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Validation of in vitro methods for human cytochrome P450 enzyme induction: Outcome of a multi-laboratory study

Bernasconi, Camilla

Toxicology in vitro. Volume 60 (2019); pp 212-228 -- Elsevier

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  • Title:
    Validation of in vitro methods for human cytochrome P450 enzyme induction: Outcome of a multi-laboratory study
  • Author: Bernasconi, Camilla;
    Pelkonen, Olavi;
    Andersson, Tommy B.;
    Strickland, Judy;
    Wilk-Zasadna, Iwona;
    Asturiol, David;
    Cole, Thomas;
    Liska, Roman;
    Worth, Andrew;
    Müller-Vieira, Ursula;
    Richert, Lysiane;
    Chesne, Christophe;
    Coecke, Sandra
  • Found In: Toxicology in vitro. Volume 60 (2019); pp 212-228
  • Journal Title: Toxicology in vitro
  • Subjects: Toxicity testing--In vitro--Periodicals; Toxicology--Periodicals; CYP induction--human hepatocytes--HepaRG--metabolism--in vitro hepatic system--validation; Dewey: 615.9
  • Rights: legaldeposit
  • Publication Details: Elsevier
  • Abstract: Abstract:

    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.

    Highlights:

    Paper summarises the results of a multi-laboratory validation study.

    Two human derived metabolically competent test systems used.

    In vitro methods validated as reliable and relevant for CYP enzyme induction assessment.

    Two in vitro methods can support regulatory chemical risk assessment with HepaRG-based method better suited for routine chemical testing.

    CYP enzyme induction biomarker for thyroid and nuclear receptor-mediated disruption.


  • Identifier: System Number: LDEAvdc_100091278540.0x000001; Journal ISSN: 0887-2333; 10.1016/j.tiv.2019.05.019
  • Publication Date: 2019
  • Physical Description: Electronic
  • Shelfmark(s): ELD Digital store

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