Development and application of mass spectrometry proteomics approaches to study the molecular mechanism of drug-induced skin toxicity

药物的二次反应是一类在临床上经常被忽视的疾病，因此很少被登记。尽管这些症状在治疗中断后可能会消失，但在最近的一份报告中，它们的重要性已被强调为六大主要死亡原因之一。由于市场上药品的不断完善和种类繁多，这种反应很容易成为一个严重的社会问题。令人惊讶的是，许多皮肤过敏反应是由摄入大量药物引起的。据信，一种药物要引起免疫介导的继发性反应，至少要发生两个主要事件。首先，药物必须转化为一种能修饰基本大分子（如蛋白质）的活性化合物。其次，应该存在细胞压力。这可能是由于细胞蛋白的上调或下调或翻译后修饰的差异引起的。虽然关于这些过程中靶向蛋白质的信息是理解药物二次反应背后的分子机制的关键一步，但迄今为止仅获得有限的数据。这主要是由于缺乏敏感的分析方法。然而，随着电泳、纳米液相色谱和最先进的质谱技术的最新进展，所需的技术是可用的，但需要开发和评估创新的方法。因此，基于质谱和现代分离方法的新策略将被开发和应用于研究逆转录抑制剂药物引起的免疫介导的皮肤不良反应的机制。这些药物被广泛用于治疗感染人类免疫缺陷病毒的患者。在某些情况下，这些患者中高达16%的人出现皮肤过敏反应，严重时导致死亡。预计将开发和应用的新策略将成为提高我们对药物引起的皮肤不良反应机制的认识的重要工具。

Secondary reactions to drugs represent a class of diseases that are often neglected in the clinic and therefore rarely registered. Despite that symptoms may cease when the treatment is interrupted, their significance has been emphasized in a recent report to be among the top six leading causes of fatality. Owing to a continuous increase in consummation and extensive variety of drugs available on the market, such reactions are prone to become a serious problem for the society. Surprisingly many allergic skin reactions are caused by the ingestion of numerous drugs. It is believed that, for a drug to cause an immune-mediated secondary reaction, at least two major events have to take place. First, the drug must be converted into a reactive compound that can modify essential macromolecules such as proteins. Secondly, a cellular stress should be present. This may be caused by either up or down regulation of cellular proteins or by differential post translational modification. While information about the proteins that are targeted in these processes is a crucial step in understanding the molecular mechanism behind secondary drug reactions, only limited data have so far been obtained. This has mainly been due to a lack of sensitive analytical approaches. However, with recent progress in electrophoresis, nanoliquid chromatography and state-of-the-art mass spectrometry, the techniques required are available but innovative approaches need to be developed and evaluated. Therefore, new strategies based on mass spectrometry and modern separation methods will be developed and applied to study the mechanism of immune-mediated adverse skin reactions caused by reverse transcription inhibitor drugs. These are drugs that are widely used for treatment of patients infected with human immunodeficiency virus. In certain cases up to 16% of these patients develop skin allergy reactions that in severe cases result in death. The new strategies that will be developed and applied are anticipated to become important tools to advance our knowledge about the mechanisms involved in drug induced adverse skin reactions.