IMPAIRED HEPATOCANALICULAR ORGANIC ANION TRANSPORT IN ENDOTOXEMIC RATS

To investigate the mechanism of sepsis-associated hyperbilirubinemia w e have studied hepatocanalicular transport of organic anions in a rat model of endotoxemia. Rats were injected intravenously with lipopolysa ccharides (LPS), and at different times after injection, canalicular t ransport of 2,4-dinitrophenyl-S-glutathione (GS-DNP), as a model organ ic anion, was measured in perfused livers and isolated hepatocytes. In isolated liver perfusion experiments the initial biliary GS-DNP secre tion rate was found to be significantly decreased 18 h after injection with 2 mg/kg LPS. In isolated hepatocytes from these rats, GS-DNP eff lux 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 efflux-in isolated endotoxemic he patocytes was dose dependent and reached a maximum with 0.25 mg/kg LPS . Inhibition was maximal at 12 h after LPS injection. Transport activi ty gradually returned to normal in 4-5 days after endotoxemia was indu ced. Dexamethasone pretreatment partially reversed the inhibition of G S-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, bu t could not restore the transport activity of endotoxemic hepatocytes to control levels. These results show that canalicular organic anion t ransport is decreased in the endotoxemic liver; this may play a role i n the frequently observed hyperbilirubinemia during sepsis.