Sinusoidal efflux of taurocholate correlates with the hepatic expression level of Mrp3

Multidrugresistance-associatedprotein3(Mrp3/ABCC3),whichcanmediatethecellularextrusionofbileacids,isinducedonthehepaticsinusoidalmembraneofMrp2/ABCC2-deficientrats(Eisaihyperbilirubinemicrats;EHBRs)andphenobarbital-treatedSprague–Dawleyrats.Inthepresentstudy,thecorrelationbetweenthesinusoidaleffluxclearance(PS eff )of[ 3 H]taurocholate(TC)andthehepaticexpressionofMrp3wasinvestigatedusingperfusedliverfromtheserats.AsignificantcorrelationwasobservedbetweenthePS eff andthehepaticexpressionlevelofMrp3,suggestingacontributionbyMrp3tothesinusoidaleffluxofTC.Theresultsofthekineticanalysisalsosuggestedthatothertransporter(s)onthesinusoidalplasmamembranemayparticipateintheeffluxofTCunderphysiologicalconditions.ThecontributionofMrp3tothesinusoidaleffluxofTCinEHBRsandphenobarbital(80and40mg/kg)-treatedratswasrevealedtobe58%,48%,and31%,respectively. 2002ElsevierScience(USA).Allrightsreserved. Keywords:Mrp3;Bileacid;Perfusedliver;Sinusoidalefflux Theliverplaysanimportantroleinthehomeostasisofbileacidsinthebody.Thebileacidsynthesisisrate-limitedbythe7a-hydroxylationofcholesterolcatalyzedbycholesterol7a-hydroxylase(cytochromeP4507A;Cyp7A)[1].Alongwiththemetabolismand/orbio-synthesisofbileacids,thetransportersonthesinusoidalandcanalicularmembranessynergisticallyplayanim-portantroleinthehepaticdispositionofbileacids.IthasbeenestablishedthattheuptakeofbileacidsintohepatocytesismediatedbybothNa