Impaired localisation and transport function of canalicular Bsep in taurolithocholate induced cholestasis in the rat

Crocenzi, F.A.; Mottino, A.D.; Pozzi, E.J. Sánchez; Pellegrino, J.M.; Garay, E.A. Rodríguez; Milkiewicz, P.; Vore, M.; Coleman, R.; Roma, M.G.
August 2003
Gut;Aug2003, Vol. 52 Issue 8, p1170
Academic Journal
Background: Taurolithocholate induced cholestasis is a well established model of drug induced cholestasis with potential clinical relevance. This compound impairs bile salt secretion by an as yet unclear mechanism. Aims: To evaluate which step/s of the hepatocellular bile salt transport are impaired by taurolithocholate, focusing on changes in localisation of the canalicular bile salt transporter, Bsep, as a potential pathomechanism. Methods: The steps in bile salt hepatic transport were evaluated in rats in vivo by performing pharmacokinetic analysis of [sup 14]C taurocholate plasma disappearance. Bsep transport activity was determined by assessing secretion of [sup 14]C taurocholate and cholyl-lysylfluorescein in vivo and in isolated rat hepatocyte couplets (IRHC), respectively. Localisation of Bsep and F-actin were assessed both in vivo and in IRHC by specific fluorescent staining. Results: In vivo pharmacokinetic studies revealed that taurolithocholate (3 µmol/100 g body weight) diminished by 58% canalicular excretion and increased by 96% plasma reflux of [sup 14]C taurocholate. Analysis of confocal images showed that taurolithocholate induced internalisation of Bsep into a cytosolic vesicular compartment, without affecting F-actin cytoskeletal organisation. These effects were reproduced in IRHC exposed to taurolithocholate (2.5 µM). Preadministration of dibutyryl-cAMP, which counteracts taurolithocholate induced impairment in bile salt secretory function in IRHC, restored Bsep localisation in this model. Furthermore, when preadministered in vivo, dibutyryl-cAMP accelerated recovery of both bile flow and bile salt output, and improved by 106% the cumulative output of [sup 14]C taurocholate. Conclusions: Taurolithocholate impairs bile salt secretion at the canalicular level. Bsep internalisation may be a causal factor which can be prevented by dibutyryl-cAMP.


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