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  • 1.
    Ulvestad, Maria
    et al.
    AstraZeneca, Sweden / Cellectis AB, Sweden / University of Oslo, Norway.
    Nordell, Pär
    AstraZeneca, Sweden.
    Asplund, Annika
    Cellectis AB, Sweden.
    Rehnström, Marie
    Cellectis AB, Sweden.
    Jacobsson, Susanna
    Cellectis AB, Sweden.
    Holmgren, Gustav
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Sweden / Sahlgrenska University Hospital, Sweden.
    Davidson, Lindsay
    University of Dundee, Scotland.
    Brolén, Gabriella
    AstraZeneca, Sweden.
    Edsbagge, Josefina
    Cellectis AB, Sweden.
    Björquist, Petter
    Cellectis AB, Sweden.
    Küppers-Munther, Barbara
    University of Skövde, School of Life Sciences. University of Skövde, The Systems Biology Research Centre. Cellectis AB, Sweden.
    Andersson, Tommy B.
    AstraZeneca, Sweden / Karolinska Institute, Sweden.
    Drug metabolizing enzyme and transporter protein profiles of hepatocytes derived from human embryonic and induced pluripotent stem cells2013In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 86, no 5, p. 691-702Article in journal (Refereed)
    Abstract [en]

    Human embryonic and induced pluripotent stem cell-derived hepatocytes (hESC-Hep and hiPSC-Hep) have the potential to provide relevant human in vitro model systems for toxicity testing and drug discovery studies. In this study, the expression and function of important drug metabolizing cytochrome P450 (CYP) enzymes and transporter proteins in hESC-Hep and hiPSC-Hep were compared to cryopreserved human primary hepatocytes (hphep) and HepG2 cells. Overall, CYP activities in hESC-Hep and hiPSC-Hep were much lower than in hphep cultured for 4 h, but CYP1A and 3A activities were comparable to levels in hphep cultured for 48 h (CYP1A: 35% and 26% of 48 h hphep, respectively; CYP3A: 80% and 440% of 48 h hphep, respectively). Importantly, in hESC-Hep and hiPSC-Hep, CYP activities were stable or increasing for at least one week in culture which was in contrast to the rapid loss of CYP activities in cultured hphep between 4 and 48 h after plating. With regard to transporters, in hESC-Hep and hiPSC-Hep, pronounced NTCP activity (17% and 29% of 4 h hphep, respectively) and moderate BSEP activity (6% and 8% of 4 h hphep, respectively) were observed. Analyses of mRNA expression and immunocytochemistry supported the observed CYP and transporter activities and showed expression of additional CYPs and transporters. In conclusion, the stable expression and function of CYPs and transporters in hESC-Hep and hiPSC-Hep for at least one week opens up the possibility to reproducibly perform long term and extensive studies, e.g. chronic toxicity testing, in a stem cell-derived hepatic system. (C) 2013 Elsevier Inc. All rights reserved.

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