Impaired hepatocanalicular organic anion transport in endotoxemic rats. Roelofsen, Han, Berry Schoemaker, Conny Bakker, Roelof Ottenhoff, Peter L. M. Jansen, and Ronald P. J. Oude Elferink. Division of Gastrointestinal and Liver Diseases, Academical Medical Centre, Amsterdam, The Netherlands. Present address: Dept. Hepatology and Gastroenterology, Academic Hospital University of Groningen, The Netherlands.
APStracts 2:0077G, 1995.
In order to investigate the mechanism of sepsis associated hyperbilirubinemia we have studied the hepatocanalicular transport of organic anions in a rat model of endotoxemia. Rats were injected intravenously with lipopolysaccharides (LPS) and at different times after injection, canalicular transport of 2,4-dinitrophenyl-S -glutathione (GS-DNP) as a model organic anion, was measured in perfused livers and isolated hepatocytes. In isolated liver perfusion experiments the initial biliary GS-DNP secretion rate was found to be significantly decreased 18 h after injection with 2 mg/kg LPS. In isolated hepatocytes from these rats, GS-DNP efflux rate was also significantly decreased (193.0 +/- 67 and 448.3 +/- 53 nmol/min.g dry wt. in endotoxemic and normal hepatocytes respectively). Inhibition of GS-DNP efflux in isolated endotoxemic hepatocytes was dose dependent and reached a maximum with 0.25 mg/kg LPS. Inhibition was maximal at 12 h after LPS injection. Transport activity gradually returned to normal in 4 to 5 days after inducing endotoxemia. Dexamethasone pretreatment partially reversed the inhibition of GS -DNP transport in isolated endotoxemic hepatocytes. The phorbol ester PMA, increased GS-DNP efflux by 73 +/- 16% and 24 +/- 8% in endotoxemic and control hepatocytes, respectively, but could not restore the transport activity of endotoxemic hepatocytes to control levels. These results show that canalicular organic anion transport is decreased in the endotoxemic liver; this may play a role in the frequently observed hyperbilirubinemia during sepsis. 

Received 29 July 1994; accepted in final form 12 April 1995.
APS Manuscript Number G283-4.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on  2 May 1995.