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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Human Multidrug Resistance Protein 2 Transports the Therapeutic Bile Salt Tauroursodeoxycholate

Virginia Commonwealth University, Medical College of Virginia Campus, Department of Pharmaceutics, Richmond, Virginia (P.M.G.); and University of Kentucky, Graduate Center for Toxicology, Lexington, Kentucky (P.M.G., W.L., V.M., M.V.)

The multidrug resistance protein 2 (MRP2/ABCC2) mediates the biliary excretion of glucuronide and glutathione conjugates of endogenous and exogenous compounds. We examined the activation of human MRP2-mediated ATP-dependent transport by the choleretic bile salt ursodeoxycholic acid (UDC) and its taurine and glycine amidates in Sf9 cell membranes expressing MRP2 using -estradiol 17-(-D-glucuronide) (E₂17G) and -estradiol 3-(-D-glucuronide) (E₂3G) as substrates. MRP2 transported E₂3G via classic Michaelis-Menten kinetics (K_m = 122 µM; V_max = 3.0 nmol/mg/min), whereas E₂17G transport showed positive cooperativity (Hill slope, 2.15; K_m = 75 µM; V_max = 3.8 nmol/mg/min). UDC, tauroursodeoxycholate, and glycoursodeoxycholate (80–100 µM) maximally stimulated E₂3G transport 9-, 7.9-, and 3.6-fold, respectively, whereas higher concentrations (1–2 mM) inhibited transport. At low (0.3 µM) concentrations, tauroursodeoxycholate was transported only in the presence of E₂17G or E₂3G, but not other MRP2 substrates such as methotrexate, leukotriene C₄, or S-methylglutathione. Kinetic analysis of higher concentrations of tauroursodeoxycholate transport by MRP2 showed positive cooperativity (Hill slope, 1.84; K_m = 127 µM; V_max = 779 pmol/mg/min). Taurocholate (2–100 µM) was not detectably transported by MRP2 either alone or in the presence of E₂17G but was transported in the presence of E₂3G. Thus, UDC, tauroursodeoxycholate, and glycoursodeoxycholate activated MRP2 transport. Tauroursodeoxycholate was transported by MRP2 and demonstrated positive cooperativity, identifying it as the second MRP2 substrate able to stimulate its own transport. The data suggest MRP2 binding sites that can require specific complementarities between substrates and modulators of MRP2-mediated transport.

Address correspondence to: Dr. Mary Vore, University of Kentucky, Graduate Center for Toxicology, Room 306 HSRB, Lexington, KY 40536-0305. E-mail: maryv{at}uky.edu

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