Abstract
Liver injury is the leading cause of drug-induced 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 steatosis-inducing 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 dose*time point.
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Acknowledgments
The authors wish to thank Dr. E.H. Jansen, P.K. 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: 050-06-510.
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Vitins, A.P., Kienhuis, A.S., Speksnijder, E.N. et al. Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models. Arch Toxicol 88, 1573–1588 (2014). https://doi.org/10.1007/s00204-014-1211-0
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DOI: https://doi.org/10.1007/s00204-014-1211-0