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Vol. 59, Issue 5, 1077-1085, May 2001
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Tokyo, Japan
Multidrug resistance-associated protein 2 (MRP2) transports glutathione
conjugates, glucuronide conjugates, and sulfated conjugates of bile
acids. In the present study, we examined the role of charged amino acids in the transmembrane domains of rat Mrp2, conserved among
MRP families, using the isolated membrane vesicles from Sf9 cells
infected with the recombinant baculoviruses. By normalizing the
transport activity for compounds by that for estradiol
17
-D-glucuronide (E217G), it was
indicated that the site-directed mutagenesis from Lys to Met at 325 (K325M) and from Arg to Leu at 586 (R586L) results in a marked
reduction in the transport for glutathione conjugates
[2,4-dinitrophenyl-S-glutathione (DNP-SG) and
leukotriene (LT) C4] without affecting that for
6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridymethyl) benzothiazole glucuronide and taurolithocholate sulfate. In
contrast to the reduced affinity for DNP-SG, the affinity for
E217G was increased severalfold in these mutant Mrp2s,
suggesting the amino acids at 325 and 586 play an important role in
distinguishing between glutathione and glucuronide conjugates. The
comparable affinity for LTD4, LTE4, and
LTF4 in these mutant Mrp2s with that in wild-type Mrp2
indicates that recognition of LTC4 metabolites by Mrp2 is
different from that of LTC4. The transport activity for
glutathione conjugate was retained on R586K, whereas no such complementary cationic amino acid effect was observed in K325R. In
addition, R1206M and E1208Q exhibited the loss of transport activity
for the tested compounds. The results of the present study demonstrate
that the charged amino acids in the transmembrane domain of rat Mrp2
may play an important role in the recognition and/or transport of its substrates.
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