Different Dose-Dependent Mechanisms are Involved in Early Cyclosporine A-Induced Cholestatic Effects in HepaRG Cells. - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Review of Economic Dynamics Année : 2014

Different Dose-Dependent Mechanisms are Involved in Early Cyclosporine A-Induced Cholestatic Effects in HepaRG Cells.

Résumé

: Mechanisms involved in drug-induced cholestasis in humans remain poorly understood. Although cyclosporine A (CsA) and tacrolimus (FK506) share similar immunosuppressive properties, only CsA is known to cause dose-dependent cholestasis. Here, we have investigated the mechanisms implicated in early cholestatic effects of CsA using the differentiated human HepaRG cell line. Inhibition of efflux and uptake of taurocholate was evidenced as early as 15 minutes and 1 hour respectively after addition of 10 μM CsA; it peaked at around 2 hours and was reversible. These early effects were associated with generation of oxidative stress and deregulation of cPKC pathway. At higher CsA concentrations (≥50 μM) alterations of efflux and uptake activities were enhanced and became irreversible, pericanalicular F-actin microfilaments were disorganized and bile canaliculi were constricted. These changes were associated with induction of endoplasmic reticulum stress that preceded generation of oxidative stress. Concentration-dependent changes were observed on total bile acid disposition, which were characterized by an increase and a decrease in culture medium and cells respectively, after a 24-hour treatment with CsA. Accordingly, genes encoding hepatobiliary transporters and bile acid synthesis enzymes were differently deregulated depending on CsA concentration. By contrast, FK506 induced limited effects only at 25-50 μM and did not alter bile canaliculi. Our data demonstrate involvement of different concentration-dependent mechanisms in CsA-induced cholestasis and point out a critical role of endoplasmic reticulum stress in the occurrence of the major cholestatic features.

Domaines

Chimie organique

Dates et versions

hal-01016342 , version 1 (30-06-2014)

Identifiants

Citer

Ahmad Sharanek, Pamela Bachour-El Azzi, Houssein Al-Attrache, Camille C Savary, Lydie Humbert, et al.. Different Dose-Dependent Mechanisms are Involved in Early Cyclosporine A-Induced Cholestatic Effects in HepaRG Cells.. Review of Economic Dynamics, 2014, 141 (1), pp.244-253. ⟨10.1093/toxsci/kfu122⟩. ⟨hal-01016342⟩
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