ToxSci Advance Access published online on November 12, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn237
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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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* Department of Health Risk Analysis and Toxicology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, the Netherlands
Business Unit Biosciences, TNO Quality of Life, P.O. Box 360, 3700 AJ, Zeist, the Netherlands
Department of Surgery, University Hospital Maastricht and Nutrition and Toxicology Research Institute (NUTRIM), Maastricht University, P.O. Box 5800, 6202 AZ, Maastricht, the Netherlands
National Center for Toxicogenomics, Research Triangle Park, NC 27709, USA
1 Corresponding author Anne S. Kienhuis, Department of Health Risk Analysis and Toxicology, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands. Telephone: +31 71 527 5782. Telefax: +31 71 527 5274. E-mail: a.s.kienhuis{at}chem.leidenuniv.nl
Received September 6, 2008; revision received November 5, 2008; accepted November 6, 2008
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Abstract |
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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. Conclusion: 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.
Key Words: Hepatocyte-based in vitro models; liver injury; acetaminophen; interspecies extrapolation; gene expression profiling; T-profiler.
Anne S. Kienhuis, a.s.kienhuis{at}chem.leidenuniv.nl; Marcel C.G. van de Poll, mcg.vandepoll{at}ah.unimaas.nl; Heleen Wortelboer, heleen.wortelboer{at}tno.nl; Marcel van Herwijnen, m.vanherwijnen{at}grat.unimaas.nl; Ralph Gottschalk, r.gottschalk{at}grat.unimaas.nl; Cornelis H.C. Dejong, c.dejong{at}surgery.azm.nl; André Boorsma, andre.boorsma{at}tno.nl; Richard S. Paules, paules{at}niehs.nih.gov; Jos C.S. Kleinjans, j.kleinjans{at}grat.unimaas.nl; Rob H. Stierum, rob.stierum{at}tno.nl; Joost H.M. van Delft, j.vandelft{at}grat.unimaas.nl