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OtherDRUG METABOLISM AND DISPOSITION

Characterization of Efflux Transport of Organic Anions in a Mouse Brain Capillary Endothelial Cell Line

Hiroyuki Kusuhara, Hiroshi Suzuki, Mikihiko Naito, Takashi Tsuruo and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1260-1265;
Hiroyuki Kusuhara
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Hiroshi Suzuki
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Mikihiko Naito
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Takashi Tsuruo
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Yuichi Sugiyama
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Abstract

Cumulative evidence suggests that several organic anions are actively effluxed from the brain to the blood across the blood-brain barrier (BBB). We examined the possibility of the presence of primary active transporters for organic anions (multidrug resistance associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT)) on the BBB by measuring the ATP-dependent uptake of 2,4-dinitrophenyl-S-glutathione (DNP-SG) and leukotriene C4(LTC4) into membrane vesicles prepared from a cell line derived from mouse brain capillary endothelial cells (MBEC4). The ATP-dependent uptake of DNP-SG into the membrane vesicles was osmotically sensitive and was also supported by GTP, but not by AMP or ADP. An ATPase inhibitor, vanadate, blocked the ATP-dependent uptake of DNP-SG. The ATP-dependent uptake process was saturable, withKm values of 0.56 and 0.22 μM, and Vmax values of 5.5 and 27.5 pmol/min/mg protein for DNP-SG and LTC4, respectively. Northern and Western blot analyses showed the expression of murine MRP but not cMOAT in MBEC4 cells. Western blot analysis of the rat cerebral endothelial cells indicated the expression of protein(s) that is detectable with MRPr1, an antibody against MRP. These results, together with previous findings that both DNP-SG and LTC4 are good ligands for MRP, suggest that MRP is responsible for the unidirectional, energy-dependent efflux of organic anions from the brain into the circulating blood across the BBB.

Footnotes

  • Send reprint requests to: Dr. Yuichi Sugiyama, Faculty of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.

  • Abbreviations:
    BBB
    blood-brain barrier
    CNS
    central nervous system
    MRP
    multidrug resistance associated protein
    P-gp
    P-glycoprotein
    DNP-SG
    2,4-dinitrophenyl-S-glutathione
    LTC4
    leukotriene C4
    hMRP
    human multidrug resistance associated protein
    cMOAT
    canalicular multispecific organic anion transporter
    ATP
    adenosine 5′-triphosphate
    AMP
    adenosine 5′-monophosphate
    GTP
    guanosine 5′-triphosphate
    SDS
    sodium dodecyl sulfate
    • Received October 13, 1997.
    • Accepted February 24, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherDRUG METABOLISM AND DISPOSITION

Characterization of Efflux Transport of Organic Anions in a Mouse Brain Capillary Endothelial Cell Line

Hiroyuki Kusuhara, Hiroshi Suzuki, Mikihiko Naito, Takashi Tsuruo and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1260-1265;

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OtherDRUG METABOLISM AND DISPOSITION

Characterization of Efflux Transport of Organic Anions in a Mouse Brain Capillary Endothelial Cell Line

Hiroyuki Kusuhara, Hiroshi Suzuki, Mikihiko Naito, Takashi Tsuruo and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1260-1265;
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