TY - JOUR T1 - INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 IN RAT LIVER IS ASSOCIATED WITH ALTERED VECTORIAL EXCRETION OF ACETAMINOPHEN METABOLITES JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1176 LP - 1186 DO - 10.1124/dmd.31.9.1176 VL - 31 IS - 9 AU - A. L. Slitt AU - N. J. Cherrington AU - J. M. Maher AU - C. D. Klaassen Y1 - 2003/09/01 UR - http://dmd.aspetjournals.org/content/31/9/1176.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -