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Parallelogram approach using rat-human In vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans

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Author: Kienhuis, A.S. · Poll, M.C.G. van de · Wortelboer, H. · Herwijnen, M. van · Gottschalk, R. · Jong, C.H.C. de · Boorsma, A. · Paules, R.S. · Kleinjans, J.C.S. · Stierum, R.H. · Delft, J.H.M. van
Institution: TNO Kwaliteit van Leven
Source:Toxicological Sciences, 2, 107, 544-552
Identifier: 241412
doi: doi:10.1093/toxsci/kfn237
Keywords: Toxicology · Biotechnology · Acetaminophen · Gene expression profiling · Hepatocyte-based in vitro models · Interspecies extrapolation · Liver injury · T-profiler · oxidoreductase · paracetamol · adult · aged · animal cell · animal experiment · animal model · animal tissue · article · biological activity · cell function · chemical analysis · controlled study · energy consumption · enzyme activity · female · gene expression profiling · gene repression · human · human cell · human tissue · human versus animal comparison · in vitro study · in vivo study · liver cell · liver metabolism · liver mitochondrion · liver toxicity · male · nonhuman · rat · species comparison · toxicogenetics · Acetaminophen · Adult · Aged · Analgesics, Non-Narcotic · Animals · Cell Survival · Cells, Cultured · Female · Hepatitis, Toxic · Hepatocytes · Humans · In Situ Hybridization · Male · Predictive Value of Tests · Rats · Rats, Inbred F344 · Rats, Wistar · RNA · Species Specificity · Toxicogenetics · Rattus · Rodentia


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.