Camilla Bernasconi, Olavi Pelkonen, Tommy B. Andersson, Judy Strickland, Iwona Wilk-Zasadna, David Asturiol, Thomas Cole, Roman Liska, Andrew Worth, Ursula Müller-Vieira, Lysiane Richert, Christophe Chesne, Sandra Coecke, Validation of in vitro methods for human cytochrome P450 enzyme induction: Outcome of a multi-laboratory study, Toxicology in Vitro, Volume 60, 2019, Pages 212-228, ISSN 0887-2333, https://doi.org/10.1016/j.tiv.2019.05.019
Validation of in vitro methods for human cytochrome P450 enzyme induction : outcome of a multi-laboratory study
|Author:||Bernasconi, Camilla1; Pelkonen, Olavi2,3; Andersson, Tommy B.4,5;|
1European Commission, Joint Research Centre (JRC), Ispra, Italy
2Research Unit of Biomedicine/Pharmacology and Toxicology, Faculty of Medicine, Aapistie 5B, University of Oulu, FIN-90014, Finland
3Clinical Research Center, Oulu University Hospital, Finland
4Drug Metabolism and Pharmacokinetics, Cardiovascular, Renal and Metabolism, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
5Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, SE-171 77 Stockholm, Sweden
6Integrated Laboratory Systems (contractor supporting NICEATM), Research Triangle Park, North, Carolina, 27709, USA
7Boehringer Ingelheim, Germany. Department of Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, an der Riss, Germany
8KaLy-Cell, 20A, rue du Général Leclerc, 67115 Plobsheim, Franceg Biopredic International, Parc d’activité de la Bretèche Bâtiment A4, 35760 Saint Grégoire, France
9Biopredic International, Parc d’activité de la Bretèche Bâtiment A4, 35760 Saint Grégoire, France
|Online Access:||PDF Full Text (PDF, 2.8 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe202003067580
|Publish Date:|| 2020-03-06
CYP enzyme induction is a sensitive biomarker for phenotypic metabolic competence of in vitro test systems; it is a key event associated with thyroid disruption, and a biomarker for toxicologically relevant nuclear receptor-mediated pathways. This paper summarises the results of a multi-laboratory validation study of two in vitro methods that assess the potential of chemicals to induce cytochrome P450 (CYP) enzyme activity, in particular CYP1A2, CYP2B6, and CYP3A4. The methods are based on the use of cryopreserved primary human hepatocytes (PHH) and human HepaRG cells.
The validation study was coordinated by the European Union Reference Laboratory for Alternatives to Animal Testing of the European Commission's Joint Research Centre and involved a ring trial among six laboratories. The reproducibility was assessed within and between laboratories using a validation set of 13 selected chemicals (known human inducers and non-inducers) tested under blind conditions. The ability of the two methods to predict human CYP induction potential was assessed. Chemical space analysis confirmed that the selected chemicals are broadly representative of a diverse range of chemicals.
The two methods were found to be reliable and relevant in vitro tools for the assessment of human CYP induction, with the HepaRG method being better suited for routine testing. Recommendations for the practical application of the two methods are proposed.
Toxicology in vitro
|Pages:||212 - 228|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
© 2019 European Commission. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).