Adverse drug reactions, transcription factors and transcriptomics

Abstract

It is currently believed that most idiosyncratic adverse drug reactions arise because of enzymatic modification of the parent drug structure to produce reactive chemical intermediates. However, there is very little direct evidence that can link the formation of a reactive metabolite with a particular idiosyncratic adverse drug reaction. Further study is required to understand the relationship between metabolic bioactivation, induction of oxidative stress and the particular pathways underlying the biological response. In particular, an understanding of the early processes in cellular signalling and defensive manifestations after oxidative insult may help determine the final outcome, i.e. recovery or toxicity. A stress response is initiated when the reductive capacity of a cell, or specialised compartment within a cell, becomes compromised. This could be via depletion of the first line of cellular defences such as glutathione or ascorbate, or by oxidation of critical sulphydryl groups on the surface of redox-sensitive proteins. Once detected, the cell activates the expression of genes involved in antioxidant response. This `switching-on' of gene expression is performed by transcription factors that encode for specific groups of genes that contain the particular transcriptional response element within the promoter region of the gene. Through the profiling of transcription factors and the subsequent genetic regulation, after oxidative insult or exposure to reactive chemical species, we will gain an insight into the underlying biological pathways. Using this information we can identify areas for potential therapeutic modulation as well as obtaining more detailed and predictive toxicity fingerprints for informative decision-making during the drug development process.