Decreased bilirubin transport in the perfused liver of endotoxemic rats.
OBJECTIVE
Hyperbilirubinemia associated with sepsis is frequently observed in humans. In this study, an experimental rat model was developed to study bilirubin metabolism and transport during endotoxemia.


METHODS
Rats were injected intravenously with a single bolus of lipopolysaccharide (1 mg/kg); after 18 hours, the liver was removed for single-pass perfusion. Unconjugated bilirubin, bilirubin ditaurate (125 nmol/min), and/or taurocholate (1.5 mumol/min) were infused. Rate constants for uptake were determined from the disappearance of a bolus of bilirubin ditaurate in a recirculating perfusion.


RESULTS
In endotoxemic livers, biliary excretion of bilirubin-glucuronides was reduced by 49% (2.04 +/- 0.2 and 3.99 +/- 0.24 nmol.min-1.g liver-1). Similar results were obtained with bilirubin ditaurate, indicating that the reduced transport is not caused by a reduced conjugation capacity. The rate constant of sinusoidal uptake was significantly reduced during endotoxemia (0.191 +/- 0.034 vs. 0.090 +/- 0.035, respectively). Secretion of taurocholate into bile was also reduced (92 +/- 22 vs. 127 +/- 10 nmol.min-1.g liver-1).


CONCLUSIONS
In endotoxemic rats, biliary clearance of bilirubin and taurocholate is substantially decreased, suggesting that decreased output of bilirubin-glucuronides is not caused by impaired conjugation but by a reduction in transport.
Roelofsen
H
H
Division of Gastrointestinal and Liver Diseases, Academic Medical Center, Amsterdam, The Netherlands.
van der Veere
C N
CN
Ottenhoff
R
R
Schoemaker
B
B
Jansen
P L
PL
Oude Elferink
R P
RP
D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D001663:Bilirubin / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D001692:Biological Transport; D004731:Endotoxins / Q000097:blood*; D004926:Escherichia coli; D005965:Glucuronates / Q000378:metabolism; D006735:Horseradish Peroxidase / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013654:Taurine / Q000031:analogs & derivatives / Q000378:metabolism; D013656:Taurocholic Acid / Q000493:pharmacokinetics
D001647:Bile Acids and Salts; D004731:Endotoxins; D005965:Glucuronates; D013654:Taurine; D013656:Taurocholic Acid; C054146:bilirubin ditaurine; D006735:Horseradish Peroxidase; D001663:Bilirubin