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Mechanisms and in vitro models of drug-induced cholestasis

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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.

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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

References

  • Afonso MB, Rodrigues PM, Simao AL et al (2016) Activation of necroptosis in human and experimental cholestasis. Cell Death Dis 7:e2390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Aleo MD, Shah F, He K et al (2017) Evaluating the role of multidrug resistance protein 3 (MDR3) inhibition in predicting drug-induced liver injury using 125 pharmaceuticals. Chem Res Toxicol 30:1219–1229

    Article  CAS  PubMed  Google Scholar 

  • Ali I, Welch MA, Lu Y et al (2017) Identification of novel MRP3 inhibitors based on computational models and validation using an in vitro membrane vesicle assay. Eur J Pharm Sci 103:52–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Allen K, Kim ND, Moon JO et al (2010) Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling. Toxicol Appl Pharmacol 243:63–67

    Article  CAS  PubMed  Google Scholar 

  • Allen K, Jaeschke H, Copple BL (2011) Bile acids induce inflammatory genes in hepatocytes: a novel mechanism of inflammation during obstructive cholestasis. Am J Pathol 178:175–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Annaert PP, Brouwer KL (2005) Assessment of drug interactions in hepatobiliary transport using rhodamine 123 in sandwich-cultured rat hepatocytes. Drug Metab Dispos 33:388–394

    Article  CAS  PubMed  Google Scholar 

  • Anthérieu S, Chesné C, Li R et al (2010) Stable expression, activity, and inducibility of cytochromes P450 in differentiated HepaRG cells. Drug Metab Dispos 38:516–525

    Article  CAS  PubMed  Google Scholar 

  • Anthérieu S, Bachour-El Azzi P, Dumont J et al (2013) Oxidative stress plays a major role in chlorpromazine-induced cholestasis in human HepaRG cells. Hepatology 57:1518–1529

    Article  CAS  PubMed  Google Scholar 

  • Arduini A, Serviddio G, Escobar J et al (2011) Mitochondrial biogenesis fails in secondary biliary cirrhosis in rats leading to mitochondrial DNA depletion and deletions. Am J Physiol Gastrointest Liver Physiol 301:G119–G127

    Article  CAS  PubMed  Google Scholar 

  • Bachour-El Azzi P, Sharanek A, Burban A et al (2015) Comparative localization and functional activity of the main hepatobiliary transporters in HepaRG Cells and primary human hepatocytes. Toxicol Sci 145:157–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bale SS, Vernetti L, Senutovitch N et al (2014) In vitro platforms for evaluating liver toxicity. Exp Biol Med 239:1180–1191

    Article  CAS  Google Scholar 

  • Baze A, Parmentier C, Hendriks DFG et al (2018) Three-dimensional spheroid primary human hepatocytes in monoculture and coculture with nonparenchymal cells. Tissue Eng Part C Methods 24:534–545

    Article  CAS  PubMed  Google Scholar 

  • Begriche K, Massart J, Robin MA, Borgne-Sanchez A et al (2011) Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J Hepatol 54:773–794

    Article  CAS  PubMed  Google Scholar 

  • Bell CC, Hendriks DF, Moro SM et al (2016) Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Sci Rep 6:25187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bell CC, Lauschke VM, Vorrink SU et al (2017) Transcriptional, functional, and mechanistic comparisons of stem cell-derived hepatocytes, HepaRG cells, and three-dimensional human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury. Drug Metab Dispos 45:419–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bell CC, Dankers ACA, Lauschke VM et al (2018) Comparison of hepatic 2D sandwich cultures and 3D spheroids for long-term toxicity applications: a multicenter study. Toxicol Sci 162:655–666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benien P, Swami A (2014) 3D tumor models: history, advances and future perspectives. Future Oncol 10:1311–1327

    Article  CAS  PubMed  Google Scholar 

  • Birben E, Sahiner UM, Sackesen C et al (2012) Oxidative stress and antioxidant defense. World Allergy Organ J 5:9–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhamidimarri KR, Schiff E (2013) Drug-induced cholestasis. Clin Liver Dis 17:519–531

    Article  PubMed  Google Scholar 

  • Bhat TA, Chaudhary AK, Kumar S et al (2017) Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer. Biochim Biophys Acta 1867:58–66

    CAS  Google Scholar 

  • Brophy CM, Luebke-Wheeler JL, Amiot BP et al (2009) Rat hepatocyte spheroids formed by rocket technique maintain differentiated hepatocyte gene expression and function. Hepatology 49:578–586

    Article  PubMed  Google Scholar 

  • Burban A, Sharanek A, Hue R et al (2017) Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways. Sci Rep 7:1815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burban A, Sharanek A, Guguen-Guillouzo C et al (2018) Endoplasmic reticulum stress precedes oxidative stress in antibiotic-induced cholestasis and cytotoxicity in human hepatocytes. Free Radic Biol Med 115:166–178

    Article  CAS  PubMed  Google Scholar 

  • Burbank MG, Burban A, Sharanek A et al (2016) Early alterations of bile canaliculi dynamics and the rho kinase/myosin light chain kinase pathway are characteristics of drug-induced intrahepatic cholestasis. Drug Metab Dispos 44:1780–1793

    Article  CAS  PubMed  Google Scholar 

  • Cai J, DeLaForest A, Fisher J et al (2012) Protocol for directed dedifferentiation of human pluripotent stem cells toward a hepatocyte facte. In: StemBook (Harvard Stem Cell Institute)

  • Cai SY, Ouyang X, Chen Y et al (2017) Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2:e90780

    Article  PubMed  PubMed Central  Google Scholar 

  • Castell JV, Jover R, Martinez-Jimenez CP et al (2006) Hepatocyte cell lines: their use, scope and limitations in drug metabolism studies. Expert Opin Drug Metab Toxicol 2:183–212

    Article  CAS  PubMed  Google Scholar 

  • Chatterjee S, Annaert P (2018) Drug-induced cholestasis: mechanisms, models and markers. Curr Drug Metab 19:808–818

    Article  CAS  PubMed  Google Scholar 

  • Chatterjee S, Richert L, Augustijns P et al (2014) Hepatocyte-based in vitro model for assessment of drug-induced cholestasis. Toxicol Appl Pharmacol 274:124–136

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Zhang C, Wang H et al (2009) Altered integrity and decreased expression of hepatocyte tight junctions in rifampicin-induced cholestasis in mice. Toxicol Appl Pharmacol 240:26–36

    Article  CAS  PubMed  Google Scholar 

  • Copple BL, Jaeschke H, Klaassen CD (2010) Oxidative stress and the pathogenesis of cholestasis. Semin Liver Dis 30:195–204

    Article  CAS  PubMed  Google Scholar 

  • Cuperus FJ, Claudel T, Gautherot J et al (2014) The role of canalicular ABC transporters in cholestasis. Drug Metab Dispos 42:546–560

    Article  CAS  PubMed  Google Scholar 

  • Das S (2018) Chapter 7: extrapolation of in vitro results to predict human toxicity. In Vitro Toxicol 2018:127–142

    Article  Google Scholar 

  • Dixon PH, Weerasekera N, Linton KJ et al (2000) Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet 9:1209–1217

    Article  CAS  PubMed  Google Scholar 

  • De Bruyn T, Chatterjee S, Fattah S et al (2013) Sandwich-cultured hepatocytes: utility for in vitro exploration of hepatobiliary drug disposition and drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 9:589–616

    Article  CAS  PubMed  Google Scholar 

  • de Lima TVM, Tagliati CA (2014) Hepatobiliary transporters in drug-induced cholestasis: a perspective on the current identifying tools. Expert Opin Drug Metab Toxicol 10:581–597

    Article  CAS  Google Scholar 

  • Donato MT, Jover R, Gomez-Lechon MJ (2013) Hepatic cell lines for drug hepatotoxicity testing: limitations and strategies to upgrade their metabolic competence by gene engineering. Curr Drug Metab 14:946–968

    Article  CAS  PubMed  Google Scholar 

  • Du Y, Han R, Wen F et al (2008) Synthetic sandwich culture of 3D hepatocyte monolayer. Biomaterials 29:290–301

    Article  CAS  PubMed  Google Scholar 

  • Erlinger S (2015) NTCP deficiency: a new inherited disease of bile acid transport. Clin Res Hepatol Gastroenterol 39:7–8

    Article  PubMed  Google Scholar 

  • European Association for the Study of the Liver (2009) EASL Clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 51:237–267

    Article  Google Scholar 

  • Fickert P, Trauner M, Fuchsbichler A et al (2002) Cytokeratins as targets for bile acid-induced toxicity. Am J Pathol 160:491–499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fraczek J, Bolleyn J, Vanhaecke T et al (2013) Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies. Arch Toxicol 87:577–610

    Article  CAS  PubMed  Google Scholar 

  • Fukuda J, Sakai Y, Nakazawa K (2006) Novel hepatocyte culture system developed using microfabrication and collagen/polyethylene glycol microcontact printing. Biomaterials 27:1061–1070

    Article  CAS  PubMed  Google Scholar 

  • Gao L, Lv G, Guo X et al (2014) Activation of autophagy protects against cholestasis-induced hepatic injury. Cell Biosci 4:47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Y, Zhang X, Zhang L et al (2017) Distinct gene expression and epigenetic signatures in hepatocyte-like cells produced by different strategies from the same donor. Stem Cell Reports 9:1813–1824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garzel B, Yang H, Zhang L et al (2014) The role of bile salt export pump gene repression in drug-induced cholestatic liver toxicity. Drug Metab Dispos 42:318–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Godoy P, Hewitt NJ, Albrecht U et al (2013) Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol 87:1315–1530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gong Z, Zhou J, Zhao S et al (2016) Chenodeoxycholic acid activates NLRP3 inflammasome and contributes to cholestatic liver fibrosis. Oncotarget 7:83951–83963

    PubMed  PubMed Central  Google Scholar 

  • Greupink R, Nabuurs SB, Zarzycka B et al (2012) In silico identification of potential cholestasis-inducing agents via modeling of Na(+)-dependent taurocholate cotransporting polypeptide substrate specificity. Toxicol Sci 129:35–48

    Article  CAS  PubMed  Google Scholar 

  • Gripon P, Rumin S, Urban S et al (2002) Infection of a human hepatoma cell line by hepatitis B virus. Proc Nati Acad Sci USA 99:15655–15660

    Article  CAS  Google Scholar 

  • Guguen-Guillouzo C, Guillouzo A (2010) General review on in vitro hepatocyte models and their applications. Methods Mol Biol 640:1–40

    Article  CAS  PubMed  Google Scholar 

  • Guguen-Guillouzo C, Corlu A, Guillouzo A (2010) Stem cell-derived hepatocytes and their use in toxicology. Toxicology 270:3–9

    Article  CAS  PubMed  Google Scholar 

  • Gujral JS, Farhood A, Bajt ML et al (2003) Neutrophils aggravate acute liver injury during obstructive cholestasis in bile duct-ligated mice. Hepatology 38:355–363

    Article  PubMed  Google Scholar 

  • Gujral JS, Liu J, Farhood A et al (2004) Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation. Hepatology 40:998–1007

    Article  PubMed  Google Scholar 

  • Gunness P, Mueller D, Shevchenko V et al (2013) 3D organotypic cultures of human HepaRG cells: a tool for in vitro toxicity studies. Toxicol Sci 133:67–78

    Article  CAS  PubMed  Google Scholar 

  • Hassanein T, Frederick T (2004) Mitochondrial dysfunction in liver disease and organ transplantation. Mitochondrion 4:609–620

    Article  CAS  PubMed  Google Scholar 

  • Halilbasic E, Baghdasaryan A, Trauner M (2013) Nuclear receptors as drug targets in cholestatic liver diseases. Clin Liver Dis 17:161–189

    Article  PubMed  PubMed Central  Google Scholar 

  • Hannan NRF, Segeritz CP, Touboul T et al (2013) Production of hepatocyte like cells from human pluripotent stem cells. Nat Protoc 8:430–437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hasirci V, Berthiaume F, Bondre DP et al (2001) Expression of liver-specific functions by rat hepatocytes seeded in treated poly (lactic-co-glycocholic) acid biodegradable foams. Tissue Eng 7:379–386

    Article  Google Scholar 

  • Hendriks DFG, Puigvert LF, Messner S et al (2016) Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability. Sci Rep 6:35434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hengstler JG, Utesch D, Steinberg P et al (2000) Cryopreserved primary hepatocytes as a constantly available in vitro model for the evaluation of human and animal drug metabolism and enzyme induction. Drug Metab Rev 32:81–118

    Article  CAS  PubMed  Google Scholar 

  • Hengstler JG, Hammad S, Ghallab A et al (2014) In vitro systems for hepatotoxicity testing. Vitro Toxicol Syst 2014:27–44

    Article  Google Scholar 

  • Henkel AS, LeCuyer B, Olivares S et al (2017) Endoplasmic reticulum stress regulates hepatic bile acid metabolism in mice. Cell Mol Gastroenterol Hepatol 3:261–271

    Article  PubMed  Google Scholar 

  • Hoffmaster KA, Turncliff RZ, Lecluyse EL et al (2004) P-glycoprotein expression, localization, and function in sandwich-cultured primary rat and human hepatocytes: relevance to the hepatobiliary disposition of a model opioid peptide. Pharm Res 21:1294–1302

    Article  CAS  PubMed  Google Scholar 

  • Huang P, Zhang L, Gao Y et al (2014) Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 14:370–384

    Article  CAS  PubMed  Google Scholar 

  • Humbert L, Maubert MA, Wolf C et al (2012) Bile acid profiling in human biological samples: comparison of extraction procedures and application to normal and cholestatic patients. J Chromatogr B Analyt Technol Biomed Life Sci 899:135–145

    Article  CAS  PubMed  Google Scholar 

  • Hyogo H, Tazuma S, Kajiyama G et al (1999) Transcytotic vesicle fusion is reduced in cholestatic rats: redistribution of phospholipids in the canalicular membrane. Dig Dis Sci 44:1662–1668

    Article  CAS  PubMed  Google Scholar 

  • Imagawa K, Takayma K, Isoyama S et al (2017) Generation of a bile salt export pump deficiency model using patient-specific induced pluripotent stem cell-derived hepatocyte-like cells. Sci Rep 7:41806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaeschke H (2011) Reactive oxygen and mechanisms of inflammatory liver injury: present concepts. J Gastroenterol Hepatol 1:173–179

    Article  CAS  Google Scholar 

  • Jaeschke H, Krell H, Pfaff E (1983) No increase of biliary permeability in ethinylestradiol-treated rats. Gastroenterology 85:808–814

    Article  CAS  PubMed  Google Scholar 

  • Jaeschke H, Trummer E, Krell H (1987) Increase in biliary permeability subsequent to intrahepatic cholestasis by estradiol valerate in rats. Gastroenterology 93:533–538

    Article  CAS  PubMed  Google Scholar 

  • Jansen PL, Ghallab A, Vartak N et al (2017) The ascending pathophysiology of cholestatic liver disease. Hepatology 65:722–738

    Article  CAS  PubMed  Google Scholar 

  • Kawamoto T, Ito Y, Morita O et al (2017) Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics. J Toxicol Sci 42:427–436

    Article  CAS  PubMed  Google Scholar 

  • Keller GM (1995) In vitro differentiation of embyronic stem cells. Curr Opin Cell Biol 7:862–869

    Article  CAS  PubMed  Google Scholar 

  • Kelm JM, Fussenegger M (2004) Microscale tissue engineering using gravity-enforced cell assembly. Trends Biotechnol 22:195–202

    Article  CAS  PubMed  Google Scholar 

  • Kelm JM, Timmins NE, Brown CJ et al (2003) Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol Bioeng 83:173–180

    Article  CAS  PubMed  Google Scholar 

  • Kia R, Sison RLC, Heslop J et al (2013) Stem cell-derived hepatocytes as a predictive model for drug-induced liver injury: are we there yet? Br J Clin Pharmacol 75:885–896

    Article  PubMed  Google Scholar 

  • Kim ND, Moon JO, Slitt AL et al (2006) Early growth response factor-1 is critical for cholestatic liver injury. Toxicol Sci 90:586–595

    Article  CAS  PubMed  Google Scholar 

  • Köck K, Ferslew BC, Netterberg I et al (2014) Risk factors for development of cholestatic drug-induced liver injury: inhibition of hepatic basolateral bile acid transporters multidrug resistance-associated proteins 3 and 4. Drug Metab Dispos 42:665–674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kotsampasakou E, Ecker GF (2017) Predicting drug-induced cholestasis with the help of hepatic transporters—an in silico modeling approach. J Chem Inf Model 57:608–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krell H, Höke H, Pfaff E (1982) Development of intrahepatic cholestasis by alpha-naphthylisothiocyanate in rats. Gastroenterology 82:507–514

    CAS  PubMed  Google Scholar 

  • Lakshmipathy U, Verfaillie C (2005) Stem cell plasticity. Blood Rev 19:29–38

    Article  PubMed  Google Scholar 

  • Landry J, Bernier D, Ouellet C et al (1985) Spheroidal aggregate culture of rat liver cells: histotypic reorganization, biomatrix deposition, and maintenance of functional activities. J Cell Biol 101:914–923

    Article  CAS  PubMed  Google Scholar 

  • Lang C, Meier Y, Stieger B et al (2007) Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury. Pharmacogenet Genomics 17:47–60

    Article  CAS  PubMed  Google Scholar 

  • Laverty HG, Antoine DJ, Benson C et al (2010) The potential of cytokines as safety biomarkers for drug-induced liver injury. Eur J Clin Pharmacol 66:961–976

    Article  CAS  PubMed  Google Scholar 

  • Lerche-Legrand C, Toutain HJ (2000) Precision-cut liver slices: characteristics and use for in vitro pharmaco-toxicology. Toxicology 153:221–253

    Article  Google Scholar 

  • Li T, Apte U (2015) Bile acid metabolism and signaling in cholestasis, inflammation, and cancer. Adv Pharmacol 74:263–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li P, He K, Li J et al (2017) The role of Kupffer cells in hepatic diseases. Mol Immunol 85:222–229

    Article  CAS  PubMed  Google Scholar 

  • Linkermann A, Green DR (2014) Necroptosis. N Engl J Med 370:455–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malhi H, Kaufman RJ (2011) Endoplasmic reticulum stress in liver disease. J Hepatol 54:795–809

    Article  CAS  PubMed  Google Scholar 

  • Manley S, Ni HM, Kong B et al (2014) Suppression of autophagic flux by bile acids in hepatocytes. Toxicol Sci 137:478–490

    Article  CAS  PubMed  Google Scholar 

  • Mariotti V, Strazzabosco M, Fabris L et al (2017) Animal models of biliary injury and altered bile acid metabolism. Biochim Biophys Acta 1864:1254–1261

    Article  CAS  PubMed Central  Google Scholar 

  • Messner S, Agarkova I, Moritz W et al (2013) Multi-cell type human liver microtissues for hepatotoxicity testing. Arch Toxicol 87:209–213

    Article  CAS  PubMed  Google Scholar 

  • Messner S, Fredriksson L, Lauschke VM et al (2018) Transcriptomic, proteomic, and functional long-term characterization of multicellular three-dimensional human liver microtissues. Applied In Vitro Toxicology 4:1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchell C, Mahrouf-Yorgov M, Mayeuf A et al (2011) Overexpression of Bcl-2 in hepatocytes protects against injury but does not attenuate fibrosis in a mouse model of chronic cholestatic liver disease. Lab Invest 91:273–282

    Article  CAS  PubMed  Google Scholar 

  • Morgan RE, Trauner M, van Staden CJ et al (2010) Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci 118:485–500

    Article  CAS  PubMed  Google Scholar 

  • Moscona A (1961) Rotation-mediated histogenetic aggregation of dissociated cells. A quantifiable approach to cell interactions in vitro. Exp Cell Res 22:455–475

    Article  CAS  PubMed  Google Scholar 

  • Mottino AD, Cao J, Veggi LM et al (2002) Altered localization and activity of canalicular Mrp2 in estradiol-17β-d-glucuronide-induced cholestasis. Hepatology 35:1409–1419

    Article  CAS  PubMed  Google Scholar 

  • Mottino AD, Hoffman T, Crocenzi FA et al (2007) Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17β-D-glucuronide-induced cholestasis. Am J Physiol Gastrointest Liver Physiol 293:G391–G402

    Article  CAS  PubMed  Google Scholar 

  • Mueller SO, Guillouzo A, Hewitt PG et al (2015) Drug biokinetic and toxicity assessments in rat and human primary hepatocytes and HepaRG cells within the EU-funded Predict-IV project. Toxicol In Vitro 30:19–26

    Article  CAS  PubMed  Google Scholar 

  • Natale A, Boeckmans J, Desmae T et al (2018) Hepatic cells derived from human skin progenitors show a typical phospholipidotic response upon exposure to amiodarone. Toxicol Lett 284:184–194

    Article  CAS  PubMed  Google Scholar 

  • Nguyen KD, Sundaram V, Ayoub WS (2014) Atypical causes of cholestasis. World J Gastroenterol 20:9418–9426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ni X, Gao Y, Wu Z et al (2016) Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: a novel in vitro cholestatic model. Sci Rep 6:38694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noor F (2015) A shift in paradigm towards human biology-based systems for cholestatic-liver diseases. J Physiol 593:5043–5055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Olinga P, Elferink MG, Draaisma AL et al (2008) Coordinated induction of drug transporters and phase I and II metabolism in human liver slices. Eur J Pharm Sci 33:380–389

    Article  CAS  PubMed  Google Scholar 

  • Olson H, Betton G, Robinson D et al (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 32:56–67

    Article  CAS  PubMed  Google Scholar 

  • Oorts M, Richert L, Annaert P (2015) Drug-induced cholestasis detection in cryopreserved rat hepatocytes in sandwich culture. J Pharmacol Toxicol Methods 73:63–71

    Article  CAS  PubMed  Google Scholar 

  • Oorts M, Baze A, Bachellier P et al (2016) Drug-induced cholestasis risk assessment in sandwich-cultured human hepatocytes. Toxicol In Vitro 2016:179–186

    Article  CAS  Google Scholar 

  • Ozer J, Ratner M, Shaw M et al (2008) The current state of serum biomarkers of hepatotoxicity. Toxicology 245:194–205

    Article  CAS  PubMed  Google Scholar 

  • Padda MS, Sanchez M, Akhtar AJ et al (2011) Drug-induced cholestasis. Hepatology 53:1377–1387

    Article  CAS  PubMed  Google Scholar 

  • Palmeira CM, Rolo AP (2004) Mitochondrially-mediated toxicity of bile acids. Toxicology 203:1–15

    Article  CAS  PubMed  Google Scholar 

  • Parent R, Marion MJ, Furio L et al (2004) Origin and characterization of a human bipotent liver progenitor cell line. Gastroenterology 126:1147–1156

    Article  PubMed  Google Scholar 

  • Parmentier C, Truisi GL, Moenks K et al (2013) Transcriptomic hepatotoxicity signature of chlorpromazine after short-and long-term exposure in primary human sandwich cultures. Drug Metab Dispos 41:1835–1842

    Article  CAS  PubMed  Google Scholar 

  • Parmentier C, Hendriks DFG, Heyd B et al (2018) Inter-individual differences in the susceptibility of primary human hepatocytes towards drug-induced cholestasis are compound and time dependent. Toxicol Lett 295:187–194

    Article  CAS  PubMed  Google Scholar 

  • Pauli-Magnus C, Meier PJ (2006) Hepatobiliary transporters and drug-induced cholestasis. Hepatology 44:778–787

    Article  CAS  PubMed  Google Scholar 

  • Perez MJ, Briz O (2009) Bile-acid-induced cell injury and protection. World J Gastroenterol 15:1677–1689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Przybylak KR, Cronin MT (2012) In silico models for drug-induced liver injury–current status. Expert Opin Drug Metab Toxicol 8:201–217

    Article  CAS  PubMed  Google Scholar 

  • Qiu X, Zhang Y, Liu T et al (2016) Disruption of BSEP function in HepaRG cells alters bile acid disposition and is a susceptive factor to drug-induced cholestatic injury. Mol Pharm 13:1206–1216

    Article  CAS  PubMed  Google Scholar 

  • Ramboer E, Vanhaecke T, Rogiers V et al (2013) Primary hepatocyte cultures as prominent in vitro tools to study hepatic drug transporters. Drug Metab Rev 45:196–217

    Article  CAS  PubMed  Google Scholar 

  • Rathinam Vijay AK, Vanaja Sivapriya K, Waggoner L et al (2012) TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150:606–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodrigues RM, De Kock J, Branson S et al (2013) Human skin-derived stem cells as a novel cell source for in vitro hepatotoxicity screening of pharmaceuticals. Stem Cells Dev 23:44–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodrigues RM, Sachinidis A, De Boe V et al (2015) Identification of potential biomarkers of hepatitis B-induced acute liver failure using hepatic cells derived from human skin precursors. Toxicol In Vitro 29:1231–1239

    Article  CAS  PubMed  Google Scholar 

  • Rodrigues RM, Branson S, De Boe V et al (2016) In vitro assessment of drug-induced liver steatosis based on human dermal stem cell-derived hepatic cells. Arch Toxicol 90:677–689

    Article  CAS  PubMed  Google Scholar 

  • Russell WMS, Burch RL (1959) The principles of humane experimental technique

  • Sasaki M, Yoshimura-Miyakoshi M, Sato Y et al (2015) A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis. J Gastroenterol 50:984–995

    Article  PubMed  Google Scholar 

  • Schulz S, Schmitt S, Wimmer R et al (2013) Progressive stages of mitochondrial destruction caused by cell toxic bile salts. Biochim Biophys Acta 1828:2121–2133

    Article  CAS  PubMed  Google Scholar 

  • Seglen PO, Reith A (1976) Ammonia inhibition of protein degradation in isolated rat hepatocytes. Quantitative ultrastructural alterations in the lysosomal system. Exp Cell Res 100:276–280

    Article  CAS  PubMed  Google Scholar 

  • Sharanek A, Azzi PB, Al-Attrache H et al (2014) Different dose-dependent mechanisms are involved in early cyclosporine a-induced cholestatic effects in HepaRG cells. Toxicol Sci 141:244–253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharanek A, Burban A, Burbank M et al (2016) Rho-kinase/myosin light chain kinase pathway plays a key role in the impairment of bile canaliculi dynamics induced by cholestatic drugs. Sci Rep 6:24709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharanek A, Burban A, Humbert L et al (2017) Progressive and preferential cellular accumulation of hydrophobic bile acids induced by cholestatic drugs is associated with inhibition of their amidation and sulfatation. Drug Metab Dispos 45:1292–1303

    Article  CAS  PubMed  Google Scholar 

  • Sison-Young RL, Mitsa D, Jenkins RE et al (2015) Comparative proteomic characterization of 4 human liver-derived single cell culture models reveals significant variation in the capacity of drug disposition, bioactivation and detoxication. Toxicol Sci 147:412–424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith DJ, Gordon ER (1987) Membrane fluidity and cholestasis. J Hepatol 5:362–365

    Article  CAS  PubMed  Google Scholar 

  • Snykers S, De Kock J, Rogiers V et al (2009) In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Stem cells 27:577–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snykers S, De Kock J, Vanhaecke V et al (2011) Hepatic differentiation of mesenchymal stem cells: in vitro strategies. Methods Mol Biol 698:305–314

    Article  CAS  PubMed  Google Scholar 

  • Soldatow VY, LeCluyse EL, Griffith LG et al (2013) In vitro models for liver toxicity testing. Toxicol Res (Camb) 2:23–39

    Article  CAS  Google Scholar 

  • Song JY, Van Marle J, Van Noorden CJ et al (1996) Redistribution of Ca2+, Mg2+-ATPase activity in relation to alterations of the cytoskeleton and tight junctions in hepatocytes of cholestatic rat liver. Eur J Cell Biol 71:277–285

    CAS  PubMed  Google Scholar 

  • Song JY, Van Noorden CJF, Frederiks WM (1998) The involvement of altered vesicle transport in redistribution of Ca2+, Mg2+-ATPase in cholestatic rat liver. Histochem J 30:909–916

    Article  CAS  PubMed  Google Scholar 

  • Song Z, Cai J, Liu Y et al (2009) Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res 19:1233–1242

    Article  PubMed  Google Scholar 

  • Spivey JR, Bronk SF, Gores GJ (1993) Glycochenodeoxycholate-induced lethal hepatocellular injury in rat hepatocytes. Role of ATP depletion and cytosolic free calcium. J Clin Invest 92:17–24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Starokozhko V, Greupink R, van de Broek P et al (2017a) Rat precision-cut liver slices predict drug-induced cholestatic injury. Arch Toxicol 91:3403–3413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Starokozhko V, Vatakuti S, Schievink B et al (2017b) Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days. Arch Toxicol 91:2079–2092

    Article  CAS  PubMed  Google Scholar 

  • Stehlik C, Lee SH, Dorfleutner A et al (2003) Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation. J Immunol 171:6154–6163

    Article  CAS  PubMed  Google Scholar 

  • Strnad P, Stumptner C, Zatloukal K et al (2008) Intermediate filament cytoskeleton of the liver in health and disease. Histochem Cell Biol 129:735–749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swift B, Pfeifer ND, Brouwer KLR (2010) Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab Rev 42:446–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szabo M, Veres Z, Baranyai Z et al (2013) Comparison of human hepatoma HepaRG cells with human and rat hepatocytes in uptake transport assays in order to predict a risk of drug induced hepatotoxicity. PLoS One 8:e59432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szalowska E, Stoopen G, Groot MJ et al (2013) Treatment of mouse liver slices with cholestatic hepatotoxicants results in down-regulation of Fxr and its target genes. BMC Med Genom 6:39

    Article  Google Scholar 

  • de Vree JM, Jacquemin E, Sturm E et al (1998) Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci USA 95:282–287

    Article  PubMed  PubMed Central  Google Scholar 

  • Tagliacozzi D, Mozzi AF, Casetta B et al (2003) Quantitative analysis of bile acids in human plasma by liquid chromatography-electrospray tandem mass spectrometry: a simple and rapid one-step method. Clin Chem Lab Med 41:1633–1641

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  CAS  PubMed  Google Scholar 

  • Takahashi Y, Hori Y, Yamamoto T (2015) 3D spheroid cultures improve the metabolic gene expression profiles of HepaRG cells. Biosci Rep 35:e00208

    PubMed  PubMed Central  Google Scholar 

  • Tamaki N, Hatano E, Taura K et al (2008) CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury. Am J Physiol Gastrointest Liver Physiol 294:G498–G505

    Article  CAS  PubMed  Google Scholar 

  • Tiao MM, Lin TK, Wang PW et al (2009) The role of mitochondria in cholestatic liver injury. Chang Gung Med J 32:346–353

    PubMed  Google Scholar 

  • Tostões RM, Leite SB, Serra M et al (2012) Human liver cell spheroids in extended perfusion bioreactor culture for repeated-dose drug testing. Hepatology 55:1227–1236

    Article  CAS  PubMed  Google Scholar 

  • Trauner M, Boyer JL (2003) Bile salt transporters: molecular characterization, function and regulation. Physiol Rev 83:663–671

    Article  Google Scholar 

  • Trauner M, Arrese M, Soroka CJ et al (1997) The rat canalicular conjugate export pump (Mrp2) is down-regulated in intrahepatic and obstructive cholestasis. Gastroenterology 113:255–264

    Article  CAS  PubMed  Google Scholar 

  • Van den Hof WF, Coonen ML, van Herwijnen M et al (2014) Classification of hepatotoxicants using HepG2 cells: a proof of principle study. Chem Res Toxicol 27:433–442

    Article  CAS  PubMed  Google Scholar 

  • van Zijl F, Mikulits W (2010) Hepatospheres: three dimensional cell cultures resemble physiological conditions of the liver. World J Hepatol 2:1–7

    Article  PubMed  PubMed Central  Google Scholar 

  • Vartak N, Damle-Vartak A, Richter B et al (2016) Cholestasis-induced adaptive remodeling of interlobular bile ducts. Hepatology 63:951–964

    Article  CAS  PubMed  Google Scholar 

  • Vatakuti S, Pennings JL, Gore E et al (2016) Classification of cholestatic and necrotic hepatotoxicants using transcriptomics on human precision-cut liver slices. Chem Res Toxicol 29:342–351

    Article  CAS  PubMed  Google Scholar 

  • Vatakuti S, Olinga P, Pennings JL et al (2017) Validation of precision-cut liver slices to study drug-induced cholestasis: a transcriptomics approach. Arch Toxicol 91:1401–1412

    Article  CAS  PubMed  Google Scholar 

  • Vinken M, Elaut G, Henkens T et al (2006) Rat hepatocyte cultures: collagen gel sandwich and immobilization cultures. Methods Mol Biol 320:247–254

    CAS  PubMed  Google Scholar 

  • Vinken M, Landesmann B, Goumenou M et al (2013) Development of an adverse outcome pathway from drug-mediated bile salt export pump inhibition to cholestatic liver injury. Toxicol Sci 136:97–106

    Article  CAS  PubMed  Google Scholar 

  • Vorrink SU, Ullah S, Schmidt S et al (2017) Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics. FASEB J 31:2696–2708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vorrink SU, Zhou Y, Ingelman-Sundberg M et al (2018) Prediction of drug-induced hepatotoxicity using long-term stable primary hepatic 3D spheroid cultures in chemically defined conditions. Toxicol Sci 163:655–665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wagner M, Zollner G, Trauner M (2009) New molecular insights into the mechanisms of cholestasis. J Hepatol 51:565–580

    Article  CAS  PubMed  Google Scholar 

  • Wei Y, Rector RS, Thyfault JP et al (2008) Nonalcoholic fatty liver disease and mitochondrial dysfunction. World J Gastroenterol 14:193–199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woolbright BL, Jaeschke H (2012) Novel insight into mechanisms of cholestatic liver injury. World J Gastroenterol 18:4985–4993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woolbright BL, Jaeschke H (2017) The impact of sterile inflammation in acute liver injury. J Clin Transl Res 3(Suppl 1):170–188

    CAS  PubMed  PubMed Central  Google Scholar 

  • Woolbright BL, Antoine DJ, Jenkins RE et al (2013) Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice. Toxicol Appl Pharmacol 273:524–531

    Article  CAS  PubMed  Google Scholar 

  • Woolbright BL, Li F, Xie Y et al (2014) Lithocholic acid feeding results in direct hepato-toxicity independent of neutrophil function in mice. Toxicol Lett 228:56–66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woolbright BL, Dorko K, Antoine DJ et al (2015) Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis. Toxicol Appl Pharmacol 283:168–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woolbright BL, McGill MR, Yan H et al (2016) Bile acid-induced toxicity in HepaRG cells recapitulates the response in primary human hepatocytes. Basic Clin Pharmacol Toxicol 118:160–167

    Article  CAS  PubMed  Google Scholar 

  • Yang K, Köck K, Sedykh A et al (2013) An updated review on drug-induced cholestasis: mechanisms and investigation of physicochemical properties and pharmacokinetic parameters. J Pharm Sci 102:3037–3057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang K, Guo C, Woodhead JL et al (2016) Sandwich-cultured hepatocytes as a tool to study drug disposition and drug-induced liver injury. J Pharm Sci 105:443–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao X, Li Y, Cheng X et al (2016) ER stress contributes to alpha-naphthyl isothiocyanate-induced liver injury with cholestasis in mice. Pathol Res Pract 212:560–567

    Article  CAS  PubMed  Google Scholar 

  • Yasumiba S, Tazuma S, Ochi H et al (2001) Cyclosporin A reduces canalicular membrane fluidity and regulates transporter function in rats. Biochem J 354:591–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu T, Wang L, Lee H et al (2014) Decreasing mitochondrial fission prevents cholestatic liver injury. J Biol Chem 289:34074–34088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeilinger K, Freyer N, Damm G et al (2016) Cell sources for in vitro human liver cell culture models. Exp Biol Med (Maywood) 241:1684–1698

    Article  CAS  Google Scholar 

  • Zhang Y, Hong JY, Rockwell CE et al (2012) Effect of bile duct ligation on bile acid composition in mouse serum and liver. Liver Int 32:58–69

    Article  CAS  PubMed  Google Scholar 

  • Zhu F, Li XX, Yang SY et al (2018) Clinical success of drug targets prospectively predicted by in silico study. Trends Pharmacol Sci 39:229–231

    Article  CAS  PubMed  Google Scholar 

  • Zollner G, Trauner M (2006) Molecular mechanisms of cholestasis. Wien Med Wochenschr 156:380–385

    Article  PubMed  Google Scholar 

  • Zollner G, Trauner M (2008) Mechanisms of cholestasis. Clin Liver Dis 12:1–26

    Article  PubMed  Google Scholar 

  • Zollner G, Marschall HU, Wagner M et al (2006) Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm 3:231–251

    Article  CAS  PubMed  Google Scholar 

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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.

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Authors and Affiliations

  1. Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium

    Eva Gijbels, Vânia Vilas-Boas & Mathieu Vinken

  2. Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, O&N2, Herestraat 49, Bus 921, 3000, Leuven, Belgium

    Neel Deferm & Pieter Annaert

  3. Basic and Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Faculty of Medicine and Health Sciences, Ghent University, C. Heymanslaan 10, 9000, Ghent, Belgium

    Lindsey Devisscher

  4. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 1018, Kansas City, KS, 66160, USA

    Hartmut Jaeschke

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  1. Eva Gijbels
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  2. Vânia Vilas-Boas
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Gijbels, E., Vilas-Boas, V., Deferm, N. et al. Mechanisms and in vitro models of drug-induced cholestasis. Arch Toxicol 93, 1169–1186 (2019). https://doi.org/10.1007/s00204-019-02437-2

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