肝脏中 NAD 依赖性乙醇脱氢酶代谢氧化乙醇和苏氨酸分解代谢产生的。DNA 加合物的形成被认为是乙醛致突变性和致癌性机制中的关键因素。乙醛与 DNA 中的 2'-脱氧鸟苷反应，主要生成 N(2)-亚乙基-2'-脱氧鸟苷。随后，N(2)-亚乙基鸟嘌呤与另一个乙醛分子反应，生成 1,N(2)-丙烷-2'-脱氧鸟苷（1,N(2)-丙烷 dGuo），这是一种加合物，也作为丙醛与 dGuo 反应的产物。然而，体内多于一个乙醛分子反应生成的加合物仍然存在争议。在这项研究中，通过用 [(13)C(2)]-乙醛处理人细胞，明确评估了乙醛生成 1,N(2)-丙烷 dGuo 的情况。通过 HPLC/MS/MS 检测标记的 1,N(2)-丙烷 dGuo。在乙醛暴露（703 μM）后，观察到 1,N(2)-乙撑-2'-脱氧鸟苷（1,N(2)-εdGuo）和 1,N(2)-丙烷 dGuo 的水平均增加，1,N(2)-εdGuo 是由脂质过氧化过程中形成的α,β-不饱和醛产生的。可以使用在暴露于这种醛的细胞中明确形成 1,N(2)-丙烷 dGuo 的方法来阐明与乙醛暴露和癌症风险相关的机制。
