title: Parallelogram approach using rat-human in vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans.
abstract: The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression profiles and infers mechanisms between several systems. In the present study, acetaminophen (APAP) was used as a model compound to compare gene expression responses between rat and human using in vitro cellular models, hepatocytes, and between rat in vitro and in vivo. Comparison at the level of modulated biochemical pathways and biological processes rather than at that of individual genes appears preferable as it increases the overlap between various systems. Pathway analysis by T-profiler revealed similar biochemical pathways and biological processes repressed in rat and human hepatocytes in vitro, as well as in rat liver in vitro and in vivo. Repressed pathways comprised energy-consuming biochemical pathways, mitochondrial function, and oxidoreductase activity. The present study is the first that used a toxicogenomics-based parallelogram approach, extrapolating in vitro to in vivo and interspecies, to reveal relevant mechanisms indicative of APAP-induced liver toxicity in humans in vivo.
authors.affiliation: Department of Health Risk Analysis and Toxicology, Maastricht University, Maastricht, The Netherlands. anne.kienhuis@rivm.nl
authors.forename: Anne S
authors.initials: AS
authors.lastname: Kienhuis
authors.forename: Marcel C G
authors.initials: MC
authors.lastname: van de Poll
authors.forename: Heleen
authors.initials: H
authors.lastname: Wortelboer
authors.forename: Marcel
authors.initials: M
authors.lastname: van Herwijnen
authors.forename: Ralph
authors.initials: R
authors.lastname: Gottschalk
authors.forename: Cornelis H C
authors.initials: CH
authors.lastname: Dejong
authors.forename: André
authors.initials: A
authors.lastname: Boorsma
authors.forename: Richard S
authors.initials: RS
authors.lastname: Paules
authors.forename: Jos C S
authors.initials: JC
authors.lastname: Kleinjans
authors.forename: Rob H
authors.initials: RH
authors.lastname: Stierum
authors.forename: Joost H M
authors.initials: JH
authors.lastname: van Delft
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000328:Adult; D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D011237:Predictive Value of Tests; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D013045:Species Specificity; D043922:Toxicogenetics / Q000379:methods*
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D012313:RNA