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Vol. 285, Issue 3, 1260-1265, June 1998
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan (H.K., H.S., Y.S.) and
Institute of Molecular and Cellular Biosciences, The University of
Tokyo, Yayoi, Bunkyo-ku, Tokyo 113, Japan (M.N., T.T.)
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, with
Km 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.
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