Document Detail


Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers.
MedLine Citation:
PMID:  21081137     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
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.
Authors:
Katja A Matheis; Emmanuelle Com; Jean-Charles Gautier; Nelson Guerreiro; Arnd Brandenburg; Hans Gmuender; Alexandra Sposny; Philip Hewitt; Alexander Amberg; Olaf Boernsen; Bjoern Riefke; Dana Hoffmann; Angela Mally; Arno Kalkuhl; Laura Suter; Frank Dieterle; Frank Staedtler
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Publication Detail:
Type:  Journal Article     Date:  2010-11-21
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  252     ISSN:  1096-0333     ISO Abbreviation:  Toxicol. Appl. Pharmacol.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  112-22     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
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