Evaluation of a human in vitro hepatocyte-NPC co-culture model for the prediction of idiosyncratic drug-induced liver injury: A pilot study. (2017)

• Record Type: Journal Article
• Authors: Granitzny, Anne; Knebel, Jan; Müller, Meike; Braun, Armin; Steinberg, Pablo; Dasenbrock, Clemens; Hansen, Tanja
• Is Part Of: Toxicology reports. Volume 4(2017)
• Page Start: 89
• Page End: 103
• Publication Date: 2017
• Subjects: CD cluster of differentiation -- DAMP damage-associated molecular pattern -- EC effective concentration -- EpCAM epithelial cellular adhesion molecule -- HSP heat shock protein -- iDILI idiosyncratic drug-induced liver injury -- JNK c-Jun N-terminal kinase -- LPS bacterial lipopolysaccharide -- NF-κB nuclear factor kappa B -- NPC non-parenchymal cell -- NSAID nonsteriodal anti-inflammatory drug -- PAMP pathogen-associated molecular pattern -- SD standard deviation -- TNF tumor necrosis factor; Idiosyncratic -- Drug-induced liver injury -- Co-culture model -- Inflammation -- Preclinical research; Toxicology -- Periodicals; Clinical toxicology -- Periodicals; Drug-Related Side Effects and Adverse Reactions; Hazardous Substances; Poisoning; Toxicology; Electronic journals; Periodicals; Periodicals; 571.9505
• DOI: 10.1016/j.toxrep.2017.02.001
• Languages: English
• ISSNs: 2214-7500

Abstract

Highlights: Co-cultures of liver and immune cells can be used to detect iDILI compounds. Pro-inflammatory factors are involved in the development of iDILI. The co-exposure of a drug candidate with TNF might be sufficient to predict iDILI. Abstract: 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.