Title: Toxicity and intracellular accumulation of bile acids in sandwich-cultured rat hepatocytes: role of glycine conjugates
Authors: Chatterjee, Sagnik
Bijsmans, I.T.G.W
Van Mil, S.W.C.
Augustijns, Patrick
Annaert, Pieter # ×
Issue Date: 2014
Publisher: Pergamon
Series Title: Toxicology in Vitro vol:28 issue:2 pages:218-230
Abstract: Excessive intrahepatic accumulation of bile acids (BAs) is a key mechanism underlying
cholestasis. The aim of this study was to quantitatively explore the relationship between cytotoxicity of
BAs and their intracellular accumulation in sandwich-cultured rat hepatocytes (SCRH). Following
exposure of SCRH (on day-1 after seeding) to various BAs for 24h, glycine-conjugated BAs were most
potent in exerting toxicity. Moreover, unconjugated BAs showed significantly higher toxicity in day-1
compared to day-3 SCRH. When day-1/-3 SCRH were exposed (0.5-4 h) to 5-100 μM (C)DCA,
intracellular levels of unconjugated (C)DCA were similar, while intracellular levels of glycine
conjugates were up to 4-fold lower in day-3 compared to day-1 SCRH. Sinusoidal efflux was by far the
predominant efflux pathway of conjugated BAs both in day-1 and day-3 SCRH, while canalicular BA
efflux showed substantial interbatch variability. After 4h exposure to (C)DCA, intracellular glycine
conjugate levels were at least 10-fold higher than taurine conjugate levels. Taken together, reduced BA
conjugate formation in day-3 SCRH results in lower intracellular glycine conjugate concentrations,
explaining decreased toxicity of (C)DCA in day-3 versus day-1 SCRH. Our data provide for the first time
a direct link between BA toxicity and glycine conjugate exposure in SCRH.
ISSN: 0887-2333
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Drug Delivery and Disposition
× corresponding author
# (joint) last author

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