Liebler Daniel C
Department of Biochemistry, Vanderbilt University School of Medicine,, Nashville, Tennessee 37232, USA.
Chem Res Toxicol. 2008 Jan;21(1):117-28. doi: 10.1021/tx700235t. Epub 2007 Dec 4.
It has been 60 years since the Millers first described the covalent binding of carcinogens to tissue proteins. Protein covalent binding was gradually overshadowed by the emergence of DNA adduct formation as the dominant paradigm in chemical carcinogenesis but re-emerged in the early 1970s as a critical mechanism of drug and chemical toxicity. Technology limitations hampered the characterization of protein adducts until the emergence of mass spectrometry-based proteomics in the late 1990s. The time since then has seen rapid progress in the characterization of the protein targets of electrophiles and the consequences of protein damage. Recent integration of novel affinity chemistries for electrophile probes, shotgun proteomics methods, and systems modeling tools has led to the identification of hundreds of protein targets of electrophiles in mammalian systems. The technology now exists to map the targets of damage to critical components of signaling pathways and metabolic networks and to understand mechanisms of damage at a systems level. The implementation of sensitive, specific analyses for protein adducts from both xenobiotic-derived and endogenous electrophiles offers a means to link protein damage to clinically relevant health effects of both chemical exposures and disease processes.
自米勒夫妇首次描述致癌物与组织蛋白的共价结合以来，已经过去了60年。随着DNA加合物形成作为化学致癌作用的主导范式出现，蛋白质共价结合逐渐被掩盖，但在20世纪70年代初又重新出现，成为药物和化学毒性的关键机制。在20世纪90年代末基于质谱的蛋白质组学出现之前，技术限制阻碍了蛋白质加合物的表征。从那时起，在亲电试剂的蛋白质靶点表征以及蛋白质损伤的后果方面取得了快速进展。最近，亲电试剂探针的新型亲和化学、鸟枪法蛋白质组学方法和系统建模工具的整合，已导致在哺乳动物系统中鉴定出数百种亲电试剂的蛋白质靶点。现在已有技术来绘制信号通路和代谢网络关键成分的损伤靶点，并在系统水平上理解损伤机制。对来自外源性和亲电性内源性物质的蛋白质加合物进行灵敏、特异的分析，为将蛋白质损伤与化学暴露和疾病过程的临床相关健康影响联系起来提供了一种手段。
