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Arch Toxicol. 2017 Mar;91(3):1401-1412. doi: 10.1007/s00204-016-1778-8. Epub 2016 Jun 25.

Validation of precision-cut liver slices to study drug-induced cholestasis: a transcriptomics approach.

Author information

1
Division of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
2
Division of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
3
National Institute for Public Health and the Environment, Bilthoven, The Netherlands.
4
Division of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands. g.m.m.groothuis@rug.nl.

Abstract

Hepatotoxicity is one of the major reasons for withdrawal of drugs from the market. Therefore, there is a need to screen new drugs for hepatotoxicity in humans at an earlier stage. The aim of this study was to validate human precision-cut liver slices (PCLS) as an ex vivo model to predict drug-induced cholestasis and identify the possible mechanisms of cholestasis-induced toxicity using gene expression profiles. Five hepatotoxicants, which are known to induce cholestasis (alpha-naphthyl isothiocyanate, chlorpromazine, cyclosporine, ethinyl estradiol and methyl testosterone) were used at concentrations inducing low (<30 %) and medium (30-50 %) toxicity, based on ATP content. Human PCLS were incubated with the drugs in the presence of a non-toxic concentration (60 µM) of a bile acid mixture (portal vein concentration and composition) as model for bile acid-induced cholestasis. Regulated genes include bile acid transporters and cholesterol transporters. Pathway analysis revealed that hepatic cholestasis was among the top ten regulated pathways, and signaling pathways such as farnesoid X receptor- and liver X receptor-mediated responses, which are known to play a role in cholestasis, were significantly affected by all cholestatic compounds. Other significantly affected pathways include unfolded protein response and protein ubiquitination implicating the role of endoplasmic reticulum stress. This study shows that human PCLS incubated in the presence of a physiological bile acid mixture correctly reflect the pathways affected in drug-induced cholestasis in the human liver. In the future, this human PCLS model can be used to identify cholestatic adverse drug reactions of new chemical entities.

KEYWORDS:

Cholestasis; Hepatotoxicity; Precision-cut liver slices; Transcriptomics

PMID:
27344345
PMCID:
PMC5316400
DOI:
10.1007/s00204-016-1778-8
[Indexed for MEDLINE]
Free PMC Article

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