0 avis
Inhibition of canalicular and sinusoidal taurocholate efflux by cholestatic drugs in human hepatoma HepaRG cells
Archive ouverte
International audience. 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.
Consulter en ligne
Suggestions
Du même auteur
