FUNCTIONAL ANALYSIS OF DOG MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 2 (MRP2) IN COMPARISON WITH RAT MRP2

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Abstract
We investigated whether the species difference in the biliary excretion activity of some Mrp2 substrates was attributable to the intrinsic transport potential or the expression level of Mrp2, especially in rat and dog. Dog Mrp2 cDNA was isolated from beagle dog liver, and a vesicle transport study was performed using recombinant rat and dog Mrp2 expressed in insect Sf9 cells. The ATP-dependent transport of 17β-estradiol 17-(β-d-glucuronide) ([3H]E217βG) and leukotriene C4 ([3H]LTC4), normalized by the absolute protein expression level, was similar in both Mrp2s. The Mrp2 protein expression in dog liver was only 10% of that in rat liver and was comparable with the reported difference in the biliary excretion clearance of temocaprilat as Mrp2 substrate. In contrast to LTC4, unique transport kinetics for E217βG were evident in dog Mrp2. In addition to the high-affinity site with a Km value of 3.25 ± 0.10 μM, which is similar to that in rat Mrp2 (4.81 ± 1.21 μM), dog Mrp2 has an additional low-affinity site (≫75 μM), which makes a major contribution to the transport of E217βG (65% of the total transport capacity at tracer concentration). In summary, the difference in the biliary excretion activity of Mrp2 substrates between rat and dog depends on the Mrp2 protein expression level rather than the intrinsic transport activity of the transporter molecules. The unique transport properties of glucuronide conjugates by dog Mrp2 may lead to the species difference involving the drug-drug interaction or drug-induced hyperbilirubinemia on the bile canalicular membrane.

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