Reference : 3D organotypic HepaRG cultures as in vitro model for acute and repeated dose toxicity...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
3D organotypic HepaRG cultures as in vitro model for acute and repeated dose toxicity studies.
Mueller, Daniel [> >]
Kramer, Lisa [> >]
Hoffmann, Esther [> >]
Klein, Sebastian [> >]
Noor, Fozia mailto [Saarland University > Biochemical Engineering]
Toxicology in vitro : an international journal published in association with BIBRA
Yes (verified by ORBilu)
[en] Animal Testing Alternatives ; Cell Culture Techniques ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/diagnosis/etiology ; Cytochrome P-450 CYP3A/metabolism ; Hep G2 Cells ; Hepatocytes/drug effects/enzymology/metabolism ; High-Throughput Screening Assays ; Humans ; Toxicity Tests/methods ; Toxicity Tests, Acute/methods ; Chronic toxicity ; HepaRG ; In vitro models ; Organotypic cultures ; Repeated dose toxicity
[en] Predictive in vitro models alternative to in vivo animal will have a significant impact in toxicology. Conventional 2D models do not reflect the complexity of a 3D organ resulting in discrepancies between experimental in vitro and in vivo data. Using 3D HepaRG organotypic cultures we tested four drugs (aflatoxin B1, amiodarone, valproic acid and chlorpromazine) for toxic effects and compared the results with 2D HepaRG and HepG2 cultures. We show that 3D HepaRG cultures are more sensitive than the other tested cultures to aflatoxin B1 which is only toxic upon metabolic activation in the liver. We observed that CYP3A4 activity is higher in the 3D HepaRG cultures compared to the 2D HepaRG cultures. Furthermore, we investigated repeated dose toxicity of chlorpromazine and assessed its effects on glucose and lactate metabolism. Sub-toxic concentrations of chlorpromazine induced significant metabolic changes in both 2D and 3D HepaRG cultures upon acute and repeated dose (3 doses) exposure. In summary, our data support the hypothesis that 3D cell culture models better mimic the in vivo tissue and improve cellular functionality. The 3D HepaRG organotypic cultures represent a high throughput system for drug toxicity screening. This system is therefore a promising tool in preclinical testing of human relevance which can allow reducing and/or replacing animal testing for drug adverse effects.
Copyright (c) 2013 Elsevier Ltd. All rights reserved.

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