Data mining reveals a network of early-response genes as a consensus signature of drug-induced in vitro and in vivo toxicity.
Gene signatures of drug-induced toxicity are of broad interest, but they are often identified from small-scale, single-time point experiments, and are therefore of limited applicability. To address this issue, we performed multivariate analysis of gene expression, cell-based assays, and histopathological data in the TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation system) database. Data mining highlights four genes-EGR1, ATF3, GDF15 and FGF21-that are induced 2 h after drug administration in human and rat primary hepatocytes poised to eventually undergo cytotoxicity-induced cell death. Modelling and simulation reveals that these early stress-response genes form a functional network with evolutionarily conserved structure and intrinsic dynamics. This is underlined by the fact that early induction of this network in vivo predicts drug-induced liver and kidney pathology with high accuracy. Our findings demonstrate the value of early gene-expression signatures in predicting and understanding compound-induced toxicity. The identified network can empower first-line tests that reduce animal use and costs of safety evaluation.
pRED Pharma Research and Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, Basel, Switzerland.
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JD
Zhang
pRED Pharma Research and Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, Basel, Switzerland.
N
N
Berntenis
pRED Pharma Research and Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, Basel, Switzerland.
A
A
Roth
pRED Pharma Research and Development, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, Basel, Switzerland.
M
M
Ebeling
D057225:Data Mining; D020869:Gene Expression Profiling; D017781:Genes, Immediate-Early; D006801:Humans; D066298:In Vitro Techniques; D018675:Toxicity Tests