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 non-immune neutropenia inducing drugs, 9 proteins were found to be common to putative signaling paths across all drugs evaluated. All 9 proteins showed relevance to neutrophil biology. Geneset enrichment analysis showed that proteins associated with cancer-related processes such as apoptosis provide topological linkages between drug targets and proteins involved in neutrophil production. The algorithm can be applied towards analysis of any toxicity where the drugs and the physiological processes involved in the toxic mechanism are known.