title: The enhanced value of combining conventional and "omics" analyses in early assessment of drug-induced hepatobiliary injury.
abstract: The InnoMed PredTox consortium was formed to evaluate whether conventional preclinical safety assessment can be significantly enhanced by incorporation of molecular profiling ("omics") technologies. In short-term toxicological studies in rats, transcriptomics, proteomics and metabolomics data were collected and analyzed in relation to routine clinical chemistry and histopathology. Four of the sixteen hepato- and/or nephrotoxicants given to rats for 1, 3, or 14days at two dose levels induced similar histopathological effects. These were characterized by bile duct necrosis and hyperplasia and/or increased bilirubin and cholestasis, in addition to hepatocyte necrosis and regeneration, hepatocyte hypertrophy, and hepatic inflammation. Combined analysis of liver transcriptomics data from these studies revealed common gene expression changes which allowed the development of a potential sequence of events on a mechanistic level in accordance with classical endpoint observations. This included genes implicated in early stress responses, regenerative processes, inflammation with inflammatory cell immigration, fibrotic processes, and cholestasis encompassing deregulation of certain membrane transporters. Furthermore, a preliminary classification analysis using transcriptomics data suggested that prediction of cholestasis may be possible based on gene expression changes seen at earlier time-points. Targeted bile acid analysis, based on LC-MS metabonomics data demonstrating increased levels of conjugated or unconjugated bile acids in response to individual compounds, did not provide earlier detection of toxicity as compared to conventional parameters, but may allow distinction of different types of hepatobiliary toxicity. Overall, liver transcriptomics data delivered mechanistic and molecular details in addition to the classical endpoint observations which were further enhanced by targeted bile acid analysis using LC/MS metabonomics.
authors.affiliation: Bayer Schering Pharma AG, Wuppertal, Germany. heidrun.ellinger-ziegelbauer@bayerhealthcare.com
authors.forename: Heidrun
authors.initials: H
authors.lastname: Ellinger-Ziegelbauer
authors.forename: Melanie
authors.initials: M
authors.lastname: Adler
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
authors.forename: Arnd
authors.initials: A
authors.lastname: Brandenburg
authors.forename: John J
authors.initials: JJ
authors.lastname: Callanan
authors.forename: Susan
authors.initials: S
authors.lastname: Connor
authors.forename: Michael
authors.initials: M
authors.lastname: Fountoulakis
authors.forename: Hans
authors.initials: H
authors.lastname: Gmuender
authors.forename: Albrecht
authors.initials: A
authors.lastname: Gruhler
authors.forename: Philip
authors.initials: P
authors.lastname: Hewitt
authors.forename: Mark
authors.initials: M
authors.lastname: Hodson
authors.forename: Katja A
authors.initials: KA
authors.lastname: Matheis
authors.forename: Diane
authors.initials: D
authors.lastname: McCarthy
authors.forename: Marian
authors.initials: M
authors.lastname: Raschke
authors.forename: Björn
authors.initials: B
authors.lastname: Riefke
authors.forename: Christina S
authors.initials: CS
authors.lastname: Schmitt
authors.forename: Max
authors.initials: M
authors.lastname: Sieber
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sposny
authors.forename: Laura
authors.initials: L
authors.lastname: Suter
authors.forename: Brian
authors.initials: B
authors.lastname: Sweatman
authors.forename: Angela
authors.initials: A
authors.lastname: Mally
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000235:genetics*; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods*; D008297:Male; D055432:Metabolomics / Q000379:methods*; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017208:Rats, Wistar