RT Journal Article
SR Electronic
T1 Carcinogen and Anticancer Drug Transport by Mrp2 in Vivo: Studies Using <em>Mrp2</em> (<em>Abcc2</em>) Knockout Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 319
OP 327
DO 10.1124/jpet.106.101774
VO 318
IS 1
A1 M. L. H. Vlaming
A1 K. Mohrmann
A1 E. Wagenaar
A1 D. R. de Waart
A1 R. P. J. Oude Elferink
A1 J. S. Lagas
A1 O. van Tellingen
A1 L. D. Vainchtein
A1 H. Rosing
A1 J. H. Beijnen
A1 J. H. M. Schellens
A1 A. H. Schinkel
YR 2006
UL http://jpet.aspetjournals.org/content/318/1/319.abstract
AB The ATP-binding-cassette (ABC) transporter multidrug resistance protein (MRP) 2 (ABCC2) forms a natural barrier and efflux system for various (conjugates of) drugs, other xenotoxins, and endogenous compounds. To obtain insight in the pharmacological and physiological functions of Mrp2, we generated Mrp2 knockout mice, which were viable and fertile but suffered from mild hyperbilirubinemia due to impaired excretion of bilirubin monoglucuronides into bile. The mice also had an 80-fold decreased biliary glutathione excretion and a 63% reduced bile flow. Levels of Mrp3 (Abcc3) in liver and Mrp4 (Abcc4) in kidney of Mrp2-/- mice were approximately 2-fold increased. After oral administration of the food-derived carcinogens [14C]PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) and [14C]IQ (2-amino-3-methylimidazo[4,5-f]quinoline) plasma values were 1.9- and 1.7-fold higher in Mrp2-/- mice versus wild-type mice, respectively, demonstrating the role of Mrp2 in restricting exposure to these compounds. At a high dose of 50 mg/kg of the drug [3H]methotrexate, the plasma area under the curve for i.v. administration was 1.8-fold higher in Mrp2-/- mice (1345 ± 207 versus 734 ± 81 min ·μg/ml). No clear plasma concentration difference arose at low dose (1 mg/kg). Subsequently, Mdr1a/b/Mrp2 knockout mice were generated. Their biliary excretion of doxorubicin after i.v. administration (5 mg/kg) was 54-fold decreased (0.32 ± 0.13 versus 17.30 ± 6.59 nmol/g liver in wild type), and a role for both Mdr1a/b and Mrp2 in this process was revealed. Our results demonstrate that the Mrp2-/- mouse provides a valuable tool for studies of the impact of Mrp2 on behavior of drugs and other toxins, especially when combined with other ABC transporter knockout mice. The American Society for Pharmacology and Experimental Therapeutics