An Overview of National Toxicology Program’s Toxicogenomic Applications: DrugMatrix and ToxFX

Abstract

DrugMatrix and its automated toxicogenomics reporting system, ToxFX are the scientific communities’ largest molecular toxicology reference database and informatics systems. DrugMatrix consists of the comprehensive results of thousands of highly controlled and standardized toxicological experiments where rats or primary rat hepatocytes were systematically treated with more than 600 therapeutic, industrial, or environmental chemicals at both non-toxic and toxic doses. Following administration in vivo, comprehensive studies of the effects of these compounds were carried out after multiple durations of exposure, and in multiple target organs. Study types included pharmacology, clinical chemistry, hematology, histology, body and organ weights, and clinical observations. Additionally, a curation team extracted all relevant information on the compounds from the literature, the Physicians’ Desk Reference, package inserts, and other relevant sources. At the heart of the DrugMatrix database are thousands of gene expression data sets generated by extracting RNA from the toxicologically relevant organs and tissues and analyzing these RNAs using the GE Codelink rat array, and the Affymetrix whole-genome 230 2.0 rat GeneChip array systems. Additionally, the database contains 148 scorable genomic signatures, covering 96 distinct phenotypes derive from mining the DrugMatrix gene expression data. The signatures are informative of organ-specific pathology (e.g., hepatic steatosis), and mode of toxicological action (e.g., PXR activation in the liver). The phenotypes cover several common target tissues in toxicity testing (liver, kidney, heart, bone marrow, spleen, and skeletal muscle). Taken as a whole, DrugMatrix enables a toxicologist to formulate a comprehensive picture of toxicity with greater efficiency than traditional methods.