Print Email Facebook Twitter Parallelogram approach using rat-human In vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans Title Parallelogram approach using rat-human In vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans Author Kienhuis, A.S. van de Poll, M.C.G. Wortelboer, H. van Herwijnen, M. Gottschalk, R. de Jong, C.H.C. Boorsma, A. Paules, R.S. Kleinjans, J.C.S. Stierum, R.H. van Delft, J.H.M. TNO Kwaliteit van Leven Publication year 2009 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. © The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. Subject ToxicologyBiotechnologyAcetaminophenGene expression profilingHepatocyte-based in vitro modelsInterspecies extrapolationLiver injuryT-profileroxidoreductaseparacetamoladultagedanimal cellanimal experimentanimal modelanimal tissuearticlebiological activitycell functionchemical analysiscontrolled studyenergy consumptionenzyme activityfemalegene expression profilinggene repressionhumanhuman cellhuman tissuehuman versus animal comparisonin vitro studyin vivo studyliver cellliver metabolismliver mitochondrionliver toxicitymalenonhumanratspecies comparisontoxicogeneticsAcetaminophenAdultAgedAnalgesics, Non-NarcoticAnimalsCell SurvivalCells, CulturedFemaleHepatitis, ToxicHepatocytesHumansIn Situ HybridizationMalePredictive Value of TestsRatsRats, Inbred F344Rats, WistarRNASpecies SpecificityToxicogeneticsRattusRodentia To reference this document use: http://resolver.tudelft.nl/uuid:02e25cf1-4eed-44b0-a49a-159a1c2cc8cb DOI https://doi.org/10.1093/toxsci/kfn237 TNO identifier 241412 ISSN 1096-6080 Source Toxicological Sciences, 107 (2), 544-552 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.