Induction of multidrug resistance protein 3 in rat liver is associated with altered vectorial excretion of acetaminophen metabolites.
Treatment with the microsomal enzyme inducer trans-stilbene oxide (TSO) can decrease biliary excretion of acetaminophen-glucuronide (AA-GLUC) and increase efflux of AA-GLUC into blood. The hepatic canalicular multidrug resistance protein (Mrp) 2 and sinusoidal protein Mrp3 transport AA-GLUC conjugates into bile and blood, respectively. Thus, TSO-induced alterations in the vectorial excretion of AA-GLUC may occur via increased hepatic Mrp3 levels. The goal of this study was to determine whether TSO, diallyl sulfide (DAS), and oltipraz (OLT) treatments can up-regulate Mrp3 protein expression, and whether treatment with DAS and OLT can correspondingly increase hepatovascular efflux of AA metabolites. Rats were administered phenobarbital, TSO, DAS, OLT, or vehicle for 4 days. Interestingly, all of the chemicals increased the plasma concentration and urinary excretion of AA-GLUC and decreased its biliary excretion. In control animals, approximately 77% and 23% of AA-GLUC was excreted into bile or urine, respectively, whereas with inducer-pretreated animals, <32% of AA-GLUC was excreted into bile and >68% was excreted into urine. Correspondingly, all of the compounds increased hepatic Mrp3 mRNA levels by 13- to 37-fold and protein levels by 2- to 6-fold, respectively. In conclusion, these studies correlate increased Mrp3 protein levels in liver with increased hepatovascular excretion of AA-GLUC and suggest that induction of Mrp3 affects the route of drug excretion.
Slitt
A L
AL
Department of Pharmacology, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA.
Cherrington
N J
NJ
Maher
J M
JM
Klaassen
C D
CD
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D000498:Allyl Compounds / Q000494:pharmacology; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D021121:Branched DNA Signal Amplification Assay; D018432:Drug Resistance, Multiple; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D010634:Phenobarbital / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012269:Ribosomal Proteins / Q000096:biosynthesis / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics; D013267:Stilbenes / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology; D013871:Thiones; D013876:Thiophenes; D013997:Time Factors
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000498:Allyl Compounds; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D011719:Pyrazines; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D013267:Stilbenes; D013440:Sulfides; D013871:Thiones; D013876:Thiophenes; D000082:Acetaminophen; C038491:allyl sulfide; C026209:oltipraz; C037386:acetaminophen glucuronide; C095122:multidrug resistance protein 3; C025906:stilbene oxide; C045667:acetaminophen sulfate ester; D010634:Phenobarbital