Journal Title
Title of Journal: Arch Toxicol
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Abbravation: Archives of Toxicology
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Publisher
Springer Berlin Heidelberg
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Authors: Alexa P Vitins Anne S Kienhuis Ewoud N Speksnijder Marianne Roodbergen Mirjam Luijten Leo T M van der Ven
Publish Date: 2014/02/18
Volume: 88, Issue: 8, Pages: 1573-1588
Abstract
Liver injury is the leading cause of druginduced toxicity For the evaluation of a chemical compound to induce toxicity in this case steatosis or fatty liver it is imperative to identify markers reflective of mechanisms and processes induced upon exposure as these will be the earliest changes reflective of disease Therefore an in vivo mouse toxicogenomics study was completed to identify common pathways nuclear receptor NR binding sites and genes regulated by three known human steatosisinducing compounds amiodarone AMD valproic acid VPA and tetracycline TET Over 1 4 and 11 days of treatment AMD induced changes in clinical chemistry parameters and histopathology consistent with steatosis Common processes and NR binding sites involved in lipid retinol and drug metabolism were found for AMD and VPA but not for TET which showed no response Interestingly the pattern of enrichment of these common pathways and NR binding sites over time was unique to each compound Eleven biomarkers of steatosis were identified as dose responsive and time sensitive to toxicity for AMD and VPA Finally this in vivo mouse study was compared to an AMD rat in vivo an AMD mouse primary hepatocyte and a VPA human primary hepatocyte study to identify concordance for steatosis We conclude that concordance is found on the process level independent of species model or dosetime pointThe authors wish to thank Dr EH Jansen PK Beekhof and J Robinson for performing clinical chemistry and histotechnology procedures and Dr I Tonk for help in the dose response analysis This work was supported by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research NWO no 05006510
Keywords:
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- Alternative methods to safety studies in experimental animals
- Retrospective analysis of the Draize test for serious eye damage/eye irritation: importance of understanding the in vivo endpoints under UN GHS/EU CLP for the development and evaluation of in vitro test methods
- Acknowledgement to referees
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