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Evaluation of a human in vitro hepatocyte-NPC co-culture model for the prediction of idiosyncratic drug-induced liver injury: A pilot study

: Granitzny, Anne; Knebel, Jan; Müller, Meike; Braun, Armin; Steinberg, Pablo; Dasenbrock, Clemens; Hansen, Tanja

Volltext urn:nbn:de:0011-n-4814685 (2.3 MByte PDF)
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Erstellt am: 27.1.2018

Toxicology reports 4 (2017), S.89-103
ISSN: 2214-7500
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer ITEM ()
Idiosyncratic; drug-induced liver injury; co-culture model; inflammation; preclinical research

Interactions between hepatocytes and immune cells as well as inflammatory episodes are frequently discussed to play a critical role in the alteration of the individual susceptibility to idiosyncratic drug-induced liver injury (iDILI). To evaluate this hypothesis and to face the urgent need for predictive in vitro models, we established two co-culture systems based on two human cell lines in presence or absence of pro-inflammatory factors (LPS, TNF), i.e. hepatoma HepG2 cells co-cultured with monocytic or macrophage-like THP-1 cells. HepG2 monocultures served as control scenario. Mono- or co-cultures were treated with iDILI reference substances (Troglitazone [TGZ], Trovafloxacin [TVX], Diclofenac [DcL],Ketoconazole [KC]) or their non-iDILI partner compounds (Rosiglitazone, Levofloxacin, Acetylsalicylic Acid, Fluconazole). The liver cell viability was subsequently determined via WST-Assay. An enhanced cytotoxicity (synergy) or a hormetic response compared to the drug effect in the HepG2 monoculture was considered as iDILI positive. TGZ synergized in co-cultures with monocytes without an additional pro-inflammatory stimulus, while DcL and KC showed a hormetic response. All iDILI drugs synergized with TNF in the simple HepG2 monoculture, indicating its relevance as an initiator of iDILI. KC showed a synergy when co-exposed to both, monocytes and LPS, while TVX and DcL showed a synergy under the same conditions with macrophages. All described iDILI responses were not observed with the corresponding non-iDILI partner compounds. Our first results confirm that an inflammatory environment increases the sensitivity of liver cells towards iDILI compounds and point to an involvement of pro-inflammatory factors, especially TNF, in the development of iDILI.