Three-dimensional HepaRG model as an attractive tool for toxicity testing

Abstract: 

The culture of HepaRG cells as 3D structures in the spinner-bioreactor may represent added value as a hepatic system for toxicological purposes. The use of a cost-effective commercially available bioreactor, which is compatible with high-throughput cell analysis, constitutes an attractive approach for routine use in the drug testing industry. In order to assess specific aspects of the biotransformation capacity of the bioreactor-based HepaRG system, the induction of CYP450 enzymes (i.e. CYP1A2, 2B6, 2C9 and 3A4) and the activity of the phase II enzyme, UGT, were tested. The long term functionality of the system was demonstrated by 7 weeks stable profiles of albumin secretion, CYP3A4 induction and UGT activities. Immunofluorescence-based staining showed formation of tissue-like arrangements including bile canaliculi-like structures and polar distribution of transporters. The use of in silico models to analyse the in vitro data related to hepatotoxic activity of acetaminophen (APAP) demonstrated the advantage of the integration of kinetic and dynamic aspects for a better understanding of the in vitro cell behaviour. The bioactivation of APAP and its related cytotoxicity was assessed in a system compatible to high-throughput screening. The approach also proved to be a good strategy to reduce the time necessary to obtain fully differentiated cell cultures. In conclusion, HepaRG cells cultured in a 3D spinner-bioreactors are an attractive tool for toxicological studies, showing a liver-like performance and demonstrating a practical applicability for toxicodynamic approaches.

Authors
Authors: 
CHESNE Christopher, ZALDIVAR COMENGES Jose', GUGUEN-GUILLOUZO Christiane, WILK-ZASADNA Iwona, GUILLOU Claude, COECKE Sandra, REIS FERNANDES Marcos Antonio, ALVES Paula M., MENNECOZZI Milena, AIROLA Elodie, LEITE Sofia Batista
Publication Year
Publication Year: 
2012
Type

Type:

Appears in Collections
Appears in Collections: 
Institute for Health and Consumer Protection
Science Areas
JRC Institutes
Publisher
Publisher: 
OXFORD UNIV PRESS
ISSN
ISSN: 
1096-6080
URI
URI : 
Citation
Citation: 
TOXICOLOGICAL SCIENCES p. 106?116 no. 1 vol. 130
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