A Systems Biology Approach for Detecting Toxicity-Related Hotspots inside Protein Interaction Networks

Drug-induced Neutropenia can be fatal when severe and therefore requires an improved understanding of its mechanism(s) of toxicity. Systems biology provides an opportunity to understand adverse events after drug administration using analysis of biomolecular networks. In this study, a human protein interaction network was analyzed to identify proteins that are most central to topological paths connecting a drug's target proteins to hematopoiesis-related proteins. For a set of 19 non-immune neutropenia inducing drugs, we found 270 proteins involved in putative signaling paths of which 9 proteins were found to be common across all drugs evaluated and all 9 proteins showed relevance to neutrophil biology. This study provides an understanding of downstream effects for drugs known to induce non-immune neutropenia.  We believe that the algorithm developed here can be applied towards analysis of any toxicity where the drugs and the physiological processes involved in the toxic mechanism are known.