Adductomics: characterizing exposures to reactive electrophiles.
Adductomics: characterizing exposures to reactive electrophiles.
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DOI：
10.1016/j.toxlet.2011.04.002
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发表时间：
2012-08-13
影响因子：
3.5
通讯作者：
Williams ER
中科院分区：
文献类型：
--
作者：
Rappaport SM;Li H;Grigoryan H;Funk WE;Williams ER
为了了解疾病的环境原因，需要无偏见的方法来表征人类的有害物质组，它代表了人们从外源性和内源性来源暴露的所有有毒物质。因为它们直接修饰DNA和重要的蛋白质，反应性亲电体可能是最重要的组成部分。暴露于反应性亲电体可以通过测量来自循环亲电体与血液亲核体之间的反应的加合物来表征。我们将“内收体”定义为具有给定亲核靶标的此类加合物的总和。由于它们在人血液中的丰度和停留时间更长，血红蛋白（Hb）和人血清白蛋白（HSA）的加合物比DNA和谷胱甘肽的加合物更适合用于表征加合物。事实上，由HSA（HSA-Cys 34）中唯一的游离巯基代表的亲核热点为加合实验提供了特别的优势。虽然HSA-Cys 34的靶向加合物已经被监测了几十年，但直到最近才报道了用于可视化HSA-Cys 34“亚加合物”的无偏倚方法。该方法依赖于一种新的质谱应用程序，称为固定步骤选择反应监测（FS-SRM），配置Cys 34加合物在HSA的胰蛋白酶消化。在这里，我们选择性地回顾了文献的潜力，内收部分阐明人类神经元，特别是注意HSA-Cys 34 subadductome。
To understand environmental causes of disease, unbiased methods are needed to characterize the human exposome, which represents all toxicants to which people are exposed from both exogenous and endogenous sources. Because they directly modify DNA and important proteins, reactive electrophiles are probably the most important constituents of the exposome. Exposures to reactive electrophiles can be characterized by measuring adducts from reactions between circulating electrophiles and blood nucleophiles. We define an ‘adductome’ as the totality of such adducts with a given nucleophilic target. Because of their greater abundance and residence times in human blood, adducts of hemoglobin (Hb) and human serum albumin (HSA) are preferable to those of DNA and glutathione for characterizing adductomes. In fact, the nucleophilic hotspot represented by the only free sulfhydryl group in HSA (HSA-Cys34) offers particular advantages for adductomic experiments. Although targeted adducts of HSA-Cys34 have been monitored for decades, an unbiased method has only recently been reported for visualizing the HSA-Cys34 ‘subadductome’. The method relies upon a novel mass spectrometry application, termed fixed-step selected reaction monitoring (FS-SRM), to profile Cys34 adducts in tryptic digests of HSA. Here, we selectively review the literature regarding the potential of adductomics to partially elucidate the human exposome, with particular attention to the HSA-Cys34 subadductome.