||Mar 18, 2014
||Dr. Takeki Uehara
||Application of toxicogenomics for drug toxicity screening
Toxicogenomics is a promising approach for identifying compounds with potential safety problems based on genome-wide gene expression profiles. In general, toxicogenomics has been applied in two broad research areas: mechanistic research and predictive toxicology. The toxicogenomic approach facilitates investigations of the molecular mode of action of toxic substances. Predictive toxicology approach, using predictive biomarker gene signatures, enables the efficient selection of drug candidates at an early stage of drug development, resulting in a significant reduction in the time and cost associated with development of new molecular entities. In Japan, the Toxicogenomics Project (TGP; Uehara et al, 2010), which is a collaboration consortium involving the National Institute of Health Sciences, the National Institute of Biomedical Innovation, and 15 pharmaceutical companies, has constructed a large-scale toxicogenomics database named TG-GATEs. Data from about 20,000 microarrays were generated through both in vitro and in vivo experiments for over 170 compounds. Specifically, in the single dose study, rats were treated in one of the three dose levels with concurrent controls and sacrificed at 3, 6, 9, or 24 h after a single administration. In the repeated-dose study, rats were also treated at the three dose levels with concurrent controls, but sacrificed at 24 h after the last dose of repeated administration for 3, 7, 14, and 28 days. Other data obtained include histopathological examination, blood chemistry, hematology, body weight, organ weight, and general symptoms. In vitro datasets contain information regarding the effects on rat and human hepatocytes resulting from exposure to the same compounds. The online version of this database, Open TG-GATEs, is now available for free public download (http://toxico.nibio.go.jp/open-tggates/english/search.html). In this seminar, I will share our efforts on toxicogenomics research, with particular focus on developing TG-GATEs database, and the practical application of toxicogenomics for drug toxicity screening.
Uehara T, Ono A, Maruyama T, et al. The Japanese toxicogenomics project: application of toxicogenomics. Mol Nutr Food Res. 2010; 54:218-27.