INVESTIGADORES
SANCHEZ POZZI Enrique Juan
artículos
Título:
Impaired localization and transport function of canalicular BSEP in taurolithocholate-induced cholestasis in the rat.
Autor/es:
CROCENZI, FERNANDO A; MOTTINO, ALDO D; ENRIQUE JUAN SANCHEZ POZZI; PELLEGRINO, JOSÉ M; RODRÍGUEZ GARAY, EMILIO A; PIOTR MILKIEWICZ,; VORE, MARY; ROGER COLEMAN,; ROMA, MARCELO G
Revista:
GUT - AN INTERNATIONAL JOURNAL OF GASTROENTEOROLOGY AND HEPATOLOGY
Editorial:
B M J PUBLISHING GROUP
Referencias:
Lugar: Londres; Año: 2003 vol. 52 p. 1170 - 1177
ISSN:
0017-5749
Resumen:
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 (14)C taurocholate plasma
disappearance. Bsep transport activity was determined by assessing
secretion of (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 micro
mol/100 g body weight) diminished by 58% canalicular excretion and
increased by 96% plasma reflux of (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 micro M). 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 (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.