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Article Dans Une Revue Toxicological Sciences Année : 2015

Cellular accumulation and toxic effects of bile acids in cyclosporine A-treated HepaRG hepatocytes

Résumé

Alteration of bile acid (BA) profiles and secretion by cholestatic drugs represents a major clinical issue. Species differences exist in BA composition, synthesis and regulation; however presently, there is no in vitro reproducible cell model to perform studies on BAs in humans. We have evaluated the capacity of the human HepaRG cell line to synthesize, conjugate and secrete BAs, and analyzed changes in BA content and profile after cyclosporine A (CsA) treatment. Our data show that HepaRG cells produced normal BAs at daily levels comparable, though in different proportions, to those measured in primary human hepatocytes. A 4h treatment with CsA led to BA accumulation and profile changes associated with occurrence of cholestatic features, while after 24h BAs were decreased in cell layers and increased in media. The latter effects resulted from reduced function of BA uptake transporter (NTCP), reduced expression of BA metabolizing enzymes, including CYP7A1, CYP8B1 and CYP27A1, and induction of alternative basolateral transporters. Noteworthy, HepaRG cells incubated in a 2% serum-supplemented medium showed dose-dependent accumulation of the cytotoxic BA lithocholic acid in a nonsulfoconjugated form associated with early inhibition of the canalicular transporter MRP2 and sulfotransferase 2A1. In summary, our data bring the first demonstration that an in vitro human liver cell line is able to produce and secrete conjugated BAs, and to accumulate endogenous BAs transiently, concomitantly to occurrence of various other cholestatic features following CsA treatment. Retention of the hydrophobic lithocholic acid supports its toxic role in drug-induced cholestasis. Overall, our results argue on the suitability of HepaRG cells for investigating mechanisms involved in the development of the disease

Dates et versions

hal-01187306 , version 1 (26-08-2015)

Identifiants

Citer

Ahmad Sharanek, Audrey Burban, Lydie Humbert, Pamela Bachour-El Azzi, Neuza Felix-Gomes, et al.. Cellular accumulation and toxic effects of bile acids in cyclosporine A-treated HepaRG hepatocytes. Toxicological Sciences, 2015, 147 (2), pp.573-587. ⟨10.1093/toxsci/kfv155⟩. ⟨hal-01187306⟩
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