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

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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.