Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Biopharmaceutics and Drug Disposition Année : 2022

Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells

Résumé

HepaRG cells are highly-differentiated human hepatoma cells, which are increasingly recognized as a convenient cellular model for in vitro evaluation of hepatic metabolism, transport and/or toxicity of drugs. The present study was designed to evaluate whether HepaRG cells can also be useful for studying drug-mediated inhibition of canalicular and/or sinusoidal hepatic efflux of bile acids, which constitutes a major mechanism of drug-induced liver toxicity (DILI). For this purpose, HepaRG cells, initially loaded with the bile acid taurocholate (TC), were re-incubated in TC-free transport assay medium, in the presence or absence of calcium or drugs, before analysis of TC retention. This method allowed to objectivise and quantitatively measure biliary and sinusoidal efflux of TC from HepaRG cells, through distinguishing cellular and canalicular compartments. In particular, time-course analysis of the TC-free re-incubation period of HepaRG cells, i.e., the efflux period, indicated that a 20 min-efflux period allowed to reach biliary and sinusoidal excretion indexes for TC around 80 % and 60 %, respectively. Addition of the prototypical cholestatic drugs bosentan, cyclosporin A, glibenclamide or troglitazone during the TC-free efflux phase period was demonstrated to markedly inhibit canalicular and sinusoidal secretion of TC, whereas, by contrast, incubation with the non-cholestatic compounds salicylic acid or flumazenil was without effect. Such data therefore support the use of human HepaRG cells for in vitro predicting DILIs due to inhibition of hepatic bile acid secretion, using a biphasic TC loading/efflux assay. This article is protected by copyright. All rights reserved.
Fichier principal
Vignette du fichier
Le Vée et al. - 2022 - Inhibition of canalicular and sinusoidal taurochol.pdf (596.93 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)
Licence : CC BY NC - Paternité - Pas d'utilisation commerciale

Dates et versions

hal-03811754 , version 1 (22-03-2023)

Identifiants

Citer

Marc Le Vée, Amelie Moreau, Elodie Jouan, Claire Denizot, Yannick Parmentier, et al.. Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells. Biopharmaceutics and Drug Disposition, 2022, 43 (6), pp.265-271. ⟨10.1002/bdd.2333⟩. ⟨hal-03811754⟩
38 Consultations
18 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More