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Published on: May 27, 2015
Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2)
Xiao-Yan Chu1, John R Strauss, Michele A Mariano
1Department of Drug Metabolism, Merck and Co., RY80, 126 E. Lincoln Ave., Rahway, NJ 07065, USA. xiaoyan_chu@merck.com
Abstract:
The multidrug resistance protein Mrp2 is an ATP-binding cassette (ABC) transporter mainly expressed in liver, kidney, and intestine. One of the physiological roles of Mrp2 is to transport bilirubin glucuronides from the liver into the bile. Current in vivo models to study Mrp2 are the transporter-deficient and Eisai hyperbilirubinemic rat strains. Previous reports showed hyperbilirubinemia and induction of Mrp3 in the hepatocyte sinusoidal membrane in the mutant rats. In addition, differences in liver cytochrome P450 and UGT1a levels between wild-type and mutant rats were detected. To study whether these compensatory mechanisms were specific to rats, we characterized Mrp2(-/-) mice. Functional absence of Mrp2 in the knockout mice was demonstrated by showing increased levels of bilirubin and bilirubin glucuronides in serum and urine, a reduction in biliary excretion of bilirubin glucuronides and total glutathione, and a reduction in the biliary excretion of the Mrp2 substrate dibromosulfophthalein. To identify possible compensatory mechanisms in Mrp2(-/-) mice, the expression levels of 98 phase I, phase II, and transporter genes were compared in liver, kidney, and intestine of male and female Mrp2(-/-) and control mice. Unlike in Mrp2 mutant rats, no induction of Mrp3 in Mrp2(-/-) mice was detected. However, Mrp4 mRNA and protein in liver and kidney were increased approximately 6- and 2-fold, respectively. Phenotypic analysis of major cytochrome P450-mediated activities in liver microsomes did not show differences between wild-type and Mrp2(-/-) mice. In conclusion, Mrp2(-/-) mice are a new valuable tool to study the role of Mrp2 in drug disposition.
Insights
Mice lacking the multidrug resistance-associated protein 2 (Mrp2) show altered bilirubin transport and increased Mrp4 expression, offering a new model for studying Mrp2
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Multidrug resistance protein 2 (Mrp2) is an ATP-binding cassette (ABC) transporter crucial for eliminating substances like bilirubin glucuronides from the liver.
- Existing rat models exhibit hyperbilirubinemia and compensatory changes in other transporters, but their species-specificity is unclear.
Purpose of the Study:
- To characterize Mrp2 knockout (Mrp2(-/-)) mice as a model system for studying Mrp2 function.
- To investigate potential compensatory mechanisms in Mrp2(-/-) mice compared to rat models.
Main Methods:
- Generation and characterization of Mrp2(-/-) mice.
- Analysis of bilirubin and glutathione excretion, and Mrp2 substrate transport.
- Quantitative comparison of gene and protein expression for 98 genes in liver, kidney, and intestine.
Main Results:
- Mrp2(-/-) mice exhibited elevated serum bilirubin and glucuronides, reduced biliary excretion of these compounds and glutathione, and impaired dibromosulfophthalein transport.
- Unlike rats, Mrp2(-/-) mice did not show Mrp3 induction but displayed significant increases in Mrp4 mRNA and protein in the liver and kidney.
- No significant differences in major cytochrome P450 activities were observed between Mrp2(-/-) and wild-type mice.
Conclusions:
- Mrp2(-/-) mice serve as a valuable new in vivo model for investigating the physiological and pharmacological roles of Mrp2.
- The compensatory upregulation of Mrp4 in Mrp2(-/-) mice highlights distinct adaptive responses compared to rat models.
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