Conduah Birt J E, Shuker D E, Farmer P B
Biomonitoring and Molecular Interactions Section, MRC Toxicology Unit, University of Leicester, UK.
Chem Res Toxicol. 1998 Feb;11(2):136-42. doi: 10.1021/tx970169z.
The consumption of alcoholic beverages has been associated with increased risks of a number of chronic disorders including cancers. It is still not clear whether ethyl alcohol or other components such as metabolites are directly involved in the carcinogenic process or whether the effects are due to the modulation of metabolism of other carcinogens. At present, there is no good biomarker of alcohol intake, particularly at low or moderate levels of consumption. A number of studies have shown the ability of the major metabolite acetaldehyde to react with proteins in vitro to give stable and unstable adducts. The interaction of acetaldehyde with model peptides, which correspond to N-terminal globin sequences, was studied. The major stable adduct was identified by mass spectrometry and NMR as a diastereoisomeric mixture of imidazolidinones. This is believed to be formed by reaction and cyclization of the initial Schiff base adduct with the N-terminal valine. Incubation of human globin with acetaldehyde (0-2 mM) yielded products which were identified as the N-terminal adducts by electrospray ionization mass spectrometry (ESI-MS) of proteolytic digests. The specificity and sensitivity of the analysis was improved by the use of on-line HPLC-ESI-MS. Tryptic digests of the modified globin which contained both the N-terminal acetaldehyde adducts of alpha-globin (heptapeptide) and beta-globin (octapeptide) were resolved. These results suggest that analysis of stable imidazolidinone adducts is a promising approach to estimation of alcohol exposure.
酒精饮料的摄入与包括癌症在内的多种慢性疾病风险增加有关。目前尚不清楚乙醇或其他成分（如代谢产物）是否直接参与致癌过程，或者这些影响是否归因于对其他致癌物代谢的调节。目前，尚无良好的酒精摄入量生物标志物，尤其是在低或中等饮酒水平时。许多研究表明，主要代谢产物乙醛在体外能够与蛋白质反应生成稳定和不稳定的加合物。研究了乙醛与对应于N端珠蛋白序列的模型肽的相互作用。通过质谱和核磁共振确定主要稳定加合物为咪唑烷酮的非对映异构体混合物。据信这是由初始席夫碱加合物与N端缬氨酸反应和环化形成的。用乙醛（0 - 2 mM）与人珠蛋白孵育产生的产物，通过对蛋白水解消化产物进行电喷雾电离质谱（ESI-MS）鉴定为N端加合物。通过使用在线HPLC-ESI-MS提高了分析的特异性和灵敏度。解析了修饰珠蛋白的胰蛋白酶消化产物，其中包含α珠蛋白（七肽）和β珠蛋白（八肽）的N端乙醛加合物。这些结果表明，对稳定咪唑烷酮加合物的分析是估计酒精暴露的一种有前景的方法。
