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Mechanisms of Drug-Induced Cholestasis

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Experimental Cholestasis Research

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1981))

Abstract

Cholestasis can be defined as any situation of impaired bile secretion with concomitant accumulation of bile acids in the liver or in the systemic circulation. A variety of factors may evoke cholestasis, including genetic disorders, metabolic pathologies, infectious diseases, immunogenic stimuli, and drugs. Drug-induced cholestasis is a mechanistically complex process. At least three triggering factors of drug-induced cholestasis have been described, including effects on drug transporters, various hepatocellular changes, and altered bile canaliculi dynamics. These stimuli induce two cellular responses, each typified by a number of key events, namely a deteriorative response activated by bile acid accumulation and an adaptive response aimed at decreasing the uptake and increasing the export of bile acids into and from the liver, respectively. The mechanistic scenario of drug-induced cholestasis is described in this chapter.

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Abbreviations

AOP(s):

Adverse outcome pathway(s)

ATF:

Activating transcription factor

BSEP:

Bile salt export pump

CHOP:

CCAAT-enhancer-binding protein homologous protein

CYP:

Cytochrome P450

DIC:

Drug-induced cholestasis

DILI:

Drug-induced liver injury

DNA:

Deoxyribonucleic acid

Egr1:

Early growth response factor-1

ER:

Endoplasmic reticulum

FXR:

Farnesoid X receptor

IRE1α:

Inositol-requiring protein 1α

Keap1:

Kelch-like ECH-associated protein 1

LC3:

Microtubule-associated protein 1 light chain 3

MDR3:

Multidrug resistance protein 3

MLKL:

Mixed lineage kinase domain-like

MRP2/3:

Multidrug resistance-associated protein 2/3

NLRP:

Nucleotide-binding and oligomerization leucine-rich repeat protein

Nrf2:

Nuclear related factor 2

PERK:

Protein kinase RNA-like endoplasmic reticulum kinase

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

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Acknowledgments

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.

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  1. Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium

    Eva Gijbels & Mathieu Vinken

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  1. Eva Gijbels
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Correspondence to Mathieu Vinken .

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  1. Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium

    Mathieu Vinken

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Gijbels, E., Vinken, M. (2019). Mechanisms of Drug-Induced Cholestasis. In: Vinken, M. (eds) Experimental Cholestasis Research. Methods in Molecular Biology, vol 1981. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9420-5_1

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  • DOI: https://doi.org/10.1007/978-1-4939-9420-5_1

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