title: A comparative integrated transcript analysis and functional characterization of differential mechanisms for induction of liver hypertrophy in the rat.
abstract: 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 β-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.
authors.affiliation: sanofi aventis R&D, Disposition, Safety & Animal Research, Vitry sur Seine, France. eric.boitier@sanofi-aventis.com
authors.forename: Eric
authors.initials: E
authors.lastname: Boitier
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
authors.forename: Valérie
authors.initials: V
authors.lastname: Barbié
authors.forename: Arne
authors.initials: A
authors.lastname: Blichenberg
authors.forename: Arnd
authors.initials: A
authors.lastname: Brandenburg
authors.forename: Hans
authors.initials: H
authors.lastname: Gmuender
authors.forename: Albrecht
authors.initials: A
authors.lastname: Gruhler
authors.forename: Diane
authors.initials: D
authors.lastname: McCarthy
authors.forename: Kirstin
authors.initials: K
authors.lastname: Meyer
authors.forename: Bjoern
authors.initials: B
authors.lastname: Riefke
authors.forename: Marian
authors.initials: M
authors.lastname: Raschke
authors.forename: Willem
authors.initials: W
authors.lastname: Schoonen
authors.forename: Maximilian
authors.initials: M
authors.lastname: Sieber
authors.forename: Laura
authors.initials: L
authors.lastname: Suter
authors.forename: Craig E
authors.initials: CE
authors.lastname: Thomas
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sajot
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000473:pathology*; D002839:Chromans / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks / Q000502:physiology*; D006984:Hypertrophy; D008297:Male; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000633:toxicity*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D045162:Thiazolidinediones; D000077288:Troglitazone