Having to withdraw a drug from the market because of unforeseen toxic side effects is every pharmaceutical executive’s nightmare. Current procedures for evaluating the toxicity of drug candidates during development involve histopathological assessments of liver tissue and biochemical measurements of liver damage. The problem with these tissue and cellular approaches is that they are not sensitive enough. In a recent Molecular & Cellular Proteomics paper (1), a team led by Stephen R. Pennington at University College Dublin in Ireland described a sensitive molecular approach to tell if a potential drug will be toxic early in the development process.
“The idea was to use transcriptomics, proteomics and metabolomics and combine the data to provide earlier markers of kidney or liver toxicity,” says Pennington. The approach involved first feeding rats a drug candidate and then measuring the liver protein expression profiles by label-free liquid chromatography-mass spectrometry. The method generated a list of proteins that changed in response to the drug. The investigators also collected transcriptomic data from the same liver samples and compiled a list of transcript changes. From all that data, the investigators had a panel of potential biomarkers for liver toxicity that they pursued with a method called selective reaction monitoring by mass spectrometry, which accurately tracks changes in expression of a given set of proteins.
Pennington says the investigators are now working to extend their approach to more readily accessible sample types, such as blood, and to apply it in other studies for diagnostics for chronic conditions, such as cancer, cardiovascular disease and arthritis.
- 1. Collins, B. C. et al. Mol. Cell. Proteomics DOI: 10.1074/mcp.M111.016493 (2012)
Rajendrani Mukhopadhyay (email@example.com) is the senior science writer for ASBMB Today and the technical editor for The Journal of Biological Chemistry. Follow her on Twitter at www.twitter.com/rajmukhop.