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Mechanisms and in vitro models of drug-induced cholestasis

  • Eva Gijbels
  • Vânia Vilas-Boas
  • Neel Deferm
  • Lindsey Devisscher
  • Hartmut Jaeschke
  • Pieter Annaert
  • Mathieu VinkenEmail author
Review Article
  • 141 Downloads

Abstract

Cholestasis underlies one of the major manifestations of drug-induced liver injury. Drug-induced cholestatic liver toxicity is a complex process, as it can be triggered by a variety of factors that induce 2 types of biological responses, namely a deteriorative response, caused by bile acid accumulation, and an adaptive response, aimed at removing the accumulated bile acids. Several key events in both types of responses have been characterized in the past few years. In parallel, many efforts have focused on the development and further optimization of experimental cell culture models to predict the occurrence of drug-induced cholestatic liver toxicity in vivo. In this paper, a state-of-the-art overview of mechanisms and in vitro models of drug-induced cholestatic liver injury is provided.

Keywords

Drug-induced cholestasis Liver Mechanisms In vitro models 

Abbreviations

ANIT

α-Naphthyl isothiocyanate

ATF

Activating transcription factor

BSEP

Bile salt export pump

CIx

Cholestatic index

CYP

Cytochrome P450

DICI

Drug-induced cholestasis index

DILI

Drug-induced liver injury

DNA

Deoxyribonucleic acid

ECM

Extracellular matrix

Egr1

Early growth response factor-1

ER

Endoplasmic reticulum

FXR

Farnesoid X receptor

iPSC

Induced pluripotent stem cells

IRE1

Inositol-requiring protein 1α

Keap1

Kelch-like ECH-associated protein 1

LC3

Microtubule-associated protein 1 light chain 3

MDR

Multidrug resistance protein

MLKL

Mixed lineage kinase domain-like

MRP

Multidrug resistance-associated protein

NLRP3

Nucleotide-binding and oligomerization leucine-rich repeat protein 3

Nrf2

Nuclear-related factor 2

OATP

Organic anion transporting polypeptides

PERK

Protein kinase RNA-like endoplasmic reticulum kinase

PCLS

Precision-cut liver slice(s)

PXR

Pregnane X receptor

RIP

Receptor interacting protein

ROCK

Rho-associated protein kinase

ROS

Reactive oxygen species

TLR9

Toll-like receptor 9

UGT

Uridine diphosphate glucuronosyltransferase

Notes

Acknowledgements

This work was supported by the Grants of the European Research Council, the Center for Alternatives to Animal Testing at Johns Hopkins University Baltimore, USA, the Fund for Scientific Research, Flanders and the University Hospital of the Willy Gepts Fonds UZ, Brussels.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Eva Gijbels
    • 1
  • Vânia Vilas-Boas
    • 1
  • Neel Deferm
    • 2
  • Lindsey Devisscher
    • 3
  • Hartmut Jaeschke
    • 4
  • Pieter Annaert
    • 2
  • Mathieu Vinken
    • 1
    Email author
  1. 1.Department of In Vitro Toxicology and Dermato-CosmetologyVrije Universiteit BrusselBrusselsBelgium
  2. 2.Drug Delivery and DispositionDepartment of Pharmaceutical and Pharmacological Sciences, KU Leuven, O&N2LeuvenBelgium
  3. 3.Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Faculty of Medicine and Health SciencesGhent UniversityGhentBelgium
  4. 4.Department of Pharmacology, Toxicology and TherapeuticsUniversity of Kansas Medical CenterKansas CityUSA

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