Integrated toxicogenomics analysis with Toxygates for inferring molecular mechanisms

Assessment of the safety of drug candidates in early research and development (R&D) stage holds the key to the successful drug development. Toxicogenomics is one of the promising approaches using omics techniques since a number of ‘omics databases is rapidly growing. Although many of these databases are open to the public, there remain some barriers for biologists regardless of their bioinformatics skills. Toxygates was originally developed as a user-friendly interface for Open TG-GATEs, which is one of the largest and most widely used toxicogenomics databases. Since the original Toxygates was developed to enable users to display the gene expression values obtained by selected compounds or experimental conditions for genes of interest, there were some limitations as an analytical platform. To overcome this situation, significant improvements have been added and finally, a new version of Toxygates allows users to analyze the data such as creating heatmap for visualization of gene expression profile, performing hierarchical clustering and creating a dendrogram with interactive display, performing several types of enrichment analysis such as gene ontology and pathways and uploading user data for further analysis. As a case study, we used Toxygates to successfully find novel insights that the hepatotoxicity caused by well-studied PPARα agonist WY-14643 may include the disruption of intracellular calcium dynamics and imbalance between PPARα signaling and Wnt signaling.