1. Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days
- Author
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Viktoriia Starokozhko, Bauke Schievink, Marjolijn T. Merema, Anders Aspegren, Suresh Vatakuti, Geny M. M. Groothuis, Jane Synnergren, Annika Asplund, Nanomedicine & Drug Targeting, Groningen Research Institute of Pharmacy, and Biopharmaceuticals, Discovery, Design and Delivery (BDDD)
- Subjects
0301 basic medicine ,PREDICTION ,Health, Toxicology and Mutagenesis ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Toxicology ,VIVO ,TISSUE-SLICES ,chemistry.chemical_compound ,Adenosine Triphosphate ,Gene expression ,Incubation ,Glycogen ,Drug transport ,General Medicine ,PHASE-I ,Biochemistry ,Liver ,Toxicity ,Inactivation, Metabolic ,Erratum ,ENZYMES ,Human precision-cut liver slices ,HEPATOTOXICITY ,RAT-LIVER ,Biology ,Xenobiotics ,03 medical and health sciences ,Organ Culture Techniques ,Albumins ,Humans ,Transcriptomics ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Cytochrome P450 ,CYTOCHROME-P450 ,Fibrosis ,VIABILITY ,Prolonged incubation ,Culture Media ,MODEL ,Oxidative Stress ,030104 developmental biology ,Metabolism ,chemistry ,Gene Expression Regulation ,biology.protein ,Xenobiotic ,Carrier Proteins ,Drug metabolism ,Ex vivo ,Toxicokinetics and Metabolism - Abstract
Human precision-cut liver slices (hPCLS) are a valuable ex vivo model that can be used in acute toxicity studies. However, a rapid decline in metabolic enzyme activity limits their use in studies that require a prolonged xenobiotic exposure. The aim of the study was to extend the viability and function of hPCLS to 5 days of incubation. hPCLS were incubated in two media developed for long-term culture of hepatocytes, RegeneMed(®), and Cellartis(®), and in the standard medium WME. Maintenance of phase I and II metabolism was studied both on gene expression as well as functional level using a mixture of CYP isoform-specific substrates. Albumin synthesis, morphological integrity, and glycogen storage was assessed, and gene expression was studied by transcriptomic analysis using microarrays with a focus on genes involved in drug metabolism, transport and toxicity. The data show that hPCLS retain their viability and functionality during 5 days of incubation in Cellartis(®) medium. Albumin synthesis as well as the activity and gene expression of phase I and II metabolic enzymes did not decline during 120-h incubation in Cellartis(®) medium, with CYP2C9 activity as the only exception. Glycogen storage and morphological integrity were maintained. Moreover, gene expression changes in hPCLS during incubation were limited and mostly related to cytoskeleton remodeling, fibrosis, and moderate oxidative stress. The expression of genes involved in drug transport, which is an important factor in determining the intracellular xenobiotic exposure, was also unchanged. Therefore, we conclude that hPCLS cultured in Cellartis(®) medium are a valuable human ex vivo model for toxicological and pharmacological studies that require prolonged xenobiotic exposure. CC BY 4.0Erratum in: Archives of Toxicology, volume 91, issue 7, page 2711 (2017). doi:10.1007/s00204-016-1895-4Received: 7 July 2016 / Accepted: 28 September 2016 / Published online: 7 October 2016The authors thank Prof. Dr. Robert Porte and all the surgeons of the University Medical Center Groningen for providing the human liver tissue. This study was financially supported by the EU-funded project NanoBio4Trans (Grant No. 304842).
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- 2017