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.
journal_name
Int J Mol Scijournal_title
International journal of molecular sciencesauthors
Knöspel F,Jacobs F,Freyer N,Damm G,De Bondt A,van den Wyngaert I,Snoeys J,Monshouwer M,Richter M,Strahl N,Seehofer D,Zeilinger Kdoi
10.3390/ijms17040584subject
Has Abstractpub_date
2016-04-16 00:00:00pages
584issue
4issn
1422-0067pii
ijms17040584journal_volume
17pub_type
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