Abstract
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.
Highlights
Assessment of the safety of drug candidates in early research and development (R&D) stage holds the key to the successful drug development since it is reported that cardiac toxicity (33%) and liver toxicity (29%) were top-ranked as primary reasons for drug withdrawals from the US, EU and Asian markets from 1998-2008 [1]
Open TG-GATEs is one of the largest and most widely used toxicogenomics databases [4], which stores about 24,000 microarray profiles of 170 different compounds obtained from rat and human, with their pathology data, obtained by the Japanese Toxicogenomics Project consortium (TGP) [5]. This database is open to the public and widely used all over the world, still there remain some barriers for biologists to explore this gold mine, such as i) download of huge amount of datasets is required, ii) programming for data analysis is required, and iii) access to third party database for annotation (e.g. gene ontology (GO), signaling pathway) is required
Users can select expression values to be used for heatmap (Log2(fold change), Normalized intensity) and dendrograms associated with the heatmap
Summary
Been widely used and contributing to the toxicogenomics area significantly, our goal was to develop a platform that enables anyone to analyze, see, the data in Open TG-GATEs
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