TITLE

HEPATOCELLULAR REDISTRIBUTION OF MULTIDRUG RESISTANT PROTEIN (MRP2): A COMPENSATORY MECHANISM IN ANTIDEPRESSANT INDUCED CHOLESTASIS

AUTHOR(S)
Milkiewicz, P.; Chilton, A.; Hubscher, S.G.; Elias, E.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA105
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Antidepressive drugs such as tricyclic antidepressants and monoamine-oxidase inhibitors may occasionally induce prolonged or even fatal jaundice. The mechanisms by which the liver responds to antidepressive drug induced cholestasis are unknown. Patients: We report two cases of antidepressant induced cholestasis. The first patient developed features of cholestasis after dothepin (a tricyclic antidepressant) and 6 years later he presented with similar symptoms associated with treatment with paroxetine, a serotonin selective reuptake inhibitor (SSRI). The occurrence of two episodes of cholestasis following two different antidepressants in one patient, as well as acute cholestasis after paroxetine, have not yet been reported. The second patient presented with acute cholestasis after another SSRI, citalopram, again a reaction which has not been reported. Clinical symptoms in both cases resolved after withdrawal of the causative drug. Histology and Immunochemlstry: In both cases liver biopsies showed features of severe cholestasis without accompanying inflammation or bile duct damage. Immunostaining for the canalicular transporter, MRP2, responsible for biliary secretion of several organic anions including bilirubin glucuronides showed canalicular expression, as seen in the normal liver. There was also aberrant expression of MRP2 on the basolateral membrane of hepatocytes, a pattern that has not been reported previously. Conclusions: We postulate that intracellular redistribution of MRP2 may reflect an adaptive, compensatory mechanism that helps in elimination of the drug or its cholestatic metabolites from the hepatocyte back to the sinusoidal space and subsequent excretion in urine. These findings may have implications for elucidating the hepatic response in other cholestatic conditions.
ACCESSION #
9748004

 

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