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

• DOI: 10.1093/toxsci/kfu122
• Publication Date: 2014-06-28T05:12:13Z
• Authors: Ahmad Sharanek; Pamela Bachour-El...; Houssein Al-Attrache; Camille C. Savary; Lydie Humbert; Dominique Rainteau; Christiane Guguen...; André Guillouzo
• Keywords: Bone canaliculus

Mechanisms involved in drug-induced cholestasis 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 early cholestatic effects of using differentiated human HepaRG cell line. Inhibition efflux uptake taurocholate was evidenced as 15 min 1 h respectively after addition 10μM CsA; it peaked at around 2 reversible. These were associated with generation oxidative stress deregulation cPKC pathway. At higher concentrations (≥50μM) alterations activities enhanced became irreversible, pericanalicular F-actin microfilaments disorganized bile canaliculi constricted. changes induction endoplasmic reticulum that preceded stress. Concentration-dependent observed on total acid disposition, which characterized by an increase a decrease culture medium cells, respectively, 24-h treatment CsA. Accordingly, genes encoding hepatobiliary transporters synthesis enzymes differently deregulated depending concentration. By contrast, FK506 induced limited 25–50μM did not alter canaliculi. Our data demonstrate involvement different concentration-dependent CsA-induced point out critical role occurrence major features.