Department of Pharmacology and Toxicology, Institute of Cellular Signaling, University of Nijmegen, 6500 HB Nijmegen, The Netherlands
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ABSTRACT |
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Renal organic anion transport systems play an important role in the elimination of drugs, toxic compounds, and their metabolites, many of which are potentially harmful to the body. The renal proximal tubule is the primary site of carrier-mediated transport from blood to urine of a wide variety of anionic substrates. Recent studies have shown that organic anion secretion in renal proximal tubule is mediated by distinct sodium-dependent and sodium-independent transport systems. Knowledge of the molecular identity of these transporters and their substrate specificity has increased considerably in the past few years by cloning of various carrier proteins. However, a number of fundamental questions still have to be answered to elucidate the participation of the cloned transporters in the overall tubular secretion of anionic xenobiotics. This review summarizes the latest knowledge on molecular and pharmacological properties of renal organic anion transporters and homologs, with special reference to their nephron and plasma membrane localization, transport characteristics, and substrate and inhibitor specificity. A number of the recently cloned transporters, such as the p-aminohippurate/dicarboxylate exchanger OAT1, the anion/sulfate exchanger SAT1, the peptide transporters PEPT1 and PEPT2, and the nucleoside transporters CNT1 and CNT2, are key proteins in organic anion handling that possess the same characteristics as has been predicted from previous physiological studies. The role of other cloned transporters, such as MRP1, MRP2, OATP1, OAT-K1, and OAT-K2, is still poorly characterized, whereas the only information that is available on the homologs OAT2, OAT3, OATP3, and MRP3-6 is that they are expressed in the kidney, but their localization, not to mention their function, remains to be elucidated.
multidrug resistance protein; peptide transporter; drug excretion; proximal tubule; kidney
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INTRODUCTION |
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THE HUMAN BODY IS CONTINUOUSLY exposed to a great variety of xenobiotics, via food, drugs, occupation, and environment. Excretory organs such as kidney, liver, and intestine defend the body against the potentially harmful effects of these compounds by biotransformation into less active metabolites and excretory transport processes. Most drugs and environmental toxicants are eventually excreted into the urine, either in the unchanged form or as biotransformation products. The mechanisms that contribute to their renal excretion are closely related to the physiological events occurring in the nephrons, i.e., filtration, secretion, and reabsorption. Carrier-mediated transport of xenobiotics and their metabolites is confined to the proximal tubule, and separate carrier systems exist for the active secretion of organic anions and cations. Both systems are characterized by a high clearance capacity and tremendous diversity of substances accepted, probably resulting from multiple transporters with overlapping substrate specificities.
This review will focus on the molecular aspects of renal organic anion
transporters. These systems play a critical role in the elimination of
a large number of drugs (e.g., antibiotics, chemotherapeutics,
diuretics, nonsteroidal anti-inflammatory drugs, radiocontrast agents,
cytostatics); drug metabolites (especially conjugation products with
glutathione, glucuronide, glycine, sulfate, acetate); and toxicants and
their metabolites (e.g., mycotoxins, herbicides, plasticizers,
glutathione S-conjugates of polyhaloalkanes, polyhaloalkenes, hydroquinones, aminophenols), many of which are specifically harmful to the kidney. For a review of the molecular pharmacology of renal organic cation transporters, the reader is
referred to a recent comprehensive paper by Koepsell et al. (79). The purpose of this paper is to give a concise
review of the latest molecular information on organic anion
transporters that contribute to the renal handling of
xenobiotics and their metabolites. These transporters are
depicted in Fig. 1 and listed in Tables
1 and
2. The
systems involved in organic anion secretion can be functionally
subdivided in the well-characterized sodium-dependent p-aminohippurate (PAH) system and a recently discovered
sodium-independent system (107, 108,
146). Both systems mediate two membrane translocation steps arranged in series: uptake from blood across the basolateral membrane of renal epithelial cells followed by efflux into urine across
the apical membrane. While transported through the cytoplasm, substrates for both systems also accumulate in intracellular
compartments. Furthermore, at the apical membrane several transport
systems have been identified that are involved in reabsorption of
anionic xenobiotics. Recent discoveries on the molecular identity of
some of the renal organic anion transporters [OAT1;
Na+-dicarboxylate cotransporter (SDCT2); anion/sulfate
exchanger (SAT1); peptide transporters (PEPT1 and PEPT2); nucleoside
transporters (CNT1 and CNT2)] have confirmed the characteristics that
have been predicted creatively by earlier functional studies performed in isolated membrane vesicles and proximal tubules. The same studies have indicated the existence of further anion transporters that have
not yet been identified at the molecular level. For other recently
cloned organic anion transporters, information on their function
[multidrug resistance protein (MRP) 1, MRP2, OATP1, OAT-K1, OAT-K2]
and renal localization (OAT2, OAT3, MRP3-6) remains to be
elucidated. Emphasis in this review is being placed on molecular characteristics, nephron and plasma membrane localization, transport properties, and substrate and inhibitor specificity of cloned renal
organic anion transporters and homologs.
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BASOLATERAL TRANSPORT SYSTEMS |
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Transport studies using isolated membrane vesicles and intact
proximal tubules have identified and characterized the classic transport system for uptake of small organic anions across the basolateral membrane by using PAH or fluorescein as a model substrate (146). These studies have established that uptake of PAH
is a tertiary active process by indirect coupling to the
Na+ gradient. This gradient, which is maintained by the
Na+-K+ ATPase, drives
Na+-dicarboxylate cotransport into the cell and enables
uptake of PAH in exchange for a dicarboxylate ion. The
PAH/dicarboxylate exchanger (Oat1) has been cloned from various
species. On the basis of similarities with transport characteristics
found in membrane vesicles, SDCT2 has been proposed as the basolateral Na+-dicarboxylate cotransporter (18).
-Ketoglutarate is by far the most abundant potential
dicarboxylate counterion within the proximal tubular cell, and it has
been shown that PAH or fluorescein uptake in renal proximal tubules
increases with increasing internal
-ketoglutarate
concentration (16, 145, 199).
The activity of the Na+/dicarboxylate exchanger accounts
for ~60% of organic anion uptake (199), whereas the
remainder can be explained by intracellularly stored
-ketoglutarate
(145). Mitochondrial metabolism seems responsible for the
generation of this dicarboxylate, and from liver studies it is known
that the mitochondrial
-ketoglutarate concentration
exceeds that in cytoplasm three- to sixfold (169, 172). These findings imply that alterations in cellular
metabolism may have a direct effect on the secretory function of kidney
proximal tubules. Apart from the classical PAH transporter, an
additional uptake system has been characterized by using the bulky
organic anion fluorescein-methotrexate as a substrate
(108). Uptake of fluorescein-methotrexate is independent
of Na+ and is not inhibited by PAH or the dicarboxylate ion
glutarate. The molecular identity of this transporter, however, has not
yet been established. Finally, a sulfate/anion exchanger has been characterized in basolateral membrane vesicles and cloned from rats
(52, 72, 85, 147).
This transporter exchanges sulfate for HCO3
or
oxalate in a Na+-independent manner. Although multiple
substrates have been proposed for the PAH/dicarboxylate and the
sulfate/anion exchanger on the basis of inhibition experiments
(188), there is as yet no evidence that these compounds
are substrates themselves.
Organic Anion Transporter Oat1 (PAH/Dicarboxylate Exchanger)
Various groups have cloned the PAH/dicarboxylate exchanger Oat1 from rat and flounder by expression cloning in Xenopus laevis oocytes (165, 175, 190, 204). Furthermore, rat Oat1 sequences have enabled cloning of the human ortholog OAT1 (86% identity to Oat1) (58, 104, 149, 151). Expression of rat Oat1 in X. laevis oocytes and human OAT1 in HeLa cells results in uptake of PAH, which is trans-stimulated by glutarate and cis-inhibited by glutarate,Oat2 and Oat3/OAT3
Functional expression in X. laevis oocytes of a putative rat liver transporter, initially designated as NLT, revealed uptake ofRace et al. (149) recently reported the cloning of OAT1 and a kidney-specific homolog called OAT3 (84% identity to Oat3). Expression of OAT3 in X. laevis oocytes, however, did not result in uptake of PAH (149), suggesting that OAT3 is not the human ortholog of rat Oat3. Brady et al. (12) have cloned a murine gene encoding a putative transporter (Roct) with highest identity to Oat3 (92%) and OAT3 (83%). Expression of murine Oat3/Roct is abundant in kidneys of wild-type mice but markedly reduced in kidneys of mice homozygous for the recessive osteosclerosis (oc) mutation (12). Both the oc mutation as well as the murine oat3/roct gene have been mapped to chromosome 19, although no mutations have yet been identified in the oat3/roct gene of oc mice (12). Similarly, the OAT3 gene has been mapped closely to the region where human recessive osteopetrosis, a disease with a similar pathophysiology as osteosclerosis, has been mapped (12, 55). Further studies are required to elucidate the relationship between these transporters and the phenotype of osteosclerosis and osteopetrosis.
Sulfate/Anion Exchanger Sat1
Expression cloning by using X. laevis oocytes has identified a sulfate/anion exchanger (Sat1) from rat kidney and liver (8, 72). In the kidney, Sat1 is located at the basolateral membrane of proximal tubules (72). Expression of Sat1 in Sf9 cells results in uptake of sulfate and oxalate, which is cis-inhibited by oxalate and sulfate, respectively (72). In addition, DIDS but not succinate inhibits Sat1-mediated sulfate uptake (8). These transport characteristics are in close agreement with those found in proximal tubule basolateral membrane vesicles (52, 85, 147). The cloning of Sat1 enables one to answer the question whether the compounds proposed as substrates on the basis of earlier inhibition studies are indeed transported by Sat1.MRP1
MRP1 is a member of the large family of ATP-binding cassette proteins and functions as an ATP-dependent transporter of anionic conjugates, such as leukotriene C4, S-(dinitrophenyl)-glutathione, estradiol-17Human MRP1 is frequently overexpressed in various multidrug resistant
cancer cell lines selected with cationic (chemotherapeutic) drugs
(20). Transfection of a human MRP1 cDNA into
drug-sensitive cells results in resistance to various cationic drugs,
such as vincristine, doxorubicin, and etoposide (21,
49, 211). In addition, mrp1 /
mice are hypersensitive to such drugs (103, 201, 203). Because administration of
etoposide to mrp1
/
mice results in polyurea, MRP1 might
protect distal parts of the nephron, which are exposed to high
concentrations of drugs as a result of water reabsorption
(203).
MRP3, MRP4, MRP5, and MRP6
Searching of the GenBank database EST sequences enabled identification of four additional human MRP-like genes alongside MRP1 and MRP2 (see apical transport systems). Expression of MRP3 (5, 77, 81, 82, 187), MRP4 (82, 163), MRP5 (5, 82, 117), and MRP6 (83) mRNA has been found in various tissues, including kidney. However, Lee et al. (89) did not find expression of MRP4 in the kidney.The subcellular localization and nephron distribution of these
novel MRPs in the kidney is at present unknown. However,
immunohistochemistry on liver sections has demonstrated the presence of
human MRP3 at the basolateral membrane of intrahepatic bile-duct
epithelial cells (cholangiocytes) and hepatocytes, whereas rat Mrp6 has
been located specifically to the hepatocyte lateral membrane
(81, 84, 106). Similarly, human
MRP5 is confined to the basolateral membrane of various epithelial
cells (202). Transport characteristics of several of these
novel MRPs have been reported recently. MDCKII cells overexpressing
human MRP3 show increased efflux of
S-(dinitrophenyl)-glutathione across the basolateral
membrane compared with the parental cells (84).
Furthermore, MRP3 confers resistance to the chemotherapeutic drugs
etoposide, teniposide, and methotrexate (84). In the cell line HepG2, endogenously expressed MRP3 mRNA is induced by
phenobarbital (77). Membrane vesicles from
LLC-PK1 cells transfected with a rat mrp3 cDNA
exhibit ATP-dependent uptake of
estradiol-17-D-glucuronide and E3040-glucuronide, but
not leukotriene C4 or
S-(dinitrophenyl)-glutathione (57). In a
T-lymphoid cell line, overexpression of human MRP4 mRNA and
MRP4 protein was found to be correlated with enhanced ATP-dependent
efflux of nucleoside monophosphate analogs (163). Substrate specificity of MRP5 has been investigated by expression of a
conjugate to green fluorescent protein in HEK-293 cells
(117). MRP5-green fluorescent protein-expressing cells
preloaded with various fluorescent organic anions show a reduced
cellular level of fluorochrome compared with the parental cells
(117). In a recent report, rat Mrp6 was shown to mediate
ATP-dependent transport of the anionic cyclopentapeptide endothelin
antagonist BQ-123 (106). Further studies are required to
determine the transport characteristics of these MRPs and to define
their role in the kidney.
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INTRACELLULAR DISPOSITION OF ANIONIC DRUGS |
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Anionic drugs accumulate in proximal tubules as a result of secretory transport, possibly in combination with reabsorption. The degree of accumulation is determined by the extent to which anionic drugs are actively transported across the basolateral membrane, their intracellular disposition, and the ease with which they can be transported across the brush-border membrane into the tubular lumen.
In vitro studies in isolated proximal tubular cells have indicated that, at low-medium concentrations, PAH and fluorescein accumulate intracellularly at concentrations three to five times the medium concentration (111). Fluorescein accumulation in proximal tubular cells during secretory transport has recently been confirmed in rat kidney in vivo (11). Confocal microscopic images of rat proximal tubular cells showed compartmentation of fluorescein in subcellular organelles. In particular, mitochondria appear to concentrate fluorescein via the metabolite anion transporters in the inner membrane (109, 111, 183). On the other hand, Miller et al. (121, 123, 124) suggested nocodazole-sensitive vesicular compartmentation in crab urinary bladder. Nocodazole disrupts the Golgi apparatus and, subsequently, microtubules, which are involved in the movement of transporting vesicles thorough the cells (13). This indicates that at least two different compartments may be involved in the intracellular sequestration of organic anions. The involvement of microtubules in vesicular compartmentation suggests a role in transcellular transport and/or secretion. Another possibility is that endosomal membranes play a role in the rapid and directed trafficking of transporters to and from the apical membrane.
Hardly any research is done on transcellular transport of organic anions in the renal proximal tubule. Two decades ago, the presence of anion binding proteins was shown, of which ligandin or glutathione S-transferase B is the most important (15, 95, 166). Several anionic drugs interact with these binding proteins, suggesting that they play a role in the reduction of free cytoplasmic drug concentrations and maybe in transcellular drug trafficking (48, 76, 95). Binding to glutathione S-transferase, however, appeared not to be a determinant for the rate of luminal secretion (142). Unfortunately, more recent data on the role of binding proteins are not available.
Finally, metabolism may be an important intracellular event associated
with renal anionic xenobiotic disposition. The biotransformation pathways reported involve oxidative, reductive, and hydrolytic reactions (phase I reactions) and conjugation to
glucuronide, sulfate, or reduced glutathione (phase II
reactions) (47, 96, 101,
128). Microsomal oxidation through cytochrome
P-450-dependent mechanisms takes place predominantly in
kidney proximal tubules (101). Glucuronide conjugates are
formed through the enzymatic activity of UDP-glucuronosyltransferase,
of which various isozymes have been identified in the kidney. Renal
sulfate conjugation is catalyzed by sulfotransferase but is
quantitatively less than glucuronide conjugation (96,
101). Conjugation to GSH is catalyzed by GSH-transferase,
and the conjugates may subsequently be transformed into cysteine
conjugates and mercapturic acid by -glutamyltranspeptidase and
N-acetyltransferase, respectively (22). The
enzymes involved in glucuronide, sulfate, or GSH conjugation are not
uniformly distributed in the kidney but show the highest activity in
the proximal tubule (61, 96,
101, 209). The different enzymes involved in
GSH-derived biotransformation reactions (
-glutamyltranspeptidase and
N-acetyltransferase) express a high activity predominantly in S3 segments of the proximal tubule (60).
Biotransformation reactions are primarily detoxification mechanisms,
although toxic metabolites may be produced as well [e.g.,
acetaminophen (27, 132), halogenated alkanes
(132), cisplatin (25, 167),
cyclosporin A (6), ochratoxin A (28,
46)].
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APICAL TRANSPORT SYSTEMS |
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Many of the transport systems for organic anions in the
brush-border membrane of the proximal tubule have initially been
characterized in membrane vesicle studies (146). Small
organic anions, such as PAH and fluorescein, are excreted via a
facilitated transporter driven by the potential difference of about
70 mV from cell to lumen. In addition, an anion exchange mechanism
has been identified in some species, such as dog, rat, and human, but
not in rabbit. Neither of these efflux systems has been cloned. On the
basis of inhibition experiments in in situ perfused proximal tubules, Ullrich and Rumrich (189) suggested multiple substrates
for these organic anion transporters. Studies with intact killifish
proximal tubules have indicated two efflux pathways for organic anions (107, 108, 122). One pathway
mediates Na+-dependent efflux of small organic anions,
independent of the membrane potential (108,
122). Bulky organic anions, such as fluorescein-methotrexate and lucifer yellow, are excreted via an
energy-dependent efflux system, which is insensitive to PAH and
depletion of Na+ but inhibited by leukotriene
C4 and S-(dinitrophenyl)-glutathione (107, 108). A likely candidate for this
transport system is the apical ATP-dependent anionic conjugate
transporter Mrp2. Apart from efflux mechanisms, the brush-border
membrane also contains transport systems for reabsorption of compounds
from primary urine. Small anionic peptides are actively taken up via
H+-peptide cotransporters by coupling to the H+
gradient (26). In addition, anionic nucleosides are
actively taken up by Na+-nucleoside cotransporters by
coupling to the Na+ gradient (39,
50, 203).
MRP2
The multidrug resistance protein 2 (MRP2) is an ATP-dependent organic anion transporter with highest identity to MRP1 (48%) and MRP3 (46%). MRP2, also described as the canalicular multispecific organic anion transporter, is expressed at the apical membrane of hepatocytes (14, 139), renal proximal tubules (162), and small intestinal villi (191). In liver, MRP2 plays an important role in the biliary excretion of multiple conjugated and unconjugated organic anions across the canalicular (apical) membrane. Defective function of Mrp2, as observed in the two mutant rat strains EHBR and TRThe transport characteristics of Mrp2 have been investigated
extensively in comparative studies with wild-type and Mrp2-deficient rats by using perfused liver and isolated canalicular membrane vesicles
or hepatocytes (135, 174). In contrast to
liver canalicular membrane vesicles, membrane vesicles from the
proximal tubule brush-border membrane are unsuitable for characterizing
Mrp2-mediated transport. Because these vesicles are exclusively
oriented rightside-out, the ATP-binding site is inaccessible for
extravesicular ATP (51). Studies with killifish renal
proximal tubules have indicated the presence of an MRP-like transporter
involved in the energy-dependent and leukotriene
C4-sensitive efflux of fluorescein-methotrexate and lucifer
yellow (107, 108). Immunohistochemistry with
a polyclonal antibody raised against rabbit Mrp2 has located a
killifish ortholog to the brush-border membrane, which further supports
this hypothesis (110). Furthermore, studies with membrane
vesicles from Mrp2-expressing Sf9 cells have identified PAH as an Mrp2
substrate, suggesting that Mrp2 might be involved in renal clearance of
PAH (193). Functional evidence exists for the presence of
apical transporters other than Mrp2 involved in renal excretion of
organic anions. For example, efflux of lucifer yellow from killifish
proximal tubules is only partly inhibited by the Mrp2 substrates
leukotriene C4 and S-(dinitrophenyl)-glutathione
(107). Also, renal clearance of the Mrp2 substrates
-naphtyl-
-D-glucuronide (29),
E3040-glucuronide (178), cefpiramide (130),
the quinolone HSR-903 (131), and lucifer yellow (Masereeuw
R and Russel FGM, unpublished observations) is not impaired in
Mrp2-deficient rats.
Like MRP1 and MRP3, human MRP2 not only transports anionic conjugates but also confers resistance to various cationic chemotherapeutic drugs (23, 80). Studies with membrane vesicles from cells expressing human MRP1 have indicated that uptake of cationic drugs, such as vincristine, daunorubicin, and aflatoxin B1, only occurs in the presence of physiological concentrations of GSH (68, 98-100). A similar GSH dependency of ATP-dependent vinblastine transport has been shown for rabbit Mrp2 (192). This explains the finding that MRP1- and MRP2-mediated drug resistance is reversed by an inhibitor of GSH synthesis (23, 195, 212). For human MRP1, the mechanism involved in GSH-stimulated ATP-dependent transport of vincristine has been identified as a GSH-vincristine cotransport mechanism (99). Daunorubicin and etoposide, unlike vincristine, did not stimulate GSH transport, indicating the involvement of a mechanism different from cotransport (99). Recent studies have shown that MRP2, like MRP1 (141, 212) and MRP5 (202) but not MRP3 (84), transports GSH itself (141). Efflux of GSH from MDCKII cells overexpressing MRP2 is sensitive to depletion of ATP (141). However, studies with membrane vesicles have indicated that rabbit Mrp2 is permeable for GSH (192).
Regulation of Mrp2-mediated transport has been investigated in isolated rat hepatocytes and killifish renal proximal tubules; however, results in these tissues are at variance. Both cAMP and PKC stimulated Mrp2-mediated efflux of an anionic conjugate across the hepatocyte apical membrane (155, 156). At least for the effect of cAMP, this efflux has been shown to be a result of stimulated sorting of Mrp2-containing vesicles to the apical membrane (156). In the killifish proximal tubule, efflux of fluorescein-methotrexate is negatively correlated with PKC activity (110). Activation of the signal transduction pathway occurs by binding of endothelin-1 to the B-type receptor (110). Because endothelins are involved in many processes in the kidney, this suggests a specific regulatory pathway for renal Mrp2.
Organic Anion Transport Polypeptides Oatp1 and Oatp3
The organic anion-transporting polypeptide 1 (Oatp1) is a Na+- and ATP-independent transporter originally cloned from rat liver (67). Oatp1 is localized to the basolateral membrane of hepatocytes, where it plays a major role in uptake of a variety of anionic, neutral, and cationic compounds from the blood (118). In contrast, Oatp1 is located at the apical membrane of S3 proximal tubules (7). Studies with transiently transfected HeLa cells have indicated that Oatp1 mediates uptake of taurocholate in exchange for HCO3Organic Anion Transporters Oat-k1 and Oat-k2
Oat-k1 and Oat-k2 are kidney-specific Na+- and ATP-independent organic anion transporters with highest identity to Oatp1 (72 and 65%, respectively) (112, 157). Both transporters are confined to the brush-border membrane of proximal tubular cells (112, 116). Oat-k1 and Oat-k2 mediate transport of methotrexate and folate, whereas Oat-k2 also transports prostaglandin E2 and taurocholate (112, 157). Additional studies are required to elucidate whether Oat-k1 and Oat-k2 mediate efflux or reabsorption of organic anions. However, Oat-k1 expressed in MDCK cells transports methotrexate across the apical membrane in both directions (114). Similarly, Oat-k2 transports taurocholate bidirectionally across the apical membrane on expression in MDCK cells (112). In a recent study, Oat-k1 was proposed as the ochratoxin A reabsorption pathway in proximal tubules on the basis of the inhibitory effect of bromosulfophthalein (24). Although bromosulfophthalein indeed inhibits Oat-k1-mediated transport (114, 157), it also inhibits Oat-k2-mediated transport (112). Furthermore, there is no evidence to suggest that ochratoxin A is a substrate of either of these transporters. In this respect, various organic anions (i.e., nonsteroidal anti-inflammatory drugs, PAH, digoxin, probenecid), bile acid analogs, and steroids are potent inhibitors but not substrates of Oat-k1 and Oat-k2 (112-115, 157). Several of these drugs can accumulate to high concentrations in the proximal tubule, suggesting that under these conditions both transporters are inhibited.Na+-Nucleoside Cotransporters CNT1 and CNT2
The concentrative nucleoside transporters CNT1 and CNT2 are involved in Na+-dependent transport of endogenous nucleosides and various synthetic (anionic) nucleosides, which are of clinical importance for their use in the treatment of cancer and viral infections (138). CNT1 (N2 subtype or cit) is selective for pyrimidines, whereas CNT2 (N1 subtype or cif) favors transport of purines, although uridine and adenosine are transported by both proteins (17, 35, 59, 152, 153, 161, 198, 207, 208). Structural features markedly distinguish rat Cnt2 from human CNT2; moreover, Cnt2 transports thymidine in contrast to CNT2 (17, 153, 198). Northern blotting and RT-PCR have identified expression of human CNT1 and CNT2 mRNA in the kidney (152, 153, 198). Although their membrane localization has not been established by immunohistochemistry, Na+-nucleoside cotransport into cells overexpressing CNT1 or CNT2 resembles transport characteristics found in brush-border membrane vesicles (39, 50, 204). This indicates that CNT1 and CNT2 mediate Na+-nucleoside cotransport across the brush-border membrane into the proximal tubule.H+-Peptide Cotransporters PEPT1 and PEPT2
Peptide transporters are involved in H+-dependent transport of small peptides and various peptide-like compounds such as anticancer drugs (bestatin, delta-aminovulinic acid), prodrugs (L-dopa-L-Phe, L-Val-azidothymidine), inhibitors of angiotensin-converting enzyme (captopril, enalapril), and various anionic ![]() |
CONCLUSIONS |
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The past few years have witnessed great advances in our understanding of the molecular pharmacology of renal organic anion transport. Considerable progress has been made in cloning key proteins involved in the transport of anionic xenobiotics and metabolites, and the list of cloned organic anion transporters is steadily growing. The challenge of future work will be to integrate this information with (patho)physiological, pharmacological, and toxicological investigations at the cellular and organ level. There is still a large gap in our knowledge about the relative contribution of individual transporters to the membrane steps involved in tubular secretion of specific anionic substrates. More detailed knowledge of the cloned carrier proteins in expression systems and the availability of specific antibodies will allow more fundamental insight into membrane translocation at the molecular level, as well as participation in overall transepithelial secretion. This will also facilitate the research on the interaction of cellular messengers with the carrier proteins and the way these transporters are synthesized and targeted to specific membrane sites in the normal and diseased kidney. An important approach to study the in vivo function of transporters and their mutual interaction is to develop and characterize (multiple) null mutants of the genes encoding these proteins. Finally, it has become increasingly clear that intracellular disposition is an important step in the active secretion of anionic xenobiotics. How these processes interact with the membrane transport mechanisms to produce secretion and at what level and to what extent they are regulated will be important questions to answer.
A detailed knowledge of the renal mechanisms that govern intracellular distribution and membrane transport of xenobiotics in the kidney is essential for the development of clinically useful drugs and will advance our understanding of the molecular, cellular, and clinical bases of renal drug clearance, drug-drug interactions, drug targeting to the kidney, and xenobiotic-induced nephropathy.
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FOOTNOTES |
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Address for reprint requests and other correspondence: F. G. M. Russel, Univ. of Nijmegen, Dept. of Pharmacology and Toxicology 233, PO Box 9101, 6500 HB Nijmegen, The Netherlands (E-mail: F.Russel{at}farm.kun.nl).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abe, T,
Kakyo M,
Sakagami H,
Tokui T,
Nishio T,
Tanemoto M,
Nomura H,
Hebert SC,
Matsuno S,
Kondo H,
and
Yawo H.
Molecular characterization and tissue distribution of a new organic anion transporter subtype (oatp3) that transports thyroid hormones and taurocholate and comparison with oatp2.
J Biol Chem
273:
22395-22401,
1998
2.
Akhteruzzaman S, Kato Y, Hisaka A, and Sugiyama Y. Primary active
transport of peptidic endothelin antagonists by rat hepatic canalicular
membrane. J Pharmacol Exp Ther 575-581, 1999.
3.
Apiwattanakul, N,
Sekine T,
Chairoungdua A,
Kanai Y,
Nakajima N,
Sophasan S,
and
Endou H.
Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes.
Mol Pharmacol
55:
847-854,
1999
4.
Balimane, PV,
Tamai I,
Guo A,
Nakanishi T,
Kitada H,
Leibach FH,
Tsuji A,
and
Sinko PJ.
Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir.
Biochem Biophys Res Commun
250:
246-251,
1998[ISI][Medline].
5.
Belinsky, MG,
Bain LJ,
Balsara BB,
Testa JR,
and
Kruh GD.
Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily of transporter proteins.
J Natl Cancer Inst
90:
1735-1741,
1998
6.
Bennett, WM.
Insights into chronic cyclosporine nephrotoxicity.
Int J Clin Pharmacol Ther
34:
515-519,
1996[ISI][Medline].
7.
Bergwerk, AJ,
Shi X,
Ford AC,
Kanai N,
Jacquemin E,
Burk RD,
Bai S,
Novikoff PM,
Stieger B,
Meier PJ,
Schuster VL,
and
Wolkoff AW.
Immunologic distribution of an organic anion transport protein in rat liver and kidney.
Am J Physiol Gastrointest Liver Physiol
271:
G231-G238,
1996
8.
Bissig, M,
Hagenbuch B,
Stieger B,
Koller T,
and
Meier P.
Functional expression cloning of the canalicular sulfate transport system of rat hepatocytes.
J Biol Chem
28:
3017-3021,
1994.
9.
Boll, M,
Herget M,
Wagener M,
Weber WM,
Markovich D,
Biber J,
Clauss W,
Murer H,
and
Daniel H.
Expression cloning and functional characterization of the kidney cortex high-affinity proton-coupled peptide transporter.
Proc Natl Acad Sci USA
93:
284-289,
1996
10.
Boll, M,
Markovich D,
Weber WM,
Korte H,
Daniel H,
and
Murer H.
Expression cloning of a cDNA from rabbit small intestine related to proton-coupled transport of peptides, beta-lactam antibiotics and ACE-inhibitors.
Pflügers Arch
429:
146-149,
1994[ISI][Medline].
11.
Boyde, A,
Capasso G,
and
Unwin RJ.
Conventional and confocal epi-reflection and fluorescence microscopy of the rat kidney in vivo.
Exp Nephrol
6:
398-408,
1998[ISI][Medline].
12.
Brady, KP,
Dushkin H,
Fornzler D,
Koike T,
Magner F,
Her H,
Gullans S,
Segre GV,
Green RM,
and
Beier DR.
A novel putative transporter maps to the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse.
Genomics
56:
254-261,
1999[ISI][Medline].
13.
Brown, D.
Epithelial cell polarity: molecular mechanisms.
In: Molecular Nephrology, edited by Sclöndorff D,
and Bonventre JV.. New York: Dekker, 1995, p. 21-32. (Kidney Function Health Dis)
14.
Büchler, M,
König J,
Brom M,
Kartenbeck J,
Spring H,
Horie T,
and
Keppler D.
cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats.
J Biol Chem
271:
15091-15098,
1996
15.
Campbell, JA,
Bass NM,
and
Kirsch RE.
Immunohistological localization of ligandin in human tissues.
Cancer
45:
503-510,
1980[ISI][Medline].
16.
Chatsudthipong, V,
and
Dantzler WH.
PAH/alpha-KG countertransport stimulates PAH uptake and net secretion in isolated rabbit renal tubules.
Am J Physiol Renal Fluid Electrolyte Physiol
263:
F384-F391,
1992
17.
Che, M,
Ortiz DF,
and
Arias IM.
Primary structure and functional expression of a cDNA encoding the bile canalicular, purine-specific Na(+)-nucleoside cotransporter.
J Biol Chem
270:
13596-13599,
1995
18.
Chen, X,
Tsukaguchi H,
Chen X-Z,
Berger UV,
and
Hediger MA.
Molecular and functional analysis of SDCT2, a novel rat sodium-dependent dicarboxylate transporter.
J Clin Invest
103:
1159-1168,
1999
19.
Cole, SPC,
Bhardwaj G,
Gerlach JH,
Mackie JE,
Grant CE,
Almquist KC,
Stewart AJ,
Kurz EU,
Duncan AM,
and
Deeley RG.
Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.
Science
258:
1650-1654,
1992[ISI][Medline].
20.
Cole, SPC,
and
Deeley RG.
Multidrug resistance mediated by the ATP-binding cassette transport protein MRP.
Bioessays
20:
931-940,
1998[ISI][Medline].
21.
Cole, SPC,
Sparks KE,
Fraser K,
Loe DW,
Grant CE,
Wilson GM,
and
Deeley RG.
Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells.
Cancer Res
54:
5902-5910,
1994[Abstract].
22.
Commandeur, JN,
Stijntjes GJ,
and
Vermeulen NP.
Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics.
Pharmacol Rev
47:
271-330,
1995[ISI][Medline].
23.
Cui, Y,
König J,
Buchholz U,
Spring H,
Leier I,
and
Keppler D.
Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells.
Mol Pharmacol
55:
929-937,
1999
24.
Dahlmann, A,
Dantzler WH,
Silbernagl S,
and
Gekle M.
Detailed mapping of ochratoxin A reabsorption along the rat nephron in vivo: the nephrotoxin can be reabsorbed in all nephron segments by different mechanisms.
J Pharmacol Exp Ther
286:
157-162,
1998
25.
Daley Yates, PT,
and
McBrien DC.
Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin.
Biochem Pharmacol
33:
3063-3070,
1984[ISI][Medline].
26.
Daniel, H,
and
Herget M.
Cellular and molecular mechanisms of renal peptide transport.
Am J Physiol Renal Physiol
273:
F1-F8,
1997
27.
Dekant, W,
and
Vamvakas S.
Biotransformation and membrane transport in nephrotoxicity.
Crit Rev Toxicol
26:
309-334,
1996[ISI][Medline].
28.
Delacruz, L,
and
Bach PH.
The role of ochratoxin A metabolism and biochemistry in animal and human nephrotoxicity.
J Biopharm Sci
1:
277-304,
1990.
29.
De Vries, MH,
Redegeld FA,
Koster AS,
Noordhoek J,
de Haan JG,
Oude Elferink RPJ,
and
Jansen PLM
Hepatic, intestinal and renal transport of 1-naphthol-beta-D-glucuronide in mutant rats with hereditary-conjugated hyperbilirubinemia.
Naunyn Schmiedebergs Arch Pharmacol
340:
588-592,
1989[ISI][Medline].
30.
Doring, F,
Walter J,
Will J,
Focking M,
Boll M,
Amasheh S,
Clauss W,
and
Daniel H.
Delta-aminolevulinic acid transport by intestinal and renal peptide transporters and its physiological and clinical implications.
J Clin Invest.
101:
2761-2767,
1998
31.
Eckhardt, U,
Schroeder A,
Stieger B,
Hochli M,
Landmann L,
Tynes R,
Meier PJ,
and
Hagenbuch B.
Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells.
Am J Physiol Gastrointest Liver Physiol
276:
G1037-G1042,
1999
32.
Evers, R,
Cnubben NHP,
Wijnholds J,
van Deemter L,
van Bladeren PJ,
and
Borst P.
Transport of glutathione prostaglandin A conjugates by the multidrug resistance protein 1.
FEBS Lett
419:
112-116,
1997[ISI][Medline].
33.
Evers, R,
Kool M,
van Deemter L,
Janssen H,
Calafat J,
Oomen LCJM,
Paulusma CC,
Oude Elferink RPJ,
Baas F,
Schinkel AH,
and
Borst P.
Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA.
J Clin Invest
101:
1310-1319,
1998
34.
Evers, R,
Zaman GJR,
van Deemter L,
Jansen H,
Calafat J,
Oomen LCJM,
Oude Elferink RPJ,
Borst P,
and
Schinkel AH.
Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells.
J Clin Invest
97:
1211-1218,
1996
35.
Fang, X,
Parkinson FE,
Mowles DA,
Young JD,
and
Cass CE.
Functional characterization of a recombinant sodium-dependent nucleoside transporter with selectivity for pyrimidine nucleosides (cNT1 rat) by transient expression in cultured mammalian cells.
Biochem J
317:
457-465,
1996[ISI][Medline].
36.
Fei, YJ,
Kanai Y,
Nussberger S,
Ganapathy V,
Leibach FH,
Romero MF,
Singh SK,
Boron WF,
and
Hediger MA.
Expression cloning of a mammalian proton-coupled oligopeptide transporter.
Nature
368:
563-566,
1994[ISI][Medline].
37.
Felipe, A,
Valdes R,
delSanto B,
Lloberas J,
Casado J,
and
PastorAnglada M.
Na+-dependent nucleoside transport in liver: two different isoforms from the same gene family are expressed in liver cells.
Biochem J
330:
997-1001,
1998[ISI][Medline].
38.
Flens, MJ,
Zaman GJR,
van der Valk P,
Izquierdo MA,
Schroeiers AB,
Scheffer GL,
van der Groep P,
de Haas M,
Meijer CJLM,
and
Scheper RJ.
Tissue distribution of the multidrug resistance protein.
Am J Pathol
148:
1237-1247,
1996[Abstract].
39.
Franco, R,
Centelles JJ,
and
Kinne RK.
Further characterization of adenosine transport in renal brush-border membranes.
Biochim Biophys Acta
1024:
241-248,
1990[ISI][Medline].
40.
Friesema, ECH,
Docter R,
Moerings EPCM,
Stieger B,
Hagenbuch B,
Meier PJ,
Krenning EP,
Hennemann G,
and
Visser TJ.
Identification of thyroid hormone transporters.
Biochem Biophys Res Commun
254:
497-501,
1999[ISI][Medline].
41.
Fromm, MF,
Leake B,
Roden DM,
Wilkinson GR,
and
Kim RB.
Human MRP3 transporter: identification of the 5'-flanking region, genomic organization and alternative splice variants.
Biochim Biophys Acta
1415:
369-374,
1999[ISI][Medline].
42.
Ganapathy, ME,
Brandsch M,
Prasad PD,
Ganapathy V,
and
Leibach FH.
Differential recognition of beta -lactam antibiotics by intestinal and renal peptide transporters, PEPT 1 and PEPT 2.
J Biol Chem
270:
25672-25677,
1995
43.
Ganapathy, ME,
Huang W,
Wang H,
Ganapathy V,
and
Leibach FH.
Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2.
Biochem Biophys Res Commun
246:
470-475,
1998[ISI][Medline].
44.
Ganapathy, ME,
Prasad PD,
Mackenzie B,
Ganapathy V,
and
Leibach FH.
Interaction of anionic cephalosporins with the intestinal and renal peptide transporters PEPT 1 and PEPT 2.
Biochim Biophys Acta
1324:
296-308,
1997[ISI][Medline].
45.
Gekle, M,
Mildenberger S,
Sauvant C,
Bednarczyk D,
Wright SH,
and
Dantzler WH.
Inhibition of initial transport rate of basolateral organic anion carrier in renal PT by BK and phenylephrine.
Am J Physiol Renal Physiol
277:
F251-F256,
1999
46.
Gekle, M,
and
Silbernagl S.
The role of the proximal tubule in ochratoxin A nephrotoxicity in vivo: toxodynamic and toxokinetic aspects.
Renal Physiol Biochem
17:
40-49,
1994[ISI][Medline].
47.
Goldberg, JP,
and
Anderson RJ.
Renal metabolism and excretion of drugs.
In: The Kidney: Physiology and Pathophysiology, edited by Seldin DW,
and Giebisch G.. New York: Raven, 1985, p. 2097-2110.
48.
Goldstein, EJ,
and
Arias IM.
Interaction of ligandin with radiographic contrast media.
Invest Radiol
11:
594-597,
1976[ISI][Medline].
49.
Grant, CE,
Valdimarsson G,
Hipfner DR,
Almquist KC,
Cole SPC,
and
Deeley RG.
Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs.
Cancer Res
54:
357-361,
1994[Abstract].
50.
Gutierrez, MM,
and
Giacomini KM.
Substrate selectivity, potential sensitivity and stoichiometry of Na(+)-nucleoside transport in brush border membrane vesicles from human kidney.
Biochim Biophys Acta
1149:
202-208,
1993[ISI][Medline].
51.
Haase, W,
Schafer A,
Murer H,
and
Kinne R.
Studies on the orientation of brush-border membrane vesicles.
Biochem J
172:
57-62,
1978[ISI][Medline].
52.
Hagenbuch, B,
Stange G,
and
Murer H.
Transport of sulphate in rat jejunal and rat proximal tubular basolateral membrane vesicles.
Pflügers Arch
405:
202-208,
1985[ISI][Medline].
53.
Halpin, PA,
and
Renfro JL.
Renal organic anion secretion: evidence for dopaminergic and adrenergic regulation.
Am J Physiol Regulatory Integrative Comp Physiol
271:
R1372-R1379,
1996
54.
Han, H,
de Vrueh RL,
Rhie JK,
Covitz KM,
Smith PL,
Lee CP,
Oh DM,
Sadee W,
and
Amidon GL.
5'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter.
Pharmacol Res
15:
1154-1159,
1998.
55.
Heany, C,
Shalev H,
Elbedour K,
Carmi R,
Staack JB,
Sheffield VC,
and
Beier DR.
Human autosomal recessive osteopetrosis maps to 11q13, a position predicted by comparative mapping of the murine osteosclerosis (oc) mutation.
Hum Mol Genet
7:
1407-1414,
1998
56.
Hirohashi, T,
Suzuki H,
Ito K,
Ogawa K,
Kume K,
Shimizu T,
and
Sugiyama Y.
Hepatic expression of multidrug resistance-associated protein-like proteins maintained in Eisai hyperbilirubinemic rats.
Mol Pharmacol
53:
1068-1075,
1998
57.
Hirohashi, T,
Suzuki H,
and
Sugiyama Y.
Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3).
J Biol Chem
274:
15181-15185,
1999
58.
Hosoyamada, M,
Sekine T,
Kanai Y,
and
Endou H.
Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney.
Am J Physiol Renal Physiol
276:
F122-F128,
1999
59.
Huang, Q,
Yao S,
Ritzel M,
Paterson A,
Cass C,
and
Young J.
Cloning and functional expression of a complementary DNA encoding a mammalian nucleoside transport protein.
J Biol Chem
269:
17757-17760,
1994
60.
Hughey, RP,
Rankin BB,
Elce JS,
and
Curthoys NP.
Specificity of a particulate rat renal peptidase and its localization along with other enzymes of mercapturic acid synthesis.
Arch Biochem Biophys
186:
211-217,
1978[ISI][Medline].
61.
Hume, R,
Coughtrie MW,
and
Burchell B.
Differential localisation of UDP-glucuronosyltransferase in kidney during human embryonic and fetal development.
Arch Toxicol
69:
242-247,
1995[ISI][Medline].
62.
Ishikawa, T,
Müller M,
Klünemann C,
Schaub TP,
and
Keppler D.
ATP-dependent primary active transport of cysteinyl leukotrienes across liver canalicular membranes.
J Biol Chem
265:
19279-19286,
1990
63.
Ishizuka, H,
Konno K,
Naganuma H,
Nishimura K,
Kouzuki H,
Suzuki H,
Stieger B,
Meier PJ,
and
Sugiyama Y.
Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide.
J Pharmacol Exp Ther
287:
37-42,
1998
64.
Ishizuka, H,
Konno K,
Naganuma H,
Sasahara K,
Kawahara Y,
Niinuma K,
Suzuki H,
and
Sugiyama Y.
Temocaprilat, a novel angiotensin-converting enzyme inhibitor, is excreted in bile via an ATP-dependent active transporter (cMOAT) that is deficient in Eisai hyperbilirubinemic mutant rats (EHBR).
J Pharmacol Exp Ther
280:
1304-1311,
1997
65.
Ito, K,
Suzuki H,
Hirohashi T,
Kume K,
Shimizu T,
and
Sugiyama Y.
Molecular cloning of canalicular multispecific organic anion transporter defective in EHBR.
Am J Physiol Gastrointest Liver Physiol
272:
G16-G22,
1997
66.
Ito, K,
Suzuki H,
Hirohashi T,
Kume K,
Shimizu T,
and
Sugiyama Y.
Functional analysis of a canalicular multispecific organic anion transporter cloned from rat liver.
J Biol Chem
273:
1684-1688,
1998
67.
Jacquemin, E,
Hagenbuch B,
Stieger B,
Wolkoff AW,
and
Meier PJ.
Expression cloning of a rat liver Na(+)-independent organic anion transporter.
Proc Natl Acad Sci USA
91:
133-137,
1994[Abstract].
68.
Jedlitschky, G,
Leier I,
Buchholz U,
Barnouin K,
Kurz G,
and
Keppler D.
Transport of glutathione, glucuronate and sulfate conjugates by the MRP gene-encoded conjugate export pump.
Cancer Res
56:
988-994,
1996[Abstract].
69.
Jedlitschky, G,
Leier I,
Buchholz U,
Hummel-Eisenbeiss J,
Burchell B,
and
Keppler D.
ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2.
Biochem J
327:
305-310,
1997[ISI][Medline].
70.
Kanai, N,
Lu R,
Bao Y,
Wolkoff AW,
and
Schuster VL.
Transient expression of Oatp organic anion transporter in mammalian cells: identification of candidate substrates.
Am J Physiol Renal Fluid Electrolyte Physiol
270:
F319-F325,
1996
71.
Kanai, N,
Lu R,
Bao Y,
Wolkoff AW,
Vore M,
and
Schuster VL.
Estradiol 17 beta-D-glucuronide is a high-affinity substrate for oatp organic anion transporter.
Am J Physiol Renal Fluid Electrolyte Physiol
270:
F326-F331,
1996
72.
Karniski, LP,
Lotscher M,
Fucentese M,
Hilfiker H,
Biber J,
and
Murer H.
Immunolocalization of sat-1 sulfate/oxalate/bicarbonate anion exchanger in the rat kidney.
Am J Physiol Renal Physiol
275:
F79-F87,
1998
73.
Kartenbeck, J,
Leuschner U,
Mayer R,
and
Keppler D.
Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson Syndrome.
Hepatology
23:
1061-1066,
1996[ISI][Medline].
74.
Keppler, D,
and
König J.
Expression and localisation of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver.
FASEB J
11:
509-516,
1997
75.
Keppler, D,
König J,
Schaub TP,
and
Leier I.
Molecular basis of ATP-dependent transport of anionic conjugates in kidney and liver.
In: Renal and Hepatic TransportSimilarities and Differences, edited by Fleck C,
Klinger W,
and Muller D.. Halle, Germany: Nova Acta Leopoldina, 1998, p. 213-221.
76.
Kirsch, R,
Fleischner G,
Kamisaka K,
and
Arias IM.
Structural and functional studies of ligandin, a major renal organic anion-binding protein.
J Clin Invest
55:
1009-1019,
1975[ISI][Medline].
77.
Kiuchi, Y,
Suzuki H,
Hirohashi T,
Tyson CA,
and
Sugiyama Y.
cDNA cloning and inducable expression of the human multidrug resistance-associated protein 3 (MRP3).
FEBS Lett
433:
149-152,
1998[ISI][Medline].
78.
Kobayashi, K,
Komatsu S,
Nishi T,
Hara H,
and
Hayashi K.
ATP-dependent transport for glucuronides in canalicular plasma membrane vesicles.
Biochem Biophys Res Com
176:
622-626,
1991[ISI][Medline].
79.
Koepsell, H,
Gorboulev V,
and
Arndt P.
Molecular pharmacology of organic cation transporters in kidney.
J Membr Biol
167:
103-117,
1999[ISI][Medline].
80.
Koike, K,
Kawabe T,
Tanaka T,
Toh S,
Uchiumi T,
Wada M,
Akiyama S-I,
Ono M,
and
Kuwano M.
A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells.
Cancer Res
57:
5475-5479,
1997[Abstract].
81.
König, J,
Rost D,
Cui Y,
and
Keppler D.
Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane.
Hepatology
29:
1156-1163,
1999[ISI][Medline].
82.
Kool, M,
de Haas M,
Scheffer GL,
Scheper RJ,
van Eijk MJT,
Juijn JA,
Baas F,
and
Borst P.
Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1) in human cancer cell lines.
Cancer Res
57:
3537-3547,
1997[Abstract].
83.
Kool, M,
van der Linden M,
de Haas M,
Baas F,
and
Borst P.
Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells.
Cancer Res
59:
175-182,
1999
84.
Kool, M,
van der Linden M,
de Haas M,
Scheffer GL,
de Vree JML,
Smith AJ,
Jansen G,
Peters GJ,
Ponne N,
Scheper RJ,
Oude Elferink RPJ,
Baas F,
and
Borst P.
MRP3, an organic anion transporter able to transport anti-cancer drugs.
Proc Natl Acad Sci USA
96:
6914-6919,
1999
85.
Kuo, SM,
and
Aronson PS.
Oxalate transport via the sulfate/HCO3 exchanger in rabbit renal basolateral membrane vesicles.
J Biol Chem
263:
9710-9717,
1988
86.
Kusuhara, H,
Han YH,
Shimoda M,
Kokue E,
Suzuki H,
and
Sugiyama Y.
Reduced folate derivatives are endogenous substrates for cMOAT in rats.
Am J Physiol Gastrointest Liver Physiol
275:
G789-G796,
1998
87.
Kusuhara, H,
Sekine T,
Utsunomiya-Tata N,
Tsuda M,
Kojima R,
Cha SH,
Sugiyama Y,
Kanai Y,
and
Endou H.
Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain.
J Biol Chem
274:
13675-13680,
1999
88.
Kuze, K,
Graves P,
Leahy A,
Wilson P,
Stuhlmann H,
and
You G.
Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells.
J Biol Chem
274:
1519-1524,
1999
89.
Lee, K,
Martin G,
Bell DW,
Testa JR,
and
Kruh GD.
Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/ canalicular multispecific organic anion transporter-related transporter.
Cancer Res
58:
2741-2747,
1998[Abstract].
90.
Leibach, FH,
and
Ganapathy V.
Peptide transporters in the intestine and the kidney.
Annu Rev Nutr
16:
99-119,
1996[ISI][Medline].
91.
Leier, I,
Jedlitschky G,
Buchholz U,
Center M,
Cole SPC,
Deeley RG,
and
Keppler D.
ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump.
Biochem J
314:
433-437,
1996[ISI][Medline].
92.
Leier, I,
Jedlitschky G,
Buchholz U,
Cole SPC,
Deeley RG,
and
Keppler D.
The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates.
J Biol Chem
269:
27807-27810,
1994
93.
Li, LQ,
Lee TK,
Meier PJ,
and
Ballatori N.
Identification of glutathione as a driving force and leukotriene C4 as a substrate for oatp1, the hepatic sinusoidal organic anion solute transporter.
J Biol Chem
273:
16184-16191,
1998
94.
Liang, R,
Fei YJ,
Prasad PD,
Ramamoorthy S,
Han H,
Yang Feng TL,
Hediger MA,
Ganapathy V,
and
Leibach FH.
Human intestinal H+/peptide cotransporter. Cloning, functional expression, and chromosomal localization.
J Biol Chem
270:
6456-6463,
1995
95.
Litwack, G,
Ketterer B,
and
Arias IM.
Ligandin: a hepatic protein which binds steroids, bilirubin, carcinogens and a number of exogenous organic anions.
Nature
234:
466-467,
1971[ISI][Medline].
96.
Lock, EA,
and
Reed CJ.
Xenobiotic metabolizing enzymes of the kidney.
Toxicol Pathol
26:
18-25,
1998[ISI][Medline].
97.
Loe, DW,
Almquist KC,
Cole SPC,
and
Deeley RG.
ATP-dependent 17-D-estradiol 17-(
-D-glucuronide) transport by multidrug resistance protein (MRP).
J Biol Chem
271:
9683-9689,
1996
98.
Loe, DW,
Almquist KC,
Deeley RG,
and
Cole SPC
Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles.
J Biol Chem
271:
9675-9682,
1996
99.
Loe, DW,
Deeley RG,
and
Cole SPC
Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione.
Cancer Res
58:
5130-5136,
1998[Abstract].
100.
Loe, DW,
Stewart RK,
Massey TE,
Deeley RG,
and
Cole SPC
ATP-dependent transport of aflatoxin B1 and its glutathione conjugates by the product of the multidrug resistance protein (MRP) gene.
Mol Pharmacol
51:
1034-1041,
1997
101.
Lohr, JW,
Willsky GR,
and
Acara MA.
Renal drug metabolism.
Pharmacol Rev
50:
107-141,
1998
102.
Lopez Nieto, CE,
You G,
Bush KT,
Barros EJ,
Beier DR,
and
Nigam SK.
Molecular cloning and characterization of NKT, a gene product related to the organic cation transporter family that is almost exclusively expressed in the kidney.
J Biol Chem
272:
6471-6478,
1997
103.
Lorico, A,
Rappa G,
Finch RA,
Yang D,
Flavell RA,
and
Sartorelli AC.
Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione.
Cancer Res
57:
5238-5242,
1997[Abstract].
104.
Lu, R,
Chan BS,
and
Schuster VL.
Cloning of the human kidney PAH transporter: narrow substrate specificity and regulation by protein kinase C.
Am J Physiol Renal Physiol
276:
F295-F303,
1999
105.
Madon, J,
Eckhardt U,
Gerloff T,
Stieger B,
and
Meier PJ.
Functional expression of the rat liver canalicular isoform of the multidrug resistance-associated protein.
FEBS Lett
406:
75-78,
1997[ISI][Medline].
106.
Madon, J,
Hagenbuch B,
Landmann L,
Meier PJ,
and
Stieger B.
Transport function and hepatocellular localization of mrp6 in rat liver.
Mol Pharmacol
57:
634-641,
2000
107.
Masereeuw, R,
Moons MM,
Toomey BH,
Russel FGM,
and
Miller DS.
Active Lucifer Yellow secretion in renal proximal tubule: evidence for organic anion transport system crossover.
J Pharmacol Exp Ther
289:
1104-1111,
1999
108.
Masereeuw, R,
Russel FGM,
and
Miller DS.
Multiple pathways of organic anion secretion in renal proximal tubule revealed by confocal microscopy.
Am J Physiol Renal Fluid Electrolyte Physiol
271:
F1173-F1182,
1996
109.
Masereeuw, R,
Saleming WC,
Miller DS,
and
Russel FG.
Interaction of fluorescein with the dicarboxylate carrier in rat kidney cortex mitochondria.
J Pharmacol Exp Ther
279:
1559-1565,
1996[Abstract].
110.
Masereeuw, R,
Terlouw SA,
van Aubel RAMH,
Russel FGM,
and
Miller DS.
Endothelin B receptor-mediated regulation of ATP-driven drug secretion in renal proximal tubule.
Mol Pharmacol
57:
59-67,
2000
111.
Masereeuw, R,
van den Bergh EJ,
Bindels RJ,
and
Russel FG.
Characterization of fluorescein transport in isolated proximal tubular cells of the rat: evidence for mitochondrial accumulation.
J Pharmacol Exp Ther
269:
1261-1267,
1994[Abstract].
112.
Masuda, M,
Ibaramoto K,
Takeuchi A,
Saito H,
Hashimoto Y,
and
Inui KI.
Cloning and functional characterization of a new multispecific organic anion transporter, OAT-K2, in rat kidney.
Mol Pharmacol
55:
743-753,
1999
113.
Masuda, M,
I'izuka Y,
Yamazaki M,
Nishigaki R,
Kato Y,
Ni'inuma K,
Suzuki H,
and
Sugiyama Y.
Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats.
Cancer Res
57:
3506-3510,
1997[Abstract].
114.
Masuda, M,
Takeuchi A,
Saito H,
Hashimoto Y,
and
Inui K-I.
Functional analysis of rat renal organic anion transporter OAT-K1: bidirectional methotrexate transport in apical membrane.
FEBS Lett
459:
128-132,
1999[ISI][Medline].
115.
Masuda, S,
Saito H,
and
Inui K-I.
Interactions of nonsteroidal anti-inflammatory drugs with rat renal organic anion transporter, OAT-K1.
J Pharmacol Exp Ther
283:
1039-1042,
1997
116.
Masuda, S,
Saito H,
Nonoguchi H,
Tomita K,
and
Inui K-I.
mRNA distribution and membrane localization of the OAT-K1 organic anion transporter in rat renal tubules.
FEBS Lett
407:
127-131,
1997[ISI][Medline].
117.
McAleer, MA,
Breen MA,
White NL,
and
Matthews N.
pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells.
J Biol Chem
274:
23541-23548,
1999
118.
Meier, PJ,
Eckhardt U,
Schroeder A,
Hagenbuch B,
and
Stieger B.
Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver.
Hepatology
26:
1667-1677,
1997[ISI][Medline].
119.
Merlin, D,
Steel A,
Gewirtz AT,
Si Tahar M,
Hediger MA,
and
Madara JL.
hPepT1-mediated epithelial transport of bacteria-derived chemotactic peptides enhances neutrophil-epithelial interactions.
J Clin Invest
102:
2011-2018,
1998
120.
Miller, DS.
Protein kinase C regulation of organic anion transport in renal proximal tubule.
Am J Physiol Renal Physiol
274:
F156-F164,
1998
121.
Miller, DS,
Barnes DM,
and
Pritchard JB.
Confocal microscopic analysis of fluorescein compartmentation within crab urinary bladder cells.
Am J Physiol Regulatory Integrative Comp Physiol
267:
R16-R25,
1994
122.
Miller, DS,
Letcher S,
and
Barnes DM.
Fluorescence imaging study of organic anion transport from renal proximal tubule cell to lumen.
Am J Physiol Renal Fluid Electrolyte Physiol
271:
F508-F520,
1996
123.
Miller, DS,
and
Pritchard JB.
Nocodazole inhibition of organic anion secretion in teleost renal proximal tubules.
Am J Physiol Regulatory Integrative Comp Physiol
267:
R695-R704,
1994
124.
Miller, DS,
Stewart DE,
and
Pritchard JB.
Intracellular compartmentation of organic anions within renal cells.
Am J Physiol Regulatory Integrative Comp Physiol
264:
R882-R890,
1993
125.
Miyamoto, K,
Shiraga T,
Morita K,
Yamamoto H,
Haga H,
Taketani Y,
Tamai I,
Sai Y,
Tsuji A,
and
Takeda E.
Sequence, tissue distribution and developmental changes in rat intestinal oligopeptide transporter.
Biochim Biophys Acta
1305:
34-38,
1996[ISI][Medline].
126.
Miyamoto, Y,
Coone JL,
Ganapathy V,
and
Leibach FH.
Distribution and properties of the glycylsarcosine-transport system in rabbit renal proximal tubule. Studies with isolated brush-border-membrane vesicles.
Biochem J
249:
247-253,
1988[ISI][Medline].
127.
Miyamoto, Y,
Ganapathy V,
and
Leibach FH.
Proton gradient-coupled uphill transport of glycylsarcosine in rabbit renal brush-border membrane vesicles.
Biochem Biophys Res Commun
132:
946-953,
1985[ISI][Medline].
128.
Monks, TJ,
and
Lau SS.
Renal transport processes and glutathione conjugate-mediated nephrotoxicity.
Drug Metab Dispos
15:
437-441,
1987[ISI][Medline].
129.
Müller, M,
Meijer CJLM,
Borst P,
Scheper RJ,
Mulder NH,
de Vries EG,
and
Jansen PLM
Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport.
Proc Natl Acad Sci USA
91:
13033-13037,
1994
130.
Muraoka, I,
Hasegawa T,
Nadai M,
Wang L,
Haghgoo S,
Tagaya O,
and
Nabeshima T.
Biliary and renal excretions of cefpiramide in Eisai hyperbilirubinemic rats.
Antimicrob Agents Chemother
39:
70-74,
1995[Abstract].
131.
Murata, M,
Tamai I,
Sai Y,
Nagata O,
Kato H,
Sugiyama Y,
and
Tsuji A.
Hepatobiliary transport kinetics of HSR-903, a new quinolone antibacterial agent.
Drug Metab Dispos
26:
1113-1119,
1998
132.
Newton, JF,
Pasino DA,
and
Hook JB.
Acetaminophen nephrotoxicity in the rat: quantitation of renal metabolic activation in vivo.
Toxicol Appl Pharmacol
78:
39-46,
1985[ISI][Medline].
133.
Nies, AT,
Cantz T,
Brom M,
Leier I,
and
Keppler D.
Expression of the apical conjugate export pump, Mrp2, in the polarized hepatoma cell line, WIF-B.
Hepatology
28:
1332-1340,
1998[ISI][Medline].
134.
Niinuma, K,
Takenaka O,
Horie T,
Kobayashi K,
Kato Y,
Suzuki H,
and
Sugiyama Y.
Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane: comparative study of S-(2,4-dinitrophenyl)-glutathione and 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole glucuronide.
J Pharmacol Exp Ther
282:
866-872,
1997
135.
Oude Elferink, RPJ,
and
Jansen PLM
The role of the canalicular multispecific organic anion transporter in the disposal of endo- and xenobiotics.
Pharmacol Ther
64:
77-97,
1994[ISI][Medline].
136.
Pajor, AM.
Sequence of a pyrimidine-selective Na+/nucleoside cotransporter from pig kidney, pkCNT1.
Biochim Biophys Acta
1415:
266-269,
1998[ISI][Medline].
137.
Pang, KS,
Wang PJ,
Chung AYK,
and
Wolkoff AW.
The modified dipeptide, enalapril, an angiotensin-converting enzyme inhibitor, is transported by the rat liver organic anion transport protein.
Hepatology
28:
1341-1346,
1998[ISI][Medline].
138.
Pastor-Anglada, M,
Felipe A,
and
Javier Casado F.
Transport and mode of action of nucleoside derivatives used in chemical and antiviral therapies.
Trends Pharmacol Sci
19:
424-430,
1998[ISI][Medline].
139.
Paulusma, CC,
Bosma PJ,
Zaman GJR,
Bakker CTM,
Otter M,
Scheffer GL,
Scheper RJ,
Borst P,
and
Oude Elferink RPJ
Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene.
Science
271:
1126-1128,
1996[Abstract].
140.
Paulusma, CC,
Kool M,
Bosma PJ,
Scheffer GL,
ter Borg F,
Scheper RJ,
Tytgat GNJ,
Borst P,
Baas F,
and
Oude Elferink RPJ
A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome.
Hepatology
25:
1539-1542,
1997[ISI][Medline].
141.
Paulusma, CC,
van Geer M,
Evers R,
Heijn M,
Ottenhoff R,
Borst P,
and
Oude Elferink RPJ
Canalicular multispecific organic anion transporter/multidrug resistance protein 2 mediates low-affinity transport of reduced glutathione.
Biochem J
338:
393-401,
1999[ISI][Medline].
142.
Pegg, DG,
and
Hook JB.
Glutathione S-transferases: an evaluation of their role in renal organic anion transport.
J Pharmacol Exp Ther
200:
65-74,
1977[Abstract].
143.
Peng, K-C,
Cluzeaud F,
Bens M,
Duong van Huyen J-P,
Wioland MA,
Lacave R,
and
Vandewalle A.
Tissue and cell distribution of the multidrug resistance-associated protein (MRP) on mouse intestine and kidney.
J Histochem Cytochem
47:
757-767,
1999
144.
Priebe, W,
Krawczyk M,
Kuo MT,
Yamane Y,
Savaraj N,
and
Ishikawa T.
Doxorubicin- and daunorubicin-glutathione conjugates, but not unconjugated drugs, competitively inhibit leukotriene C-4 transport mediated by MRP/GS-X pump.
Biochem Biophys Res Commun
247:
859-863,
1998[ISI][Medline].
145.
Pritchard, JB.
Intracellular alpha-ketoglutarate controls the efficacy of renal organic anion transport.
J Pharmacol Exp Ther
274:
1278-1284,
1995[Abstract].
146.
Pritchard, JB,
and
Miller DS.
Mechanisms mediating renal secretion of organic anions and cations.
Physiol Rev
73:
765-796,
1993
147.
Pritchard, JB,
and
Renfro JL.
Renal sulfate transport at the basolateral membrane is mediated by anion exchange.
Proc Natl Acad Sci USA
80:
2603-2607,
1983[Abstract].
148.
Pulaski, L,
Jedlitschky G,
Leier I,
Buchholz U,
and
Keppler D.
Identification of the multidrug-resistance protein (MRP) as the glutathione-S-conjugate export pump of erythrocytes.
Eur J Biochem
241:
644-648,
1996[Abstract].
149.
Race, JE,
Grassl SM,
Williams WJ,
and
Holtzman EJ.
Molecular cloning and characterization of two novel human renal organic anion transporters (hOAT1 and hOAT3).
Biochem Biophys Res Com
255:
508-514,
1999[ISI][Medline].
150.
Ramamoorthy, S,
Liu W,
Ma YY,
Yang Feng TL,
Ganapathy V,
and
Leibach FH.
Proton/peptide cotransporter (PEPT 2) from human kidney: functional characterization and chromosomal localization.
Biochim Biophys Acta
1240:
1-4,
1995[ISI][Medline].
151.
Reid, G,
Wolff NA,
Dautzenberg FM,
and
Burckhardt G.
Cloning of a human renal p-aminohippurate transporter, hROAT1.
Kidney Blood Press Res
21:
233-237,
1998[ISI][Medline].
152.
Ritzel, MW,
Yao SY,
Huang MY,
Elliott JF,
Cass CE,
and
Young JD.
Molecular cloning and functional expression of cDNAs encoding a human Na+-nucleoside cotransporter (hCNT1).
Am J Physiol Cell Physiol
272:
C707-C714,
1997
153.
Ritzel, MWL,
Yao SYM,
Ng AML,
Mackey JR,
Cass CE,
and
Young JD.
Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine.
Mol Membr Biol
15:
203-211,
1998[ISI][Medline].
154.
Roch-Ramel, F.
Renal transport of organic anions.
Curr Opin Nephrol Hypertens
7:
517-524,
1998[ISI][Medline].
155.
Roelofsen, H,
Ottenhoff R,
Oude Elferink RPJ,
and
Jansen PLM
Hepatocanalicular organic-anion transport is regulated by protein kinase C.
Biochem J
278:
637-641,
1991[ISI][Medline].
156.
Roelofsen, H,
Soroka CJ,
Keppler D,
and
Boyer JL.
Cyclic AMP stimulates sorting of the canalicular organic anion transporter (Mrp2/cMoat) to the apical domain in hepatocyte couplets.
J Cell Sci
111:
1137-1145,
1998
157.
Saito, H,
Masuda S,
and
Inui K-I.
Cloning and functional characterization of a novel rat organic anion transporter mediating basolateral uptake of methotrexate in the kidney.
J Biol Chem
271:
20719-20725,
1996
158.
Saito, H,
Okuda M,
Terada T,
Sasaki S,
and
Inui K.
Cloning and characterization of a rat H+/peptide cotransporter mediating absorption of beta-lactam antibiotics in the intestine and kidney.
J Pharmacol Exp Ther
275:
1631-1637,
1995[Abstract].
159.
Saito, H,
Terada T,
Okuda M,
Sasaki S,
and
Inui K.
Molecular cloning and tissue distribution of rat peptide transporter PEPT2.
Biochim Biophys Acta
1280:
173-177,
1996[ISI][Medline].
160.
Satlin, LM,
Amin V,
and
Wolkoff AW.
Organic anion transporting polypeptide mediates organic anion/HCO3 exchange.
J Biol Chem
272:
26340-26345,
1997
161.
Schaner, ME,
Wang J,
Zevin S,
Gerstin KM,
and
Giacomini KM.
Transient expression of a purine-selective nucleoside transporter (SPNTint) in a human cell line (HeLa).
Pharmacol Res
14:
1316-1321,
1997.
162.
Schaub, TP,
Kartenbeck J,
König J,
Vogel O,
Witzgall R,
Kriz W,
and
Keppler D.
Expression of the conjugate export pump encoded by the mrp2 gene in the apical membrane of kidney proximal tubules.
J Am Soc Nephrol
8:
1213-1221,
1997[Abstract].
163.
Schuetz, JD,
Connelly MC,
Sun D,
Paibir SG,
Flynn PM,
Srinivas RV,
Kumar A,
and
Fridland A.
MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs.
Nature Med
5:
1048-1051,
1999[ISI][Medline].
164.
Sekine, T,
Cha SH,
Tsuda M,
Apiwattanakul N,
Nakajima N,
Kanai Y,
and
Endou H.
Identification of multispecific organic anion transporter 2 expressed predominantly in the liver.
FEBS Lett
429:
179-182,
1998[ISI][Medline].
165.
Sekine, T,
Watanabe N,
Hosoyamada M,
Kanai Y,
and
Endou H.
Expression cloning and characterization of a novel multispecific organic anion transporter.
J Biol Chem
272:
18526-18529,
1997
166.
Sheehan, D,
and
Mantle TJ.
Evidence for two forms of ligandin (YaYa dimers of glutathione S-transferase) in rat liver and kidney.
Biochem J
218:
893-897,
1984[ISI][Medline].
167.
Sheikh Hamad, D,
Timmins K,
and
Jalali Z.
Cisplatin-induced renal toxicity: possible reversal by N-acetylcysteine treatment.
J Am Soc Nephrol
8:
1640-1644,
1997[Abstract].
168.
Shen, H,
Smith DE,
Yang T,
Huang YG,
Schnermann JB,
and
Brosius FC, III.
Localization of PEPT1 and PEPT2 proton-coupled oligopeptide transporter mRNA and protein in rat kidney.
Am J Physiol Renal Physiol
276:
F658-F665,
1999
169.
Siess, EA,
Brocks DG,
and
Wieland OH.
Subcellular distribution of key metabolites in isolated liver cells from fasted rats.
FEBS Lett
69:
265-271,
1976[ISI][Medline].
170.
Silbernagl, S,
Ganapathy V,
and
Leibach FH.
H+ gradient-driven dipeptide reabsorption in proximal tubule of rat kidney. Studies in vivo and in vitro.
Am J Physiol Renal Fluid Electrolyte Physiol
253:
F448-F457,
1987
171.
Simonson, GD,
Vincent AC,
Roberg KJ,
Huang Y,
and
Iwanij V.
Molecular cloning and characterization of a novel liver-specific transport protein.
J Cell Sci
107:
1065-1072,
1994
172.
Soboll, S,
Scholz R,
Friesl M,
Elbers R,
and
Heldt HW.
Distribution of metabolites between mitochondria and cytosol of perfused liver.
In: Use of Isolated Liver Cells and Kidney Tubules in Metabolic Studies, edited by Tager JM,
Söling HD,
and Williamson JR.. Amsterdam: North-Holland, 1975, p. 29-40.
173.
Stride, BD,
Grant CE,
Loe DW,
Hipfner DR,
Cole SPC,
and
Deeley RG.
Pharmacological characterization of the murine and human orthologs of multidrug-resistance protein in transfected human embryonic kidney cells.
Mol Pharmacol
52:
344-353,
1997
174.
Suzuki, H,
and
Sugiyama Y.
Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2.
Semin Liver Dis
18:
359-376,
1998[ISI][Medline].
175.
Sweet, DH,
Wolff NA,
and
Pritchard JB.
Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney.
J Biol Chem
272:
30088-30095,
1997
176.
Takahashi, K,
Nakamura N,
Terada T,
Okano T,
Futami T,
Saito H,
and
Inui KI.
Interaction of beta-lactam antibiotics with H+/peptide cotransporters in rat renal brush-border membranes.
J Pharmacol Exp Ther
286:
1037-1042,
1998
177.
Takano, M,
Nagai J,
Yasuhara M,
and
Inui K.
Regulation of p-aminohippurate transport by protein kinase C in OK kidney epithelial cells.
Am J Physiol Renal Fluid Electrolyte Physiol
271:
F469-F475,
1996
178.
Takenaka, O,
Horie T,
Suzuki H,
and
Sugiyama Y.
Different biliary excretion systems for glucuronide and sulfate of a model compound; study using Eisai hyperbilirubinemic rats.
J Pharmacol Exp Ther
274:
1362-1369,
1995[Abstract].
179.
Tamai, I,
Nakanishi T,
Nakahara H,
Sai Y,
Ganapathy V,
Leibach FH,
and
Tsuji A.
Improvement of L-dopa absorption by dipeptidyl derivation, utilizing peptide transporter PepT1.
J Pharm Sci
87:
1542-1546,
1998[ISI][Medline].
180.
Taniguchi, K,
Wada M,
Kohno K,
Nakamura T,
Kawabe T,
Kawakami M,
Kagotani K,
Okumura K,
Akiyama S-I,
and
Kuwano M.
A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation.
Cancer Res
56:
4124-4129,
1996[Abstract].
181.
Temple, CS,
and
Boyd CA.
Proton-coupled oligopeptide transport by rat renal cortical brush border membrane vesicles: a functional analysis using ACE inhibitors to determine the isoform of the transporter.
Biochim Biophys Acta
1373:
277-281,
1998[ISI][Medline].
182.
Terada, T,
Saito H,
Mukai M,
and
Inui K.
Recognition of beta-lactam antibiotics by rat peptide transporters, PEPT1 and PEPT2, in LLC-PK1 cells.
Am J Physiol Renal Physiol
273:
F706-F711,
1997
183.
Terlouw, SA,
Tanriseven O,
Russel FGM,
and
Masereeuw R.
Metabolite anion carriers mediate the uptake of the anionic drug fluorescein in renal cortical mitochondria.
J Pharmacol Exp Ther
292:
968-973,
2000
184.
Tiruppathi, C,
Ganapathy V,
and
Leibach FH.
Kinetic evidence for a common transporter for glycylsarcosine and phenylalanylprolylalanine in renal brush-border membrane vesicles.
J Biol Chem
265:
14870-14874,
1990
185.
Tojo, A,
Sekine T,
Nakajima N,
Hosoyamada M,
Kanai Y,
Kimura K,
and
Endou H.
Immunohistochemical localization of multispecific renal organic anion transporter 1 in rat kidney.
J Am Soc Nephrol
10:
464-471,
1999
186.
Tsuda, M,
Sekine T,
Takeda M,
Cha SH,
Kanai Y,
Kimura M,
and
Endou H.
Transport of ochratoxin A by renal multispecific organic anion transporter 1.
J Pharmacol Exp Ther
289:
1301-1305,
1999
187.
Uchiumi, T,
Hinoshita E,
Haga S,
Nakamura T,
Tanaka T,
Toh S,
Furukawa T,
Kawabe T,
Wada M,
Kagotani K,
Okumura K,
Kohno K,
Akiyama S-I,
and
Kuwano M.
Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport.
Biochem Biophys Res Commun
252:
103-110,
1998[ISI][Medline].
188.
Ullrich, KJ.
Renal transporters for organic anions and cations. Structural requirements for substrates.
J Membr Biol
158:
95-107,
1997[ISI][Medline].
189.
Ullrich, KJ,
and
Rumrich G.
Luminal transport step of para-aminohippurate (PAH): transport from PAH-loaded proximal tubular cells into the tubular lumen of the rat kidney in vivo.
Pflügers Arch
433:
735-743,
1997[ISI][Medline].
190.
Uwai, Y,
Okuda M,
Takami K,
Hashimoto Y,
and
Inui K-I.
Functional characterization of the rat multispecific organic anion transporter OAT1 mediating basolateral uptake of anionic drugs in the kidney.
FEBS Lett
438:
321-324,
1998[ISI][Medline].
191.
Van Aubel RAMH, Hartog A, Bindels RJM, van Os CH, and Russel FGM.
Expression and immunolocalization of multidrug resistance protein 2 in
rabbit small intestine. Eur J Pharmacol. In press.
192.
Van Aubel, RAMH,
Koenderink JB,
Peters JGP,
van Os CH,
and
Russel FGM
Mechanisms and interaction of vinblastine and reduced glutathione transport in membrane vesicles by the rabbit multidrug resistance protein Mrp2 expressed in insect cells.
Mol Pharmacol
56:
714-719,
1999
193.
Van Aubel RAMH, Peters JGP, Masereeuw R, van Os CH, and Russel
FGM. Multidrug resistance protein Mrp2 mediates ATP-dependent
transport of classic renal organic anion p-aminohippurate.
Am J Physiol Renal Physiol. In press.
194.
Van Aubel, RAMH,
van Kuijck MA,
Koenderink JB,
Deen PMT,
van Os CH,
and
Russel FGM
Adenosine triphosphate-dependent transport of anionic conjugates by the rabbit multidrug resistance-associated protein Mrp2 expressed in insect cells.
Mol Pharmacol
53:
1062-1067,
1998
195.
Versantvoort, CH,
Broxterman HJ,
Bagrij T,
Scheper RJ,
and
Twentyman PR.
Regulation by glutathione of drug transport in multidrug-resistant human lung tumour cell lines overexpressing multidrug resistance-associated protein.
Br J Cancer
72:
82-89,
1995[ISI][Medline].
196.
Wada, M,
Toh S,
Taniguchi K,
Nakamura T,
Uchiumi T,
Kohno K,
Yoshida I,
Kimura A,
Sakisaka S,
Adachi Y,
and
Kuwano M.
Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome.
Hum Mol Genet
7:
203-207,
1998
197.
Wang, H,
Fei YJ,
Ganapathy V,
and
Leibach FH.
Electrophysiological characteristics of the proton-coupled peptide transporter PEPT2 cloned from rat brain.
Am J Physiol Cell Physiol
275:
C967-C975,
1998
198.
Wang, J,
Su SF,
Dresser MJ,
Schaner ME,
Washington CB,
and
Giacomini K.
Na(+)-dependent purine nucleoside transporter from human kidney: cloning and functional characterization.
Am J Physiol Renal Physiol
273:
F1058-F1065,
1997[ISI][Medline].
199.
Welborn, JR,
Shpun S,
Dantzler WH,
and
Wright SH.
Effect of alpha-ketoglutarate on organic anion transport in single rabbit renal proximal tubules.
Am J Physiol Renal Physiol
274:
F165-F174,
1998
200.
Wenzel, U,
Gebert I,
Weintraut H,
Weber WM,
Clauss W,
and
Daniel H.
Transport characteristics of differently charged cephalosporin antibiotics in oocytes expressing the cloned intestinal peptide transporter PepT1 and in human intestinal Caco-2 cells.
J Pharmacol Exp Ther
277:
831-839,
1996[Abstract].
201.
Wijnholds, J,
Evers R,
Leusden MR,
Mol CA,
Zaman GJR,
Mayer U,
Beijnen J,
Van der Valk P,
Krimpenfort P,
and
Borst P.
Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein.
Nature Med
3:
1275-1279,
1997[ISI][Medline].
202.
Wijnholds, J,
Mol CA,
Scheffer GL,
Scheper RJ,
and
Borst P.
Multidrug resistance protein 5, a candidate multispecific organic anion transporter (Abstract).
Proc Am Assoc Cancer Res
40:
315,
1999.
203.
Wijnholds, J,
Scheffer GL,
Van der Valk M,
Van derValk P,
Beijnen JH,
Scheper RJ,
and
Borst P.
Multidrug resistance protein 1 protects the oropharyngeal mucosal layer and the testicular tubules against drug-induced damage.
J Exp Med
188:
797-808,
1998
204.
Williams, TC,
and
Jarvis SM.
Multiple sodium-dependent nucleoside transport systems in bovine renal brush-border membrane vesicles.
Biochem J
274:
27-33,
1991[ISI][Medline].
205.
Wolff, NA,
Werner A,
Burkhardt S,
and
Burckhardt G.
Expression cloning and characterization of a renal organic anion transporter from winter flounder.
FEBS Lett
417:
287-291,
1997[ISI][Medline].
206.
Yamazaki, M,
Akiyama S,
Ni'inuma K,
Nishigaki R,
and
Sugiyama Y.
Biliary excretion of pravastatin in rats: contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter.
Drug Metab Dispos
25:
1123-1129,
1997
207.
Yao, SY,
Cass CE,
and
Young JD.
Transport of the antiviral nucleoside analogs 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine by a recombinant nucleoside transporter (rCNT) expressed in Xenopus laevis oocytes.
Mol Pharmacol
50:
388-393,
1996[Abstract].
208.
Yao, SY,
Ng AM,
Ritzel MW,
Gati WP,
Cass CE,
and
Young JD.
Transport of adenosine by recombinant purine- and pyrimidine-selective sodium/nucleoside cotransporters from rat jejunum expressed in Xenopus laevis oocytes.
Mol Pharmacol
50:
1529-1535,
1996[Abstract].
209.
Yokota, H,
Inoue H,
Taniyama H,
Kobayashi T,
Iwano H,
Kagawa Y,
Okada H,
and
Yuasa A.
High induction of phenol UDP-glucuronosyltransferase in the kidney medulla of beta-naphthoflavone-treated rats.
Biochim Biophys Acta
1336:
165-170,
1997[ISI][Medline].
210.
Zaman, GJR,
Cnubben NHP,
van Bladeren PJ,
Evers R,
and
Borst P.
Transport of the glutathione conjugate of ethacrynic acid by the human multidrug resistance protein MRP.
FEBS Lett
391:
126-130,
1996[ISI][Medline].
211.
Zaman, GJR,
Flens MJ,
van Leusden MR,
de Haas M,
Mulder HS,
Lankelma J,
Pinedo HM,
Scheper RJ,
Baas F,
Broxterman HJ,
and
Borst P.
The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump.
Proc Natl Acad Sci USA
91:
8822-8826,
1994[Abstract].
212.
Zaman, GJR,
Lankelma J,
Beijnen J,
van Tellingen O,
Dekker H,
Paulusma CC,
Oude Elferink RPJ,
Baas F,
and
Borst P.
Role of glutathione in the export of compounds from cells by the multidrug resistance-associated protein.
Proc Natl Acad Sci USA
92:
7690-7694,
1995[Abstract].
213.
Zaman, GJR,
Versantvoort CH,
Smit JJ,
Eijdems EW,
de Haas M,
Smith AJ,
Broxterman HJ,
Mulder NH,
de Vries EG,
Baas F,
and
Borst P.
Analysis of the expression of MRP, the gene for a new putative transmembrane drug transporter, in human multidrug resistant lung cancer cell lines.
Cancer Res
53:
1747-1750,
1993[Abstract].