Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers

Journal Article · Fri Apr 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.11.006· OSTI ID:21535278

Com, Emmanuelle ^[1]; Gautier, Jean-Charles ^[1]; Guerreiro, Nelson ^[2]; Brandenburg, Arnd; Gmuender, Hans ^[3]; Sposny, Alexandra; Hewitt, Philip ^[4]; Amberg, Alexander ^[5]; Boernsen, Olaf ^[2]; Riefke, Bjoern ^[6]; Hoffmann, Dana; Mally, Angela ^[7]; Kalkuhl, Arno ^[8]; Suter, Laura ^[9]; Dieterle, Frank; Staedtler, Frank ^[2]

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1. Sanofi-Aventis, Paris (France)
2. Novartis Institutes for BioMedical Research (NIBR), Basel (Switzerland)
3. GeneData AG, Basel (Switzerland)
4. Merck KGaA, Darmstadt (Germany)
5. Sanofi-Aventis, Frankfurt (Germany)
6. Bayer Schering Pharma AG, Berlin (Germany)
7. Department of Toxicology, University of Wuerzburg, Wuerzburg (Germany)
8. Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach an der Riss (Germany)
9. F. Hoffmann-La Roche, Ltd., Basel (Switzerland)

The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with 'omics' data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.

• OSTI ID: 21535278
• Journal Information: Toxicology and Applied Pharmacology, Vol. 252, Issue 2; Other Information: DOI: 10.1016/j.taap.2010.11.006; PII: S0041-008X(10)00438-2; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOLOGICAL MARKERS
DAMAGE
DOSES
ELECTROPHORESIS
LIVER
MALES
RATS
SAFETY
TOXICITY
TUBULES
ANIMALS
BODY
DIGESTIVE SYSTEM
GLANDS
KIDNEYS
MAMMALS
ORGANS
RODENTS
VERTEBRATES