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Vol. 53, Issue 6, 1068-1075, June 1998
Graduate School of Pharmaceutical Sciences (T.H., H.S., K.I., K.O., Y.S.) and Graduate School of Medicine (K.K., T.S.) The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan
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Summary
Introduction
Materials & Methods
Results
Discussion
References
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The biliary excretion of several organic anions is mediated by the canalicular multispecific organic anion transporter (cMOAT), which is hereditarily defective in mutant rats such as Eisai hyperbilirubinemic rats (EHBR). In addition, using a kinetic study with isolated canalicular membrane vesicles, we recently suggested the presence of ATP-dependent organic anion transporter(s) other than cMOAT in EHBR [Pharm Res (NY) 12:1746-1755 (1995); J Pharmacol Exp Ther 282:866-872 (1997)]. The aim of this study is to provide a molecular basis for the presence of multiplicity in the biliary excretion of organic anions in rats. Based on the homology with human multidrug resistance-associated protein (hMRP), two cDNA fragments encoding the carboxyl-terminal ATP-binding cassette region were amplified by reverse transcription-polymerase chain reaction from EHBR liver. These fragments exhibited approximately 70% amino acid identity with hMRP and rat cMOAT;, therefore, they were designated MRP-like proteins (MLP-1 and MLP-2). The cloned full length cDNA of MLP-1 and -2 from the Sprague-Dawley (SD) rat liver and colon cDNA library was composed of 1502 and 1523 amino acids, respectively, had the characteristics of ATP-binding cassette transporters, and exhibited homology with hMRP and rat cMOAT. Northern blot analysis indicated that MLP-1 is expressed predominantly in the liver in both SD rats and EHBR, whereas hepatic expression of MLP-2 was observed only in EHBR. In addition, MLP-2 was markedly induced by ligation of the bile duct in SD rat liver. In both SD rats and EHBR, MLP-2 was expressed predominantly in the duodenum, jejunum, and colon. These findings suggest that MLP-1 and MLP-2 might be novel members of the MRP family responsible for the excretion of organic anions from these epithelial cells, and that MLP-2 is an inducible one.
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Introduction |
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Introduction
Materials & Methods
Results
Discussion
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Biliary
excretion is one of the major pathways for the elimination of
xenobiotics. Many xenobiotics are converted to more hydrophilic
metabolites by metabolizing enzymes responsible for oxidation
(cytochrome P450) and/or conjugation (such as glutathione S-transferase or UDP-glucuronosyltransferase) and then are
excreted into the bile. The biliary excretion of many organic anions
and glutathione or glucuronide conjugates is mediated by a primary active transporter referred to as the cMOAT (Oude Elferink et al., 1995
; Yamazaki et al., 1996; Keppler and
König, 1997). Extensive studies in our own and other laboratories
have suggested that substrates for cMOAT include nonbile acid organic
anions [such as dibromosulfophthalein (Sathirakul et al.,
1993; Sathirakul et al., 1994), cefodizime (a 
-lactam
antibiotic) (Sathirakul et al., 1994), pravastatin (a
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) (Yamazaki
et al., 1997), temocaprilat (an angiotensin-converting
enzyme inhibitor) (Ishizuka et al., 1997) and the
carboxylate forms of CPT-11 and its active metabolite (SN-38, a
topoisomerase inhibitor) (Chu et al., 1997), a cyclic anionic peptide (BQ-123, an endothelin antagonist) (Shin et
al., 1997)], glutathione conjugates [such as leukotriene
C4 (Ishikawa et al., 1990) and DNP-SG
(Kobayashi et al., 1990)], and glucuronide conjugates
[such as bilirubin glucuronide (Nishida et al., 1992), E3040 glucuronide (Takenaka et al., 1995a, 1995b) and SN-38
glucuronide (Chu et al., 1997)] as reviewed previously
(Oude Elferink et al., 1995; Yamazaki et al.,
1996; Keppler and König, 1997). The substrate specificity of
cMOAT described so far has been clarified from in vivo,
in situ, and in vitro uptake experiments with
isolated CMVs by comparing the transport properties in normal and
mutant rats (such as TR
and EHBR) whose cMOAT
function is hereditarily defective (Oude Elferink et al.,
1995; Yamazaki et al., 1996; Keppler and König, 1997).
These mutant rats suffer from jaundice because of the impaired biliary
excretion of bilirubin glucuronide via cMOAT;, therefore, they are good
animal models for Dubin-Johnson syndrome in humans (Oude Elferink
et al., 1995; Yamazaki et al., 1996; Keppler and König, 1997). Recently, we and others have focused on the fact that the substrate specificity of hMRP, also called MRP1, is similar to
that of cMOAT (Keppler and Kartenbeck, 1996; Loe et al.,
1996), and have cloned the cDNA encoding rat cMOAT, also termed Mrp2 or
canalicular Mrp, based on the homology with hMRP (Büchler et al., 1996; Ito et al., 1996; Paulusma et
al., 1996; Ito et al., 1997). In addition, the
mechanism for the mutation in TR (Paulusma
et al., 1996) and EHBR (Ito et al., 1997) was
determined. Recently, we found the ATP-dependent uptake of cMOAT
substrates into the membrane vesicles prepared from cMOAT-cDNA
transfected NIH/3T3 cells (Ito et al., 1998). Madon et
al. (1997) also succeeded in the functional analysis of cloned
cMOAT cDNA by detecting the increased efflux of DNP-SG from
cDNA-transfected COS-7 cells after preloading its precursor and from
cRNA-injected Xenopus laevis oocytes after direct
injection of this glutathione conjugate.
Although E3040 glucuronide is a good substrate for cMOAT, our recent
kinetic study using CMVs from EHBR suggested that the ATP-dependent
transport of E3040 glucuronide, but not that of DNP-SG, is maintained
in EHBR to some extent (Takenaka et al., 1995a). Moreover,
the presence of another organic anion transporter(s) in SD rats was
suggested by an inhibition study in CMVs; the ATP-dependent transport
of E3040 glucuronide was not completely inhibited by excess DNP-SG
sufficient to saturate DNP-SG uptake, whereas the uptake of DNP-SG was
almost completely inhibited by E3040 glucuronide (Niinuma et
al., 1997). In addition, the ATP-dependent transport of E3040
glucuronide into CMVs from EHBR was not affected by DNP-SG (Niinuma
et al., 1997). These findings suggested the presence of
multiple transport systems for the biliary excretion of organic anions
and conjugated metabolites across the canalicular membrane (Niinuma
et al., 1997).
The object of the present study is to provide a molecular basis for the
presence of novel members of the MRP family, particularly focusing on
molecules that are also expressed in EHBR liver. In view of the fact
that a series of primary active transporters possess highly conserved
ABCs (Hyde et al., 1990), RT-PCR was performed with
degenerate primers for hMRP using poly(A)+ RNA
from EHBR liver as a template.
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Materials & Methods
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Animals. Male SD rats (250-300 g) and EHBR (250-350 g) were purchased from Charles River Japan (Kanagawa, Japan) and SLC (Shizuoka, Japan), respectively.
RNA isolation. Total RNA was prepared by a single-step guanidium thiocyanate procedure. Subsequently, poly(A)+ RNA was purified using oligotex-dT30 (Takara Shuzo, Kyoto, Japan).
Amplification of cDNA fragments.
cDNA fragments were
amplified by RT-PCR with the total RNA of EHBR liver as a template by
using a TaKaRa RNA LA PCR kit (Takara Shuzo). Degenerate primers were
constructed on the basis of the conserved amino acid sequence in the
carboxyl ABC region of hMRP (Ito et al., 1996). The
sequences of the forward and reverse primers were
5'-dGAGAAGGTCGGCATCGTGGG(AGTC)CG(AGTC)AC(AGTC)GG-3' and
5'-dGTCCACGGCTGC(AGTC)GT(AGTC)GC(TC)TC(AG)TC-3', respectively (Ito
et al., 1996).1 RT
was performed using random primer at 30° for 10 min, 42° for 30 min, 99° for 5 min, and 5° for 5 min. Then PCR was carried out at
94° for 30 sec, 37° for 30 sec, and 72° for 1 min for 40 cycles
using Taq polymerase. The amplified 421-bp PCR products were
subcloned into the EcoRV site of pBluescript II SK(
)
(Stratagene, La Jolla, CA) and the sequence was determined. PCR
products were excised from the vector by digestion with
EcoRI and HindIII and were used as probes for
detection of their expression. Rat cMOAT cDNA probe (~1.0 kb) was
prepared as described previously (Ito et al., 1997).
Library construction and screening.
For cDNA screening, the
cDNA libraries were constructed from SD rat liver and colon using a kit
(SuperScript Choice System; Life Technologies, Gaithersburg, MD)
described previously (Ito et al., 1997). Briefly,
poly(A)+ RNA was fractionated by sucrose density
gradient and fractions containing RNA longer than ~5 kb were used as
a template for cDNA construction using reverse transcriptase and an
oligo(dT) primer. The conversion of RNA-cDNA hybrid into
double-stranded cDNA was performed using RNase H in combination with
DNA polymerase I and Escherichia coli DNA ligase.
EcoRI-NotI adapters were then added to both ends
of the double-stranded and blunt-ended cDNA. After phosphorylation with
T4 polynucleotide kinase, the resulting cDNA was
subsequently ligated to EcoRI digested and calf intestinal alkaline phosphatase-treated 
ZAP II vector (Stratagene). Packaging of those recombinants into the -phage was performed using a kit (Gigapack III Gold Packaging Extract; Stratagene). Approximately 5 × 105 independent plaques on XL1-Blue strain
were screened with the probe described. After two rounds of screening,
single positive colonies were isolated. After coinfection with the M13
helper phage (ExAssist; Stratagene), the cDNA was excised in a
pBluescript II SK() plasmid and rescued by SOLR strain.
DNA sequencing. DNA sequence analysis was performed in both directions using double-stranded cDNA as a template. A sequencer (Model 373 DNA Sequencer; Perkin Elmer, Foster City, CA) was used in combination with a kit (ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit with AmpliTaq DNA polymerase, FS; Perkin Elmer). The GenBank/EMBL database was searched with the cDNA sequence of the fragments using the BLAST program. Other sequence analysis and calculations were performed with the GENETYX-MAC program (Software Development Co., Tokyo, Japan).
Northern blot analysis.
Poly(A)+ RNA
was separated on 0.7% agarose gel containing 3.7% formaldehyde and
transferred to a nylon membrane (Biodyne; Pall Corporation, Glen Cove,
NY), before fixation by baking for 2 hr at 80°. The membranes were
prehybridized in hybridization buffer containing 4 × SSC (1×
SSC = 150 mM NaCl, 15 mM sodium citrate, pH 7.2), 5 × Denhardt's solution, 0.2% SDS, 0.1 mg/ml sonicated salmon sperm DNA and 50% formamide for 2 hr at 42° and hybridized for 10 hr at 42° in the same buffer with a
32P-labeled cDNA probe that was prepared by a
random primed labeling method (Rediprime; Amersham International,
Buckinghamshire, UK). The hybridized membrane was washed in 2 × SSC and 0.1% SDS at room temperature for 20 min, followed by washing
in 2 × SSC and 0.1% SDS at 55° for 20 min and then in 0.1 × SSC and 0.1% SDS at 55° for 20 min. Filters were exposed to a
film (Hyperfilm-MP; Amersham International) at 100° using an
intensifying screen. In some instances, the filters were exposed to an
imaging plate followed by analysis using Fujix BAS 2000 image analyzer
(Fuji Photo Film, Tokyo, Japan).
Induction of transporters.
The expression of transporters
was examined in rats with cholestasis induced by bile-duct ligation.
The proximal bile duct of SD rats was ligated under light ether
anesthesia (Schrenk et al., 1993). Three days after
ligation, liver RNA was prepared to examine by Northern blot analysis
the induction of transporters. The hybrid membranes were exposed to the
imaging plates and quantified using a Fujix BAS 2000 image analyzer.
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Materials & Methods
Results
Discussion
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Amplification of novel cDNA fragments from EHBR liver.
To
identify novel MRP family members that are maintained in EHBR liver,
RT-PCR was performed using the degenerate primers based on the sequence
of the hMRP carboxyl-terminal ABC region. Two novel 421-bp fragments
were amplified from EHBR liver. The amino acid identity of one fragment
was 62.6% with hMRP and 56.1% with rat cMOAT and that of the other
fragment was 73.2% with hMRP and 71.5% with rat cMOAT. Based on the
homology with hMRP, these fragments were designated as MLP-1 and -2, respectively. MLP-2 also showed high homology with MRP3 (84.1% amino
acid identity), which has been identified by screening databases of
human expressed sequence tags (Kool et al., 1997),
suggesting that MRP3 may be the human homologue of rat MLP-2. By
screening the library, the sequences of the amino- and
carboxyl-terminal ABC regions of MLP-1 and -2 were determined. The
sequence alignment of rat MLP-1, MLP-2, cMOAT, hMRP and MRP3 (only
carboxyl terminal) at the ABC regions indicates a high degree of
similarity among these MRP family proteins (Fig.
1). Moreover, each ABC region had the
Walker A and B motifs and the putative consensus pattern for the ABC
transporter family signatures (Hyde et al., 1990) (Fig. 1).
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cDNA cloning of the MLP-1 and -2.
Because it is possible that
MLP-1 and -2 are organic anion transporters that are expressed in EHBR
liver, cDNA cloning was performed. A full-length cDNA with a single
open reading frame of 1502 and 1523 amino acids was cloned for MLP-1
and -2, respectively (Fig. 3). A BLAST
search of the National Center for Biotechnology Information database
showed that, at deduced amino acid levels, MLP-1 and 2 exhibit high
overall identity with several ABC proteins such as hMRP, cMOAT, rabbit
epithelial basolateral chloride conductance regulator, rat sulfonylurea
receptor and yeast cadmium factor (Table
1). The identities with hMRP3-5, whose
sequences are partially reported (Kool et al., 1997), are
also listed in Table 1. The high sequence identity, in particular
within two ABC regions, was observed between MLPs and these ABC
transporters (Table 1). Fig. 4 shows that
the pattern of hydropathy plot of hMRP, rat cMOAT and rat MLP-1 and -2 resembles each other. A lesser degree of identity was observed with
human cystic fibrosis transmembrane conductance regulator, rat Mdr1 and
Mdr2.
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Induction of MLP-2 by cholestasis in SD rat liver.
The effect
of cholestasis induced by bile duct ligation on the expression of
cMOAT, MLP-1 and -2 in SD rat liver was examined by Northern
hybridization (Fig. 5). The induction
ratio was calculated as a percentage of controls in five samples after
correcting the mRNA loading amount by rehybridization of GAPDH. MLP-2
was markedly induced by bile-duct ligation. Although we can not
calculate the induction ratio of MLP-2 precisely because the expression
was not detected in untreated SD rats (Fig. 2), MLP-2 was induced by at
least 607 ± 189% (mean ± standard error) compared with
controls, assuming that the detection limit was 20% above membrane
background (p < 0.01). In contrast, MLP-1 mRNA
was reduced to 65 ± 8% compared with untreated control rats
(p < 0.05). In agreement with previous findings (Trauner et al., 1997), cMOAT mRNA levels also
slightly decreased (to 80 ± 15%), although this did not reach
statistical significance.
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Tissue expression of MLP-1 and -2. To examine the tissue distribution of MLP-1 and -2, Northern blot analysis was performed in SD rats and EHBR and the expression was compared between rats after correcting the mRNA loading amount by rehybridization of GAPDH. As shown in Fig. 2, MLP-1 was expressed predominantly in the liver of both rat strains. Although low expression of MLP-1 was observed in duodenum and kidney at the same level for both strains, the jejunum expression was enhanced somewhat in EHBR compared with SD rats (Fig. 2). High expression of MLP-2 was observed in intestinal tissues such as duodenum, jejunum and colon and, to a lesser extent, in kidney and lung (Fig. 2). In these tissues, the extent of MLP-2 expression was almost the same for SD rats and EHBR (Fig. 2).
The tissue distribution patterns of four MRP family proteins (rat MLP-1, MLP-2, cMOAT and hMRP) are summarized in Table 2. The expression of MRP in human tissues was detectable in lung, testis, kidney and spleen by Northern blot and RNase protection assay as reviewed by Loe et al. (1996)
(Table 2). The relative expression level of rat cMOAT was estimated
based on our previous Northern blot data (Ito et al., 1997)
after normalizing the mRNA loading amount by the expression of GAPDH.
The relative expression levels of MLP-1 and -2 were determined based on
Fig. 2 in the same manner. cMOAT in normal rats is extensively
expressed in liver and, to a lesser extent, in duodenum, kidney and
jejunum (Ito et al., 1997) (Table 2). The expression pattern
of cMOAT is similar to that of MLP-1 in SD rats (Table 2). In addition, the expression of both cMOAT (Ito et al., 1997) and MLP-1 in
jejunum was enhanced somewhat in EHBR (Fig. 2). On the other hand, high expression of MLP-2 was observed in intestinal tissues, which was
different from both hMRP (lung-type) and cMOAT (liver-type) (Table 2).
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Discussion |
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Summary
Introduction
Materials & Methods
Results
Discussion
References
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It has been established that the biliary excretion of many organic
anions is mediated by cMOAT which is hereditarily defective in EHBR
(Oude Elferink et al., 1995; Yamazaki et al.,
1996; Keppler and König, 1997). Previous studies from this
laboratory indicated that approximately one third of the ATP-dependent
transport activity of E3040 glucuronide in CMVs from SD rats, however,
was maintained in EHBR (Takenaka et al., 1995a). This was in
marked contrast to the fact that the ATP-dependent transport of DNP-SG
in CMVs from EHBR was almost completely abolished (Takenaka et
al., 1995a). To characterize this ATP-dependent transporter
maintained even in EHBR, we recently performed a kinetic study using
CMVs (Niinuma et al., 1997). In SD rat CMVs, the transport
of DNP-SG was almost completely inhibited by E3040 glucuronide in a
competitive manner, whereas the transport of E3040 glucuronide was
partially inhibited by excess DNP-SG (Niinuma et al., 1997).
Furthermore, low affinity ATP-dependent transport of E3040 glucuronide
was observed in EHBR CMVs, which is not affected by DNP-SG, suggesting
the presence of a primary active transporter distinct from cMOAT, in
both SD rats and EHBR (Niinuma et al., 1997). In the present
study, RT-PCR was performed to establish the molecular features of this
novel transporter.
Degenerate PCR primers were prepared for the ABC region of hMRP, an
ATP-dependent transporter for organic anions (such as glutathione- and
glucuronide-conjugates). RT-PCR with degenerate primers resulted in
amplification of MLP-1 and -2 from EHBR liver (Fig. 1). Of these two
novel cDNAs, MLP-1 was expressed in both SD rat and EHBR liver to the
same extent (Fig. 2). The cloned MLP-1, which had two ABC regions with
Walker A and B motifs and the active transporter family signatures
(Hyde et al., 1990) (Fig. 3), exhibited high homology with
hMRP and rat cMOAT (Table 1). In addition, the pattern of hydropathy
plot of MLP-1 is similar to that of these transporters (Fig. 4). These
findings suggested that MLP-1 may encode a primary active transporter
which is responsible for the ATP-dependent transport of glucuronide in
CMVs from EHBR (Takenaka et al., 1995a; Niinuma et
al., 1997), although the functional analysis and determination of
intracellular localization remain to be clarified.
The hepatic expression of MLP-2, which also exhibits similar structure
with MRP and cMOAT (Fig. 3 and 4), was significantly enhanced in EHBR
compared with SD rats (Fig. 2), suggesting that MLP-2 is an inducible
transporter. The fact that the cholestasis induced by common bile duct
ligation resulted in an increase in the expression of MLP-2 in SD rat
liver (Fig. 5) is consistent with this hypothesis. Although the hepatic
expression of mdr 1a and 1b is induced in rats by cholestasis induced
by either bile duct ligation or 
-naphthylisothiocyanate-induced
cholestasis in rats (Schrenk et al., 1993), the mechanism
for the induction may differ between MLP-2 and mdr 1, because the
expression of mdr 1 was not induced in EHBR (Suzuki H, Ogawa K,
Hirohashi T and Sugiyama Y, unpublished observations). It is possible
that the gene expression of MLP-2 was induced by endogenous
substrate(s) for cMOAT. One of the most plausible candidates for the
induction may be conjugated and unconjugated bilirubin, because plasma
concentration of total bilirubin in the bile-duct-ligated rats (3.62 mg/100 ml) (Schrenk et al., 1993) and in EHBR (4.02 mg/100
ml) (Sathirakul et al., 1993) was much higher than that of
untreated normal rats (0.154 mg/100 ml) (Sathirakul et al.,
1993). It may be plausible that MLP-2 compensates for the function of
cMOAT in EHBR, because it has been reported that, in mdr 1a knock-out
mice, the increased expression of mdr 1b, whose substrate specificity
resembles that of mdr 1a, compensates for the hepatic function of mdr
1a (Schinkel et al., 1994). The induced expression of MLP-2
was in marked contrast to the somewhat reduced expression of cMOAT and
MLP-1 after bile duct ligation (Fig. 5). Collectively, as with the
metabolic enzymes, the transporters responsible for the excretion of
xenobiotics may be classified as house-keeping (cMOAT and MLP-1) or
inducible (MLP-2).
In normal rats, MLP-2 exhibited high expression in intestinal tissues
(Fig. 2). Because the intestinal epithelium is directly exposed to a
number of xenobiotics, it is equipped with a number of metabolizing
enzymes (Peters et al., 1989) (such as cytochrome P-450,
UDP-glucuronosyltransferase and glutathione S-transferase) and a transporter (P-glycoprotein) responsible for the excretion of
hydrophobic and amphipathic compounds (Gatmaitan and Arias, 1993). In
addition to P-glycoprotein, cumulative evidence suggests the presence
of another efflux transporter for organic anions in intestinal tissues;
in Caco-2 cells, active excretion of DNP-SG (Oude Elferink et
al., 1993) and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (Collington et al., 1992) has been reported. Furthermore,
intestinal excretion of ethinylestradiol glucuronide (Schwenk et
al., 1982) and 1-naphthol glucuronide (de Vries et al.,
1989a) was demonstrated in rats in in situ experiments.
Because kinetic analysis indicated that the intestinal excretion of
1-naphthol glucuronide was not significantly different between Wistar
rats and TR rats, it was suggested that a
primary active transporter other than cMOAT may be responsible for the
excretion of organic anions from intestinal cells (de Vries et
al., 1989b). It may be possible that MLP-2, an ABC transporter
superfamily member, is responsible for the intestinal excretion of
organic anions.
The results of the present study provide a molecular basis for the
presence of MRP family proteins. An ATP-dependent efflux system(s) for
organic anions is expressed in many somatic cells, such as heart
sarcolemmal (Ishikawa, 1989) and red blood cells (Kondo et
al., 1980), as well as in the epithelium of liver and intestine.
Such efflux pumps are also observed in many kind of cultured human cell
lines (Olive and Board, 1994). The physiological role of these
transporters may be to exclude anionic xenobiotics entering from the
circulating blood/intestinal lumen and anionic waste materials produced
within cells. Because of the localization of efflux transporters on the
canalicular membrane, the liver is endowed with the ability to
eliminate endogenous and xenobiotic organic anions from the circulating
blood by excreting them into bile (Oude Elferink et al.,
1995; Yamazaki et al., 1996; Keppler and König, 1997).
In the same manner, localization of such transporters on central
endothelial cells may allow the blood-brain barrier to restrict entry
of organic anions (Suzuki et al., 1997). In addition, some
tumor cells acquire multidrug resistance by overexpression of MRP and
its related protein(s) (Ishikawa et al., 1996; Loe et
al., 1996; Kool et al., 1997). Recently, by screening
the database of human expressed sequence tags, Kool et al.
(1997) cloned three hMRP homologues (MRP3, 4 and 5). MRP3 shows
particularly high homology with MLP-2 (Fig. 1; Table 1), which
indicates that MRP3 is the human homologue of rat MLP-2. They reported
that the MRP3 is expressed in the human liver, duodenum, colon and
adrenal gland (Kool et al., 1997). If we consider that MLP-2
is an inducible transporter, it is possible that the expression of MRP3
in the liver was induced in the human subject(s) used in their study (Kool et al., 1997).
In conclusion, we identified MLP-1 and -2 as novel members of the MRP family that may be responsible for the biliary and intestinal excretion of organic anions. The results of the present study also provided a molecular basis for the presence of multiple systems for the extrusion of organic anions from many kinds of somatic cells. Drug disposition in the body and/or tumor cells can be altered by modifying the activity of these efflux transporters.
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Footnotes |
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Received December 9, 1997; Accepted March 10, 1998
This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan, and the Core Research for Evolutional Sciences and Tecnology of Japan Sciences and Technology Corporation.
1 The sequences reported in this paper have been submitted to the GenBank with the accession numbers AB010466 (MLP-1) and AB010467 (MLP-2).
Send reprint requests to: Yuichi Sugiyama, Ph.D., Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail: bxg05433{at}niftyserve.or.jp
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Abbreviations |
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cMOAT, canalicular multispecific organic anion transporter; hMRP, human multidrug resistance-associated protein; MLP, multidrug resistance-associated protein-like protein; ABC, ATP-binding cassette; DNP-SG, S-(2,4-dinitrophenyl) glutathione; E3040, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole; CMVs, canalicular membrane vesicles; SD, Sprague-Dawley; EHBR, Eisai hyperbilirubinemic rats; RT, reverse transcription; PCR, polymerase chain reaction; bp, base pair(s); kb, kilobase pair(s); SSC, standard saline citrate; SDS, sodium dodecyl sulfate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
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Summary
Introduction
Materials & Methods
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Discussion
References
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-glutamylcysteine synthetase by heavy metals in human leukemia cells.
J Biol Chem
271:
14981-14988) with inherited conjugated hyperbilirubinemia.
J Clin Invest
90:
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 S. Matsushima, K. Maeda, H. Hayashi, Y. Debori, A. H. Schinkel, J. D. Schuetz, H. Kusuhara, and Y. Sugiyama Involvement of Multiple Efflux Transporters in Hepatic Disposition of Fexofenadine Mol. Pharmacol., May 1, 2008; 73(5): 1474 - 1483. [Abstract] [Full Text] [PDF]
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 E. M. Leslie, G. Ghibellini, K.-i. Nezasa, and K. L.R. Brouwer Biotransformation and transport of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in bile duct-cannulated wild-type and Mrp2/Abcc2-deficient (TR ) Wistar rats Carcinogenesis, December 1, 2007; 28(12): 2650 - 2656. [Abstract] [Full Text] [PDF]
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A. S. Kalgutkar, B. Feng, H. T. Nguyen, K. S. Frederick, S. D. Campbell, H. L. Hatch, Y.-A. Bi, D. C. Kazolias, R. E. Davidson, R. J. Mireles, et al. Role of Transporters in the Disposition of the Selective Phosphodiesterase-4 Inhibitor (+)-2-[4-({[2-(Benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic Acid in Rat and Human Drug Metab. Dispos., November 1, 2007; 35(11): 2111 - 2118. [Abstract] [Full Text] [PDF]
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K. Okada, J. Shoda, M. Kano, S. Suzuki, N. Ohtake, M. Yamamoto, H. Takahashi, H. Utsunomiya, K. Oda, K. Sato, et al. Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers Am J Physiol Gastrointest Liver Physiol, May 1, 2007; 292(5): G1450 - G1463. [Abstract] [Full Text] [PDF]
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M. J. Zamek-Gliszczynski, K.-i. Nezasa, X. Tian, A. S. Bridges, K. Lee, M. G. Belinsky, G. D. Kruh, and K. L. R. Brouwer Evaluation of the Role of Multidrug Resistance-Associated Protein (Mrp) 3 and Mrp4 in Hepatic Basolateral Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Abcc3-/- and Abcc4-/- Mice J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1485 - 1491. [Abstract] [Full Text] [PDF]
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S. Oswald, S. Westrup, M. Grube, H. K. Kroemer, W. Weitschies, and W. Siegmund Disposition and Sterol-Lowering Effect of Ezetimibe in Multidrug Resistance-Associated Protein 2-Deficient Rats J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1293 - 1299. [Abstract] [Full Text] [PDF]
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 R. G. Deeley, C. Westlake, and S. P. C. Cole Transmembrane Transport of Endo- and Xenobiotics by Mammalian ATP-Binding Cassette Multidrug Resistance Proteins. Physiol Rev, July 1, 2006; 86(3): 849 - 899. [Abstract] [Full Text] [PDF]
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M. L. Ruiz, S. S. M. Villanueva, M. G. Luquita, M. Vore, A. D. Mottino, and V. A. Catania ETHYNYLESTRADIOL INCREASES EXPRESSION AND ACTIVITY OF RAT LIVER MRP3 Drug Metab. Dispos., June 1, 2006; 34(6): 1030 - 1034. [Abstract] [Full Text] [PDF]
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 S. Dallas, D. S. Miller, and R. Bendayan Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol. Rev., June 1, 2006; 58(2): 140 - 161. [Abstract] [Full Text] [PDF]
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 T. Nishiya, H. Kataoka, K. Mori, M. Goto, T. Sugawara, and K. Furuhama Tienilic Acid Enhances Hyperbilirubinemia in Eisai Hyperbilirubinuria Rats through Hepatic Multidrug Resistance-Associated Protein 3 and Heme Oxygenase-1 Induction Toxicol. Sci., June 1, 2006; 91(2): 651 - 659. [Abstract] [Full Text] [PDF]
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X.-Y. Chu, J. R. Strauss, M. A. Mariano, J. Li, D. J. Newton, X. Cai, R. W. Wang, J. Yabut, D. P. Hartley, D. C. Evans, et al. Characterization of Mice Lacking the Multidrug Resistance Protein Mrp2 (Abcc2) J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 579 - 589. [Abstract] [Full Text] [PDF]
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B. M. Johnson, P. Zhang, J. D. Schuetz, and K. L. R. Brouwer CHARACTERIZATION OF TRANSPORT PROTEIN EXPRESSION IN MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) 2-DEFICIENT RATS Drug Metab. Dispos., April 1, 2006; 34(4): 556 - 562. [Abstract] [Full Text] [PDF]
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C. I. Ghanem, M. L. Ruiz, S. S. M. Villanueva, M. G. Luquita, V. A. Catania, B. Jones, L. A. Bengochea, M. Vore, and A. D. Mottino Shift from Biliary to Urinary Elimination of Acetaminophen-Glucuronide in Acetaminophen-Pretreated Rats J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 987 - 995. [Abstract] [Full Text] [PDF]
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K. T. Kivisto, O. Grisk, U. Hofmann, K. Meissner, K.-U. Moritz, C. Ritter, K. A. Arnold, D. Lutjoohann, K. von Bergmann, I. Kloting, et al. DISPOSITION OF ORAL AND INTRAVENOUS PRAVASTATIN IN MRP2-DEFICIENT TR- RATS Drug Metab. Dispos., November 1, 2005; 33(11): 1593 - 1596. [Abstract] [Full Text] [PDF]
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M. G. Belinsky, P. A. Dawson, I. Shchaveleva, L. J. Bain, R. Wang, V. Ling, Z.-S. Chen, A. Grinberg, H. Westphal, A. Klein-Szanto, et al. Analysis of the In Vivo Functions of Mrp3 Mol. Pharmacol., July 1, 2005; 68(1): 160 - 168. [Abstract] [Full Text] [PDF]
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 N. Zelcer, K. van de Wetering, M. Hillebrand, E. Sarton, A. Kuil, P. R. Wielinga, T. Tephly, A. Dahan, J. H. Beijnen, and P. Borst Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception PNAS, May 17, 2005; 102(20): 7274 - 7279. [Abstract] [Full Text] [PDF]
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M. Kobayashi, H. Saitoh, M. Kobayashi, K. Tadano, Y. Takahashi, and T. Hirano Cyclosporin A, but Not Tacrolimus, Inhibits the Biliary Excretion of Mycophenolic Acid Glucuronide Possibly Mediated by Multidrug Resistance-Associated Protein 2 in Rats J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1029 - 1035. [Abstract] [Full Text] [PDF]
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N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama Impact of Drug Transporter Studies on Drug Discovery and Development Pharmacol. Rev., September 1, 2003; 55(3): 425 - 461. [Abstract] [Full Text] [PDF]
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T. Li, K. Ito, and T. Horie Transport of fluorescein methotrexate by multidrug resistance-associated protein 3 in IEC-6 cells Am J Physiol Gastrointest Liver Physiol, August 8, 2003; 285(3): G602 - G610. [Abstract] [Full Text] [PDF]
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 J E Ros, T A D Roskams, M Geuken, R Havinga, P L Splinter, B E Petersen, N F LaRusso, D M van der Kolk, F Kuipers, K N Faber, et al. ATP binding cassette transporter gene expression in rat liver progenitor cells Gut, July 1, 2003; 52(7): 1060 - 1067. [Abstract] [Full Text]
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 A. C. Lockhart, R. G. Tirona, and R. B. Kim Pharmacogenetics of ATP-binding Cassette Transporters in Cancer and Chemotherapy Mol. Cancer Ther., July 1, 2003; 2(7): 685 - 698. [Abstract] [Full Text] [PDF]
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 K. Hidemura, Y. L. Zhao, K. Ito, A. Nakao, Y. Tatsumi, H. Kanazawa, K. Takagi, M. Ohta, and T. Hasegawa Shiga-Like Toxin II Impairs Hepatobiliary Transport of Doxorubicin in Rats by Down-Regulation of Hepatic P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2 Antimicrob. Agents Chemother., May 1, 2003; 47(5): 1636 - 1642. [Abstract] [Full Text] [PDF]
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M. Trauner and J. L. Boyer Bile Salt Transporters: Molecular Characterization, Function, and Regulation Physiol Rev, April 1, 2003; 83(2): 633 - 671. [Abstract] [Full Text] [PDF]
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M. Hitzl, K. Klein, U. M. Zanger, P. Fritz, A. K. Nussler, P. Neuhaus, and M. F. Fromm Influence of Omeprazole on Multidrug Resistance Protein 3 Expression in Human Liver J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 524 - 530. [Abstract] [Full Text] [PDF]
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 M. G. Belinsky, Z.-S. Chen, I. Shchaveleva, H. Zeng, and G. D. Kruh Characterization of the Drug Resistance and Transport Properties of Multidrug Resistance Protein 6 (MRP6, ABCC6) Cancer Res., November 1, 2002; 62(21): 6172 - 6177. [Abstract] [Full Text] [PDF]
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Z. P. Lin, D. R. Johnson, R. A. Finch, M. G. Belinsky, G. D. Kruh, and A. C. Sartorelli Comparative Study of the Importance of Multidrug Resistance-associated Protein 1 and P-Glycoprotein to Drug Sensitivity in Immortalized Mouse Embryonic Fibroblasts Mol. Cancer Ther., October 1, 2002; 1(12): 1105 - 1114. [Abstract] [Full Text] [PDF]
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H. Xiong, H. Suzuki, Y. Sugiyama, P. J. Meier, G. M. Pollack, and K. L. R. Brouwer Mechanisms of Impaired Biliary Excretion of Acetaminophen Glucuronide after Acute Phenobarbital Treatment or Phenobarbital Pretreatment Drug Metab. Dispos., September 1, 2002; 30(9): 962 - 969. [Abstract] [Full Text] [PDF]
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J. Cao, B. Stieger, P. J. Meier, and M. Vore Expression of rat hepatic multidrug resistance-associated proteins and organic anion transporters in pregnancy Am J Physiol Gastrointest Liver Physiol, September 1, 2002; 283(3): G757 - G766. [Abstract] [Full Text] [PDF]
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H. Xiong, K. Yoshinari, K. L. R. Brouwer, and M. Negishi Role of Constitutive Androstane Receptor in the In Vivo Induction of Mrp3 and CYP2B1/2 by Phenobarbital Drug Metab. Dispos., August 1, 2002; 30(8): 918 - 923. [Abstract] [Full Text] [PDF]
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P. M. Gerk and M. Vore Regulation of Expression of the Multidrug Resistance-Associated Protein 2 (MRP2) and Its Role in Drug Disposition J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 407 - 415. [Abstract] [Full Text] [PDF]
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Z.-S. Chen, K. Lee, S. Walther, R. B. Raftogianis, M. Kuwano, H. Zeng, and G. D. Kruh Analysis of Methotrexate and Folate Transport by Multidrug Resistance Protein 4 (ABCC4): MRP4 Is a Component of the Methotrexate Efflux System Cancer Res., June 1, 2002; 62(11): 3144 - 3150. [Abstract] [Full Text] [PDF]
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Y. Tanaka, Y. Kobayashi, E. C. Gabazza, K. Higuchi, T. Kamisako, M. Kuroda, K. Takeuchi, M. Iwasa, M. Kaito, and Y. Adachi Increased renal expression of bilirubin glucuronide transporters in a rat model of obstructive jaundice Am J Physiol Gastrointest Liver Physiol, April 1, 2002; 282(4): G656 - G662. [Abstract] [Full Text] [PDF]
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D. Rost, S. Mahner, Y. Sugiyama, and W. Stremmel Expression and localization of the multidrug resistance-associated protein 3 in rat small and large intestine Am J Physiol Gastrointest Liver Physiol, April 1, 2002; 282(4): G720 - G726. [Abstract] [Full Text] [PDF]
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N. J. Cherrington, D. P. Hartley, N. Li, D. R. Johnson, and C. D. Klaassen Organ Distribution of Multidrug Resistance Proteins 1, 2, and 3 (Mrp1, 2, and 3) mRNA and Hepatic Induction of Mrp3 by Constitutive Androstane Receptor Activators in Rats J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 97 - 104. [Abstract] [Full Text] [PDF]
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 A. Inokuchi, E. Hinoshita, Y. Iwamoto, K. Kohno, M. Kuwano, and T. Uchiumi Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes. A TRANSCRIPTIONAL CONTROL OF A PLAUSIBLE BILE ACID TRANSPORTER J. Biol. Chem., December 7, 2001; 276(50): 46822 - 46829. [Abstract] [Full Text] [PDF]
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N. Zelcer, T. Saeki, G. Reid, J. H. Beijnen, and P. Borst Characterization of Drug Transport by the Human Multidrug Resistance Protein 3 (ABCC3) J. Biol. Chem., November 30, 2001; 276(49): 46400 - 46407. [Abstract] [Full Text] [PDF]
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K. Ito, H. Suzuki, and Y. Sugiyama Single amino acid substitution of rat MRP2 results in acquired transport activity for taurocholate Am J Physiol Gastrointest Liver Physiol, October 1, 2001; 281(4): G1034 - G1043. [Abstract] [Full Text] [PDF]
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 R. A. Peck, J. Hewett, M. W. Harding, Y.-M. Wang, P. R. Chaturvedi, A. Bhatnagar, H. Ziessman, F. Atkins, and M. J. Hawkins Phase I and Pharmacokinetic Study of the Novel MDR1 and MRP1 Inhibitor Biricodar Administered Alone and in Combination With Doxorubicin J. Clin. Oncol., June 15, 2001; 19(12): 3130 - 3141. [Abstract] [Full Text] [PDF]
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C. G. Dietrich, D.R. de Waart, R. Ottenhoff, A. H. Bootsma, A. H. van Gennip, and R. P.J.O. Elferink Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Carcinogenesis, May 1, 2001; 22(5): 805 - 811. [Abstract] [Full Text] [PDF]
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K. Ito, H. Suzuki, and Y. Sugiyama Charged Amino Acids in the Transmembrane Domains Are Involved in the Determination of the Substrate Specificity of Rat Mrp2 Mol. Pharmacol., April 16, 2001; 59(5): 1077 - 1085. [Abstract] [Full Text]
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 K. Lee, A. J. P. Klein-Szanto, and G. D. Kruh Analysis of the MRP4 Drug Resistance Profile in Transfected NIH3T3 Cells J Natl Cancer Inst, December 6, 2000; 92(23): 1934 - 1940. [Abstract] [Full Text] [PDF]
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H. Xiong, K. C. Turner, E. S. Ward, P. L. M. Jansen, and K. L. R. Brouwer Altered Hepatobiliary Disposition of Acetaminophen Glucuronide in Isolated Perfused Livers from Multidrug Resistance-Associated Protein 2-Deficient TR- Rats J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 512 - 518. [Abstract] [Full Text]
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N. Okudaira, I. Komiya, and Y. Sugiyama Polarized Efflux of Mono- and Diacid Metabolites of ME3229, an Ester-Type Prodrug of a Glycoprotein IIb/IIIa Receptor Antagonist, in Rat Small Intestine J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 717 - 723. [Abstract] [Full Text]
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 M. F. Fromm, H.-M. Kauffmann, P. Fritz, O. Burk, H. K. Kroemer, R. W. Warzok, M. Eichelbaum, W. Siegmund, and D. Schrenk The Effect of Rifampin Treatment on Intestinal Expression of Human MRP Transporters Am. J. Pathol., November 1, 2000; 157(5): 1575 - 1580. [Abstract] [Full Text] [PDF]
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H. Zeng, G. Liu, P. A. Rea, and G. D. Kruh Transport of Amphipathic Anions by Human Multidrug Resistance Protein 3 Cancer Res., September 1, 2000; 60(17): 4779 - 4784. [Abstract] [Full Text]
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P. Borst, R. Evers, M. Kool, and J. Wijnholds A Family of Drug Transporters: the Multidrug Resistance-Associated Proteins J Natl Cancer Inst, August 16, 2000; 92(16): 1295 - 1302. [Abstract] [Full Text] [PDF]
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 R. A. M. H. Van Aubel, R. Masereeuw, and F. G. M. Russel Molecular pharmacology of renal organic anion transporters Am J Physiol Renal Physiol, August 1, 2000; 279(2): F216 - F232. [Abstract] [Full Text] [PDF]
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J. Madon, B. Hagenbuch, L. Landmann, P. J. Meier, and B. Stieger Transport Function and Hepatocellular Localization of mrp6 in Rat Liver Mol. Pharmacol., March 1, 2000; 57(3): 634 - 641. [Abstract] [Full Text]
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T. Hirohashi, H. Suzuki, H. Takikawa, and Y. Sugiyama ATP-dependent Transport of Bile Salts by Rat Multidrug Resistance-associated Protein 3 (Mrp3) J. Biol. Chem., January 28, 2000; 275(4): 2905 - 2910. [Abstract] [Full Text] [PDF]
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T. Hirohashi, H. Suzuki, X.-Y. Chu, I. Tamai, A. Tsuji, and Y. Sugiyama Function and Expression of Multidrug Resistance-Associated Protein Family in Human Colon Adenocarcinoma Cells (Caco-2) J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 265 - 270. [Abstract] [Full Text]
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R. G. Tirona, E. Tan, G. Meier, and K. S. Pang Uptake and Glutathione Conjugation of Ethacrynic Acid and Efflux of the Glutathione Adduct by Periportal and Perivenous Rat Hepatocytes J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1210 - 1219. [Abstract] [Full Text]
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H. Zeng, L. J. Bain, M. G. Belinsky, and G. D. Kruh Expression of Multidrug Resistance Protein-3 (Multispecific Organic Anion Transporter-D) in Human Embryonic Kidney 293 Cells Confers Resistance to Anticancer Agents Cancer Res., December 1, 1999; 59(23): 5964 - 5967. [Abstract] [Full Text] [PDF]
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H. Ishizuka, K. Konno, T. Shiina, H. Naganuma, K. Nishimura, K. Ito, H. Suzuki, and Y. Sugiyama Species Differences in the Transport Activity for Organic Anions across the Bile Canalicular Membrane J. Pharmacol. Exp. Ther., September 1, 1999; 290(3): 1324 - 1330. [Abstract] [Full Text]
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S. Jariyawat, T. Sekine, M. Takeda, N. Apiwattanakul, Y. Kanai, S. Sophasan, and H. Endou The Interaction and Transport of beta -Lactam Antibiotics with the Cloned Rat Renal Organic Anion Transporter 1 J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 672 - 677. [Abstract] [Full Text]
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M. Kool, M. van der Linden, M. de Haas, G. L. Scheffer, J. M. L. de Vree, A. J. Smith, G. Jansen, G. J. Peters, N. Ponne, R. J. Scheper, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs PNAS, June 8, 1999; 96(12): 6914 - 6919. [Abstract] [Full Text] [PDF]
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D. F. Ortiz, S. Li, R. Iyer, X. Zhang, P. Novikoff, and I. M. Arias MRP3, a new ATP-binding cassette protein localized to the canalicular domain of the hepatocyte Am J Physiol Gastrointest Liver Physiol, June 1, 1999; 276(6): G1493 - G1500. [Abstract] [Full Text] [PDF]
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T. Hirohashi, H. Suzuki, and Y. Sugiyama Characterization of the Transport Properties of Cloned Rat Multidrug Resistance-associated Protein 3 (MRP3) J. Biol. Chem., May 21, 1999; 274(21): 15181 - 15185. [Abstract] [Full Text] [PDF]
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S. P. C. Cole Re: Characterization of MOAT-C and MOAT-D, New Members of the MRP/cMOAT Subfamily of Transporter Proteins J Natl Cancer Inst, May 19, 1999; 91(10): 888 - 888. [Full Text] [PDF]
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G. D. Kruh and M. G. Belinsky RESPONSE: Re: Characterization of MOAT-C and MOAT-D, New Members' of the MRP/cMOAT Subfamily of Transporter Proteins J Natl Cancer Inst, May 19, 1999; 91(10): 888a - 889a. [Full Text] [PDF]
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K. Niinuma, Y. Kato, H. Suzuki, C. A. Tyson, V. Weizer, J. E. Dabbs, R. Froehlich, C. E. Green, and Y. Sugiyama Primary active transport of organic anions on bile canalicular membrane in humans Am J Physiol Gastrointest Liver Physiol, May 1, 1999; 276(5): G1153 - G1164. [Abstract] [Full Text] [PDF]
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X.-Y. Chu, H. Suzuki, K. Ueda, Y. Kato, S.-I. Akiyama, and Y. Sugiyama Active Efflux of CPT-11 and Its Metabolites in Human KB-Derived Cell Lines J. Pharmacol. Exp. Ther., February 1, 1999; 288(2): 735 - 741. [Abstract] [Full Text]
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 H Roelofsen, G. Hooiveld, H Koning, R Havinga, P. Jansen, and M Muller Glutathione S-conjugate transport in hepatocytes entering the cell cycle is preserved by a switch in expression from the apical MRP2 to the basolateral MRP1 transporting protein J. Cell Sci., January 5, 1999; 112(9): 1395 - 1404. [Abstract] [PDF]
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M. Homma, H. Suzuki, H. Kusuhara, M. Naito, T. Tsuruo, and Y. Sugiyama High-Affinity Efflux Transport System for Glutathione Conjugates on the Luminal Membrane of a Mouse Brain Capillary Endothelial Cell Line (MBEC4) J. Pharmacol. Exp. Ther., January 1, 1999; 288(1): 198 - 203. [Abstract] [Full Text]
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M. Kool, M. v. d. Linden, M. de Haas, F. Baas, and P. Borst Expression of Human MRP6, a Homologue of the Multidrug Resistance Protein Gene MRP1, in Tissues and Cancer Cells Cancer Res., January 1, 1999; 59(1): 175 - 182. [Abstract] [Full Text] [PDF]
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E. M. Leslie, K.-i. Ito, P. Upadhyaya, S. S. Hecht, R. G. Deeley, and S. P. C. Cole Transport of the beta -O-Glucuronide Conjugate of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the Multidrug Resistance Protein 1 (MRP1). REQUIREMENT FOR GLUTATHIONE OR A NON-SULFUR-CONTAINING ANALOG J. Biol. Chem., July 20, 2001; 276(30): 27846 - 27854. [Abstract] [Full Text] [PDF]
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Z.-S. Chen, K. Lee, and G. D. Kruh Transport of Cyclic Nucleotides and Estradiol 17-beta -D-Glucuronide by Multidrug Resistance Protein 4. RESISTANCE TO 6-MERCAPTOPURINE AND 6-THIOGUANINE J. Biol. Chem., August 31, 2001; 276(36): 33747 - 33754. [Abstract] [Full Text] [PDF]
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