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Maintenance of drug metabolism and transport functions in human precision-cut liver slices during prolonged incubation for 5 days
Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.ORCID-id: 0000-0003-4697-0590
Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Division of Pharmacokinetics Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
Vise andre og tillknytning
2017 (engelsk)Inngår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 91, nr 5, s. 2079-2092Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
2017. Vol. 91, nr 5, s. 2079-2092
HSV kategori
Forskningsprogram
Bioinformatik; INF502 Biomarkörer
Identifikatorer
URN: urn:nbn:se:his:diva-13046DOI: 10.1007/s00204-016-1865-xISI: 000399875300004PubMedID: 27717970Scopus ID: 2-s2.0-84991020738OAI: oai:DiVA.org:his-13046DiVA, id: diva2:1039439
Tilgjengelig fra: 2016-10-24 Laget: 2016-10-24 Sist oppdatert: 2018-11-16bibliografisk kontrollert

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