Sinusoidal efflux of taurocholate is enhanced in Mrp2-deficient rat liver.
OBJECTIVE
It has been shown that plasma concentration and urinary excretion of bile acids is elevated under the cholestatic/ hyperbilirubinemic conditions. Previously, it was demonstrated that the plasma concentration of bile acids was elevated in the multidrug resistance-associated protein 2 (Mrp2)-deficient rats. The purpose of the present study was to compare the sinusoidal efflux clearance of taurocholate (TC) between Mrp2-deficient Eisai hyperbilirubinemic rats (EHBR) and normal rats.


METHODS
Hepatic disposition of the [3H]TC was examined in the perfused liver. Apparent efflux clearance (PSnet, eff) of [3H]TC from hepatocytes to outflow across the sinusoidal membrane was defined as the amount of [3H]TC excreted into the outflow from the liver divided by hepatic AUC of [3H]TC. Additionally, influx clearance (PSinf) was also determined by multiple indicator dilution method because PSnet, eff is also affected by PSinf.


RESULTS
PSnet, eff was significantly higher in EHBR than that in Sprague-Dawley (SD) rats (16.6 +/- 1.7 vs. 6.1 +/- 1.3 microL/min/g liver, P < 0.01). In contrast, PSinf was comparable between SD rats and EHBR. Kinetic analysis suggested that the intrinsic clearance for the efflux of [3H]TC across the sinusoidal membrane in EHBR was higher than that in SD rats (10.4 +/- 1.0 v.s. 23.3 +/- 1.7 microL/min/g liver, P < 0.01).


CONCLUSIONS
Enhanced sinusoidal efflux of TC in EHBR may be related to the altered disposition of bile acids in the mutant rats. Because Mrp3 transports TC and its expression is induced on the basolateral membrane of Mrp2-deficient rats, the enhanced sinusoidal efflux of TC in EHBR may be accounted for, at least partially, by the increased expression of Mrp3.
Akita
H
H
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
Suzuki
H
H
Sugiyama
Y
Y
D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006932:Hyperbilirubinemia / Q000235:genetics; D066298:In Vitro Techniques; D007201:Indicator Dilution Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D024101:Mitochondrial Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012269:Ribosomal Proteins / Q000172:deficiency* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D013656:Taurocholic Acid / Q000378:metabolism*
D002352:Carrier Proteins; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D013656:Taurocholic Acid