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Functional analysis of mouse and monkey multidrug resistance-associated protein 2 (Mrp2)

Mizuki Ninomiya1, Kousei Ito, Remi Hiramatsu

  • 1Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba, 260-8675, Japan.

Drug Metabolism and Disposition: the Biological Fate of Chemicals
|August 29, 2006
PubMed

Insights

Species differences in multidrug resistance-associated protein 2 (MRP2) transport activity exist, affecting substrates like leukotriene C4 and estradiol glucuronide. Kinetic profiles and modulator recognition also vary significantly between species.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Molecular Biology

Background:

  • Multidrug resistance-associated protein 2 (MRP2) is a key transporter involved in xenobiotic and endobiotic efflux.
  • Understanding species-specific differences in MRP2 activity is crucial for drug development and toxicology.

Purpose of the Study:

  • To investigate and compare the intrinsic transport activity of mouse and monkey MRP2.
  • To compare these activities with previously reported rat and dog MRP2 data.
  • To elucidate species-specific kinetic profiles and substrate/modulator recognition.

Main Methods:

  • Isolation of MRP2 cDNAs from mouse and monkey liver.
  • Expression of recombinant MRP2s in insect Sf9 cells.
  • Vesicle transport studies using radiolabeled substrates: leukotriene C4 (LTC4), estradiol glucuronide (E217betaG), bromosulfophthalein (BSP), and cholecystokinin octapeptide (CCK-8).

Main Results:

  • All tested MRP2s (mouse, monkey, rat, dog) transported LTC4, E217betaG, BSP, and CCK-8.
  • Significant species differences observed in LTC4 and BSP transport kinetics.
  • Complex, cooperative kinetics noted for CCK-8 transport.
  • Distinct E217betaG transport profiles: nonsaturable uptake in mouse/monkey MRP2, saturable in rat/dog MRP2.
  • Differential response to 4-methylumbelliferon glucuronide: stimulation in mouse/monkey MRP2, inhibition in rat/dog MRP2.

Conclusions:

  • While substrate specificity is broadly similar, intrinsic MRP2 transport activity exhibits significant interspecies variation.
  • These differences arise from variations in Km and Vmax values, as well as qualitative differences in substrate and modulator recognition.
  • Findings highlight the importance of considering species-specific transporter characteristics in pharmacological and toxicological assessments.

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