Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models

A.P. Vitins, A.S. Kienhuis, E.N. Speksnijder, M. Roodbergen, M. Luijten, L.T.M. van der Ven

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1573-1588
JournalArchives of Toxicology
Volume88
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

Amiodarone
Valproic Acid
Fatty Liver
Liver
Cytoplasmic and Nuclear Receptors
Toxicity
Binding Sites
Tetracycline
Hepatocytes
Toxicogenetics
Clinical Chemistry
Chemical compounds
Biomarkers
Drug-Related Side Effects and Adverse Reactions
Vitamin A
Metabolism
Pharmaceutical Preparations
Rats
Genes
Lipids

Keywords

  • gene-expression profiles
  • hepatic steatosis
  • lipid homeostasis
  • drug discovery
  • mice
  • metabolism
  • toxicogenomics
  • receptor
  • disruption
  • resistance

Cite this

Vitins, A. P., Kienhuis, A. S., Speksnijder, E. N., Roodbergen, M., Luijten, M., & van der Ven, L. T. M. (2014). Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models. Archives of Toxicology, 88(8), 1573-1588. https://doi.org/10.1007/s00204-014-1211-0
Vitins, A.P. ; Kienhuis, A.S. ; Speksnijder, E.N. ; Roodbergen, M. ; Luijten, M. ; van der Ven, L.T.M. / Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models. In: Archives of Toxicology. 2014 ; Vol. 88, No. 8. pp. 1573-1588.
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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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Vitins, AP, Kienhuis, AS, Speksnijder, EN, Roodbergen, M, Luijten, M & van der Ven, LTM 2014, 'Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models', Archives of Toxicology, vol. 88, no. 8, pp. 1573-1588. https://doi.org/10.1007/s00204-014-1211-0

Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models. / Vitins, A.P.; Kienhuis, A.S.; Speksnijder, E.N.; Roodbergen, M.; Luijten, M.; van der Ven, L.T.M.

In: Archives of Toxicology, Vol. 88, No. 8, 2014, p. 1573-1588.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Mechanisms of amiodarone and valproic acid induced liver steatosis in mouse in vivo act as a template for other hepatotoxicity models

AU - Vitins, A.P.

AU - Kienhuis, A.S.

AU - Speksnijder, E.N.

AU - Roodbergen, M.

AU - Luijten, M.

AU - van der Ven, L.T.M.

N1 - WOS:000339898700010

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - gene-expression profiles

KW - hepatic steatosis

KW - lipid homeostasis

KW - drug discovery

KW - mice

KW - metabolism

KW - toxicogenomics

KW - receptor

KW - disruption

KW - resistance

U2 - 10.1007/s00204-014-1211-0

DO - 10.1007/s00204-014-1211-0

M3 - Article

VL - 88

SP - 1573

EP - 1588

JO - Archives of Toxicology

JF - Archives of Toxicology

SN - 0340-5761

IS - 8

ER -