A comparative integrated transcript analysis and functional characterization of differential mechanisms for induction of liver hypertrophy in the rat

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

DOI:https://doi.org/10.1016/j.taap.2011.01.021· OSTI ID:21535270

Boitier, Eric ^[1]; Amberg, Alexander ^[2]; Barbie, Valerie ^[3]; Blichenberg, Arne ^[4]; Brandenburg, Arnd; Gmuender, Hans ^[5]; Gruhler, Albrecht ^[6]; McCarthy, Diane ^[7]; Meyer, Kirstin; Riefke, Bjoern; Raschke, Marian ^[8]; Schoonen, Willem ^[9]; Sieber, Maximilian ^[10]; Suter, Laura ^[11]; Thomas, Craig E ^[12]; Sajot, Nicolas ^[13]

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1. sanofi aventis R and D, Disposition, Safety and Animal Research, Vitry sur Seine (France)
2. sanofi aventis R and D, Disposition, Safety and Animal Research, Frankfurt (Germany)
3. Merck Serono S.A., Stratified Medicine, Geneva (Switzerland)
4. Nycomed GmbH, Institute for Pharmacology and Preclinical Drug Safety, Barsbuettel (Germany)
5. Genedata AG, Basel (Switzerland)
6. Novo Nordisk A/S, Protein Science, Malov (Denmark)
7. Bio-Rad Laboratories, Hercules, CA (United States)
8. Bayer Schering Pharma AG, Investigational Toxicology, Berlin (Germany)
9. MSD, Toxicology and Drug Disposition, Oss (Netherlands)
10. Universitaet Wuerzburg, Institut fuer Toxikologie, Wuerzburg (Germany)
11. Hoffmann-La Roche Ltd., Investigative Toxicology, Basel (Switzerland)
12. Eli Lilly and Company, Investigative Toxicology, Indianapolis, IN (United States)
13. Servier, Drug Safety Assessment, Orleans-Gidy (France)

The main goal of the present work was to better understand the molecular mechanisms underlying liver hypertrophy (LH), a recurrent finding observed following acute or repeated drug administration to animals, using transcriptomic technologies together with the results from conventional toxicology methods. Administration of 5 terminated proprietary drug candidates from participating companies involved in the EU Innomed PredTox Project or the reference hepatotoxicant troglitazone to rats for up to a 14-day duration induced LH as the main liver phenotypic toxicity outcome. The integrated analysis of transcriptomic liver expression data across studies turned out to be the most informative approach for the generation of mechanistic models of LH. In response to a xenobiotic stimulus, a marked increase in the expression of xenobiotic metabolizing enzymes (XME) was observed in a subset of 4 studies. Accumulation of these newly-synthesized proteins within the smooth endoplasmic reticulum (SER) would suggest proliferation of this organelle, which most likely is the main molecular process underlying the LH observed in XME studies. In another subset of 2 studies (including troglitazone), a marked up-regulation of genes involved in peroxisomal fatty acid {beta}-oxidation was noted, associated with induction of genes involved in peroxisome proliferation. Therefore, an increase in peroxisome abundance would be the main mechanism underlying LH noted in this second study subset. Together, the use of transcript profiling provides a means to generate putative mechanistic models underlying the pathogenesis of liver hypertrophy, to distinguish between subtle variations in subcellular organelle proliferation and creates opportunities for improved mechanism-based risk assessment.

• OSTI ID: 21535270
• Journal Information: Toxicology and Applied Pharmacology, Vol. 252, Issue 2; Other Information: DOI: 10.1016/j.taap.2011.01.021; PII: S0041-008X(11)00040-8; Copyright (c) 2011 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
CARBOXYLIC ACIDS
DRUGS
ENDOPLASMIC RETICULUM
ENZYMES
GENES
HYDROCARBONS
HYPERTROPHY
LIVER
PROLIFERATION
RATS
RECEPTORS
RISK ASSESSMENT
TOXICITY
ANIMALS
BODY
CELL CONSTITUENTS
DIGESTIVE SYSTEM
GLANDS
MAMMALS
MEMBRANE PROTEINS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PATHOLOGICAL CHANGES
PROTEINS
RODENTS
VERTEBRATES