Open TG-GATEs: a large-scale toxicogenomics database

Abstract

Toxicogenomics focuses on assessing the safety of compounds using gene expression profiles. Gene expression signatures from large toxicogenomics databases are expected to perform better than small databases in identifying biomarkers for the prediction and evaluation of drug safety based on a compound's toxicological mechanisms in animal target organs. Over the past 10 years, the Japanese Toxicogenomics Project consortium (TGP) has been developing a large-scale toxicogenomics database consisting of data from 170 compounds (mostly drugs) with the aim of improving and enhancing drug safety assessment. Most of the data generated by the project (e.g. gene expression, pathology, lot number) are freely available to the public via Open TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System). Here, we provide a comprehensive overview of the database, including both gene expression data and metadata, with a description of experimental conditions and procedures used to generate the database. Open TG-GATEs is available from http://toxico.nibio.go.jp/english/index.html.

Toxicogenomic module associations with pathogenesis: a network-based approach to understanding drug toxicity

“…24 Using WGCNA and 9071 liver-expressed genes, we defined 415 networks consisting of 5-656 co-expressed genes across all 654 DM experiments (Supplementary Table S1). The module correlation patterns based on scores across all treatments were represented in a simplified visual dendrogram, the TXG-MAP, analogous to phylogenetic trees used for conveying sequence similarity ( Figure 1).…”

“…The Drug Matrix (DM) 23 and open TG-GATEs (TG) 24 databases constitute two large publicly available resources describing the effects of drugs and other compounds in rat liver. They contain gene expression data from Affymetrix microarrays, linked to traditional histology and clinical chemistry results for 3528 treatment groups from TG and 654 from DM.…”

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

“…In this study, PD responses were analyzed at 8 hours and 24 hours because in vitro response data for CAF had only been measured at these timepoints 28. Although estimating PD responses induced by multiple dosing would also be very interesting, only single drug administration was considered here because no adequate in vitro response data for repeated dosing was available 28.…”

“…PICD allows a quantitative description of drug responses at the patient level by integrating in vitro toxicity data from Open TG‐GATEs28 into whole‐body PBPK models14 ( Supplementary Methods ). In short, the basic concept of PICD is the identification of in vivo doses such that the simulated drug exposure in the interstitial space of the liver is equal to the in vitro drug exposure of the in vitro assay ( Figure 1).…”

“…14 Here, PICD was applied separately on single doses of APAP and CAF to predict PD responses for genes (defined as log2 fold change) and key cellular processes (defined as mean absolute log2 fold change of all involved genes) at 8 hours and 24 hours. Note that in TG‐GATEs, in vitro response data of APAP and CAF was measured at these timepoints 28. Bioavailability values calculated from the developed PBPK models were used (APAP = 92%; CAF = 100%) to consider oral administration.…”