Impaired hepatocanalicular organic anion transport in endotoxemic rats.
To investigate the mechanism of sepsis-associated hyperbilirubinemia we have studied 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-1.g dry wt-1 in endotoxemic and normal hepatocytes, respectively). Inhibition of GS-DNP effluxin 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 4-5 days after endotoxemia was induced. Dexamethasone pretreatment partially reversed the inhibition of GS-DNP transport in isolated endotoxemic hepatocytes. The phorbol ester phorbol 12-myristate 13-acetate 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.
Roelofsen
H
H
Division of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
Schoemaker
B
B
Bakker
C
C
Ottenhoff
R
R
Jansen
P L
PL
Elferink
R P
RP
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000838:Anions / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001648:Bile Canaliculi / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004731:Endotoxins / Q000097:blood*; D005978:Glutathione / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D000838:Anions; D004731:Endotoxins; C030190:S-(2,4-dinitrophenyl)glutathione; D003907:Dexamethasone; D011493:Protein Kinase C; D005978:Glutathione; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate