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Drug Metab Dispos. 2017 Dec;45(12):1292-1303. doi: 10.1124/dmd.117.077420. Epub 2017 Sep 19.

Progressive and Preferential Cellular Accumulation of Hydrophobic Bile Acids Induced by Cholestatic Drugs Is Associated with Inhibition of Their Amidation and Sulfation.

Author information

1
INSERM UMR991/1241, Liver Metabolism and Cancer/Numecan, Rennes, France (A.S., A.B., C.G.-G., A.G.); Université de Rennes 1, Rennes, France (A.S., A.B., C.G.-G., A.G.); and ERL INSERM U1157/UMR7203, Faculté de Médecine Pierre et Marie Curie, Site Saint Antoine, Paris, France (L.H., D.R.).
2
INSERM UMR991/1241, Liver Metabolism and Cancer/Numecan, Rennes, France (A.S., A.B., C.G.-G., A.G.); Université de Rennes 1, Rennes, France (A.S., A.B., C.G.-G., A.G.); and ERL INSERM U1157/UMR7203, Faculté de Médecine Pierre et Marie Curie, Site Saint Antoine, Paris, France (L.H., D.R.) andre.guillouzo@univ-rennes1.fr.

Abstract

Drug-induced intrahepatic cholestasis is characterized by cellular accumulation of bile acids (BAs), whose mechanisms remain poorly understood. The present study aimed to analyze early and progressive alterations of BA profiles induced by cyclosporine A, chlorpromazine, troglitazone, tolcapone, trovafloxacin, and tacrolimus after 4-hour, 24-hour, and 6-day treatments of differentiated HepaRG cells. In BA-free medium, the potent cholestatic drugs cyclosporine A, chlorpromazine, and troglitazone reduced endogenous BA synthesis after 24 hours, whereas the rarely cholestatic drugs tolcapone, trovafloxacin, and tacrolimus reduced BA synthesis only after 6 days. In the presence of physiologic serum BA concentrations, cyclosporine A, chlorpromazine, and troglitazone induced early and preferential cellular accumulation of unconjugated lithocholic, deoxycholic, and chenodeoxycholic acids that increased 8- to 12-fold and 47- to 50-fold after 24 hours and 6 days, respectively. Accumulation of these hydrophobic BAs resulted from strong inhibition of amidation, and in addition, for lithocholic acid reduction of its sulfoconjugation, and was associated with variable alterations of uptake and efflux transporters. Trovafloxacin also caused BA accumulation, especially after 6 days, whereas tolcapone and tacrolimus were still without effect. However, when exogenous BAs were added to the medium at cholestatic serum concentrations, a 6-day treatment with all drugs resulted in cellular BA accumulation with higher folds of chenodeoxycholic and lithocholic acids. At the tested concentration, tolcapone had the lowest effect. These results bring the first demonstration that major cholestatic drugs can cause preferential and progressive in vitro cellular accumulation of unconjugated toxic hydrophobic BAs and bring new insights into mechanisms involved in drug-induced cellular accumulation of toxic BAs.

PMID:
28928138
DOI:
10.1124/dmd.117.077420
[Indexed for MEDLINE]

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