Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2).
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.
Chu
Xiao-Yan
XY
Department of Drug Metabolism, Merck and Co., RY80, 126 E. Lincoln Ave., Rahway, NJ 07065, USA. xiaoyan_chu@merck.com
Strauss
John R
JR
Mariano
Michele A
MA
Li
Jing
J
Newton
Deborah J
DJ
Cai
Xiaoxin
X
Wang
Regina W
RW
Yabut
Jocelyn
J
Hartley
Dylan P
DP
Evans
David C
DC
Evers
Raymond
R
D000818:Animals; D001646:Bile / Q000378:metabolism; D001663:Bilirubin / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D013448:Sulfobromophthalein / Q000493:pharmacokinetics
D001663:Bilirubin; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D013448:Sulfobromophthalein; C012479:dibromosulphthalein; C016266:bilirubin glucuronate