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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Carcinogen and Anticancer Drug Transport by Mrp2 in Vivo: Studies Using Mrp2 (Abcc2) Knockout Mice

Divisions of Experimental Therapy (M.L.H.V., K.M., E.W., J.S.L., J.H.M.S., A.H.S.) and Clinical Chemistry (O.v.T.), The Netherlands Cancer Institute, Amsterdam, The Netherlands; AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands (D.R.d.W., R.P.J.O.E.); and Slotervaart Hospital, Department of Pharmacy and Pharmacology, Amsterdam, The Netherlands (L.D.V., H.R., J.H.B.)

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.

Address correspondence to: Dr. A. H. Schinkel, The Netherlands Cancer Institute, Division of Experimental Therapy, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: a.schinkel{at}nki.nl

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