Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 252, Issue 2, Pages 73-84Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2010.10.008
Keywords
Toxicogenomics; Proteomic; Metabolomics; Predictive toxicology; FP6; Consortium
Categories
Funding
- EU
- European Union [LSHB-CT-2005-518170]
- Bayer-Schering Pharma-former Bayer and Schering
- Bio-Rad-former Ciphergen
- Boehringer Ingelheim
- F. Hoffmann-La Roche
- Genedata
- Johnson Johnson
- Lilly
- Merck-Serono-former Merck Darmstadt and Serono
- Novartis
- Novo-Nordisk
- Nycomed GmbH-former Altana Pharma AG
- sanofi-aventis
- Schering-Plough-former Organon
- Servier
- University College Dublin
- University of Hacettepe
- University of Wuerzburg
Ask authors/readers for more resources
In this publication, we report the outcome of the integrated EU Framework 6 Project: Predictive Toxicology (PredTox), including methodological aspects and overall conclusions. Specific details including data analysis and interpretation are reported in separate articles in this issue. The project, partly funded by the EU, was carried out by a consortium of 15 pharmaceutical companies, 2 SMEs, and 3 universities. The effects of 16 test compounds were characterized using conventional toxicological parameters and omics technologies. The three major observed toxicities, liver hypertrophy, bile duct necrosis and/or cholestasis, and kidney proximal tubular damage were analyzed in detail. The combined approach of omics and conventional toxicology proved a useful tool for mechanistic investigations and the identification of putative biomarkers. In our hands and in combination with histopathological assessment, target organ transcriptomics was the most prolific approach for the generation of mechanistic hypotheses. Proteomics approaches were relatively time-consuming and required careful standardization. NMR-based metabolomics detected metabolite changes accompanying histopathological findings, providing limited additional mechanistic information. Conversely, targeted metabolite profiling with LC/GC-MS was very useful for the investigation of bile duct necrosis/cholestasis. In general, both proteomics and metabolomics were supportive of other findings. Thus, the outcome of this program indicates that omics technologies can help toxicologists to make better informed decisions during exploratory toxicological studies. The data support that hypothesis on mode of action and discovery of putative biomarkers are tangible outcomes of integrated omics analysis. Qualification of biomarkers remains challenging, in particular in terms of identification, mechanistic anchoring, appropriate specificity, and sensitivity. (C) 2010 Elsevier Inc. All rights reserved.
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