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Received for publication January 30, 2006.
Revised March 28, 2006.
Accepted for publication April 10, 2006.
The ABC transporter MRP2 (ABCC2) forms a natural barrier and efflux system for various (conjugates of) drugs, other xenotoxins and many 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 about 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-fold and 1.7-fold higher in Mrp2-/- mice vs. 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 AUC for i.v. administration was 1.8-fold higher in Mrp2-/- mice (1345 ± 207 min·µg/ml vs. 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 nmol/gr liver vs. 17.30 ± 6.59 nmol/gr 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.
Key words:
ABC transporters, Bilirubin, Carcinogens, Mrp2/Abcc2, Multidrug resistance, methotrexate
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