Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis

A.S. Kienhuis, A.P. Vitins, J.L.A. Pennings, T.E. Pronk, E.N. Speksnijder, M. Roodbergen, J.H.M. van Delft, M. Luijten, L.T.M. van der Ven

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Scopus)

Abstract

In vitro models for hepatotoxicity testing are a necessity for advancement of toxicological research. Assessing the in vitro response requires in vivo validated gene sets reflective of the hepatotoxic phenotype. Cholestasis, the impairment of bile flow, is induced in C57BL/6J mice treated with cyclosporine A (CsA) to identify phenotype reflective gene sets. CsA treatment through oral gavage for 25 days induced cholestasis, as confirmed by histopathology and serum chemistry. Over 1, 4, and 11 days of CsA exposure gradual increases in serum markers were correlated to gene expression. This phenotype-directed analysis identified gene sets specific to the onset and progression of cholestasis, such as PPAR related processes and drug metabolism, by circumventing other effects of CsA, such as immunosuppression, found in dose*time group analysis. In vivo gene sets are enriched in publicly available data sets of CsA-treated HepaRG and primary mouse hepatocytes. However, genes identified within these gene sets did not overlap between in vivo and in vitro. In vitro regulated genes represent the initial response to cholestasis, whereas in vivo genes represent the later adaptive response. We conclude that the applicability of in vitro models for hepatotoxicity testing fully depends on a solid in vivo phenotype anchored analysis. (c) 2013 Elsevier Ireland Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)225-236
JournalToxicology Letters
Volume221
Issue number3
DOIs
Publication statusPublished - 2013

Fingerprint

Cholestasis
Gene expression
Cyclosporine
Genes
Phenotype
Gene Expression
Peroxisome Proliferator-Activated Receptors
In Vitro Techniques
Testing
Inbred C57BL Mouse
Ireland
Metabolism
Bile
Toxicology
Immunosuppression
Hepatocytes
Biomarkers
Serum
Research
Pharmaceutical Preparations

Keywords

  • proliferator-activated receptor
  • phospholipid transfer protein
  • nuclear receptors
  • bile-acids
  • liver
  • hepatotoxicity
  • transporters
  • mechanisms
  • mice
  • drugs

Cite this

Kienhuis, A.S. ; Vitins, A.P. ; Pennings, J.L.A. ; Pronk, T.E. ; Speksnijder, E.N. ; Roodbergen, M. ; van Delft, J.H.M. ; Luijten, M. ; van der Ven, L.T.M. / Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis. In: Toxicology Letters. 2013 ; Vol. 221, No. 3. pp. 225-236.
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abstract = "In vitro models for hepatotoxicity testing are a necessity for advancement of toxicological research. Assessing the in vitro response requires in vivo validated gene sets reflective of the hepatotoxic phenotype. Cholestasis, the impairment of bile flow, is induced in C57BL/6J mice treated with cyclosporine A (CsA) to identify phenotype reflective gene sets. CsA treatment through oral gavage for 25 days induced cholestasis, as confirmed by histopathology and serum chemistry. Over 1, 4, and 11 days of CsA exposure gradual increases in serum markers were correlated to gene expression. This phenotype-directed analysis identified gene sets specific to the onset and progression of cholestasis, such as PPAR related processes and drug metabolism, by circumventing other effects of CsA, such as immunosuppression, found in dose*time group analysis. In vivo gene sets are enriched in publicly available data sets of CsA-treated HepaRG and primary mouse hepatocytes. However, genes identified within these gene sets did not overlap between in vivo and in vitro. In vitro regulated genes represent the initial response to cholestasis, whereas in vivo genes represent the later adaptive response. We conclude that the applicability of in vitro models for hepatotoxicity testing fully depends on a solid in vivo phenotype anchored analysis. (c) 2013 Elsevier Ireland Ltd. All rights reserved.",
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Kienhuis, AS, Vitins, AP, Pennings, JLA, Pronk, TE, Speksnijder, EN, Roodbergen, M, van Delft, JHM, Luijten, M & van der Ven, LTM 2013, 'Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis', Toxicology Letters, vol. 221, no. 3, pp. 225-236. https://doi.org/10.1016/j.toxlet.2013.06.236

Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis. / Kienhuis, A.S.; Vitins, A.P.; Pennings, J.L.A.; Pronk, T.E.; Speksnijder, E.N.; Roodbergen, M.; van Delft, J.H.M.; Luijten, M.; van der Ven, L.T.M.

In: Toxicology Letters, Vol. 221, No. 3, 2013, p. 225-236.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis

AU - Kienhuis, A.S.

AU - Vitins, A.P.

AU - Pennings, J.L.A.

AU - Pronk, T.E.

AU - Speksnijder, E.N.

AU - Roodbergen, M.

AU - van Delft, J.H.M.

AU - Luijten, M.

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

N1 - WOS:000323801300009

PY - 2013

Y1 - 2013

N2 - In vitro models for hepatotoxicity testing are a necessity for advancement of toxicological research. Assessing the in vitro response requires in vivo validated gene sets reflective of the hepatotoxic phenotype. Cholestasis, the impairment of bile flow, is induced in C57BL/6J mice treated with cyclosporine A (CsA) to identify phenotype reflective gene sets. CsA treatment through oral gavage for 25 days induced cholestasis, as confirmed by histopathology and serum chemistry. Over 1, 4, and 11 days of CsA exposure gradual increases in serum markers were correlated to gene expression. This phenotype-directed analysis identified gene sets specific to the onset and progression of cholestasis, such as PPAR related processes and drug metabolism, by circumventing other effects of CsA, such as immunosuppression, found in dose*time group analysis. In vivo gene sets are enriched in publicly available data sets of CsA-treated HepaRG and primary mouse hepatocytes. However, genes identified within these gene sets did not overlap between in vivo and in vitro. In vitro regulated genes represent the initial response to cholestasis, whereas in vivo genes represent the later adaptive response. We conclude that the applicability of in vitro models for hepatotoxicity testing fully depends on a solid in vivo phenotype anchored analysis. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

AB - In vitro models for hepatotoxicity testing are a necessity for advancement of toxicological research. Assessing the in vitro response requires in vivo validated gene sets reflective of the hepatotoxic phenotype. Cholestasis, the impairment of bile flow, is induced in C57BL/6J mice treated with cyclosporine A (CsA) to identify phenotype reflective gene sets. CsA treatment through oral gavage for 25 days induced cholestasis, as confirmed by histopathology and serum chemistry. Over 1, 4, and 11 days of CsA exposure gradual increases in serum markers were correlated to gene expression. This phenotype-directed analysis identified gene sets specific to the onset and progression of cholestasis, such as PPAR related processes and drug metabolism, by circumventing other effects of CsA, such as immunosuppression, found in dose*time group analysis. In vivo gene sets are enriched in publicly available data sets of CsA-treated HepaRG and primary mouse hepatocytes. However, genes identified within these gene sets did not overlap between in vivo and in vitro. In vitro regulated genes represent the initial response to cholestasis, whereas in vivo genes represent the later adaptive response. We conclude that the applicability of in vitro models for hepatotoxicity testing fully depends on a solid in vivo phenotype anchored analysis. (c) 2013 Elsevier Ireland Ltd. All rights reserved.

KW - proliferator-activated receptor

KW - phospholipid transfer protein

KW - nuclear receptors

KW - bile-acids

KW - liver

KW - hepatotoxicity

KW - transporters

KW - mechanisms

KW - mice

KW - drugs

U2 - 10.1016/j.toxlet.2013.06.236

DO - 10.1016/j.toxlet.2013.06.236

M3 - Article

VL - 221

SP - 225

EP - 236

JO - Toxicology Letters

JF - Toxicology Letters

SN - 0378-4274

IS - 3

ER -