title: Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models.
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.
authors.affiliation: Center for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA, Bilthoven, The Netherlands, a.vitins@maastrichtuniversity.nl.
authors.forename: Alexa P
authors.initials: AP
authors.lastname: Vitins
authors.forename: Anne S
authors.initials: AS
authors.lastname: Kienhuis
authors.forename: Ewoud N
authors.initials: EN
authors.lastname: Speksnijder
authors.forename: Marianne
authors.initials: M
authors.lastname: Roodbergen
authors.forename: Mirjam
authors.initials: M
authors.lastname: Luijten
authors.forename: Leo T M
authors.initials: LT
authors.lastname: van der Ven
mesh_terms: D000638:Amiodarone / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008810:Mice, Inbred C57BL; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D059467:Transcriptome; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D014635:Valproic Acid; D000638:Amiodarone