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| Content Provider | MDPI |
|---|---|
| Author | Knöspel, Fanny Jacobs, Frank Freyer, Nora Damm, Georg De Bondt, An van den Wyngaert, Ilse Snoeys, Jan Monshouwer, Mario Richter, Marco Strahl, Nadja Seehofer, Daniel Zeilinger, Katrin |
| Abstract | Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro. |
| File Size | 3474432 |
| File Format | |
| e-ISSN | 14220067 |
| DOI | 10.3390/ijms17040584 |
| Journal | International Journal of Molecular Sciences |
| Issue Number | 4 |
| Volume Number | 17 |
| Language | English |
| Publisher Date | 2016-04-16 |
| Access Restriction | Open |
| Subject Keyword | primary human hepatocytes, in vitro hepatotoxicity model three-dimensional (3D) bioreactor diclofenac |
| Content Type | Text |
| Resource Type | Article |
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