Evaluation of a human in vitro hepatocyte-NPC co-culture model for the prediction of idiosyncratic drug-induced liver injury: A pilot study
| Autor: | Granitzny, Anne, Knebel, Jan, Müller, Meike, Braun, Armin, Steinberg, Pablo, Dasenbrock, Clemens, Hansen, Tanja |
|---|---|
| Přispěvatelé: | Publica |
| Rok vydání: | 2017 |
| Předmět: |
Inflammation
TNF tumor necrosis factor LPS bacterial lipopolysaccharide Drug-induced liver injury CD cluster of differentiation DAMP damage-associated molecular pattern Co-culture model Article EC effective concentration NSAID nonsteriodal anti-inflammatory drug EpCAM epithelial cellular adhesion molecule iDILI idiosyncratic drug-induced liver injury lcsh:RA1190-1270 Preclinical research JNK c-Jun N-terminal kinase Idiosyncratic HSP heat shock protein NPC non-parenchymal cell SD standard deviation NF-κB nuclear factor kappa B PAMP pathogen-associated molecular pattern lcsh:Toxicology. Poisons |
| Zdroj: | Toxicology Reports Toxicology Reports, Vol 4, Iss, Pp 89-103 (2017) |
| ISSN: | 2214-7500 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|