Functional expression and regulation of drug transporters in monolayer- and sandwich-cultured mouse hepatocytes

Autor: Olivier Fardel, Bruno Stieger, Yannick Parmentier, Gregory Noel, Marc Le Vee, Amélie Moreau
Přispěvatelé: Coval, Nathalie, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Contaminants Chimiques, immunité et Inflammation, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Pharmaceutique, Technologie Servier, Department of Clinical Pharmacology and Toxicology, Hôpital universitaire de Zurich, Contraintes et Apprentissage, Technologie Servier-Technologie Servier, Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes 1 (UR1), University of Zurich, Fardel, Olivier
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Mouse
Cell Culture Techniques
3003 Pharmaceutical Science
Pharmaceutical Science
610 Medicine & health
030226 pharmacology & pharmacy
Xenobiotics
Primary hepatocytes
03 medical and health sciences
Mice
0302 clinical medicine
Drug transporters
Constitutive androstane receptor
medicine
Animals
RNA
Messenger
Receptor
Cells
Cultured
030304 developmental biology
0303 health sciences
Matrigel
Pregnane X receptor
biology
Monolayer
Membrane Transport Proteins
Transporter
Biological Transport
[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Aryl hydrocarbon receptor
In vitro
Mice
Inbred C57BL
[SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences
medicine.anatomical_structure
Biochemistry
10199 Clinic for Clinical Pharmacology and Toxicology
Hepatocyte
biology.protein
Hepatocytes
Female
Sandwich
Regulation
Zdroj: European Journal of Pharmaceutical Sciences
European Journal of Pharmaceutical Sciences, 2013, 49 (1), pp.39-50. ⟨10.1016/j.ejps.2013.01.013⟩
European Journal of Pharmaceutical Sciences, Elsevier, 2013, 49 (1), pp.39-50. ⟨10.1016/j.ejps.2013.01.013⟩
ISSN: 0928-0987
1879-0720
DOI: 10.1016/j.ejps.2013.01.013⟩
Popis: International audience; Primary hepatocyte cultures are now considered as convenient models for in vitro analyzing liver drug transport. However, if primary human and rat hepatocytes have been well-characterized with respect to drug transporter expression and regulation, much less is known for primary mouse hepatocytes. The present study was therefore designed to gain insights about this point. The profile of sinusoidal and canalicular drug transporter mRNA expression in short time (4h)-cultured mouse hepatocytes was found to be highly correlated with that of freshly isolated hepatocytes; by contrast, those of counterparts cultured for a longer time (until 4days) either in monolayer configurations on plastic or collagen or in sandwich configuration with matrigel were profoundly altered: uptake drug transporters such as Oct1, Oatps and Oat2 were thus down-regulated, whereas most of efflux transporters such as Mdr1a/b, Mrp3, Mrp4 and Bcrp were induced. Moreover, short time-cultured hepatocytes exhibited the highest levels of sinusoidal influx transporter activities. Transporter-mediated drug secretion into canalicular networks was however only observed in sandwich-cultured hepatocytes. Mouse hepatocytes cultured either in monolayer or sandwich configurations were finally shown to exhibit up-regulation of referent transporters in response to exposure to prototypical activators of the drug sensing receptors pregnane X receptor, aryl hydrocarbon receptor or constitutive androstane receptor. Taken together, these data demonstrate the feasibility of using primary mouse hepatocytes for investigating potential interactions of xenobiotics with hepatic transporter activity or regulation, provided that adequate culture conditions are retained.
Databáze: OpenAIRE
Externí odkaz: