![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Departments of Medicine (S.A.E., K.T.B., R.V.S, S.K.N.), Family Medicine (V.B.), Pediatrics (S.K.N.), and Cellular and Molecular Medicine (S.K.N.), University of California, San Diego, and the Veterans Affairs Hospital, La Jolla, California
Received September 3, 2003; accepted October 3, 2003
 |
Abstract |
|---|
 Top Abstract The Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
-lactam antibiotics, probenecid, loop and thiazide diuretics, angiotensin converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and methotrexate, among others, as well as various endogenous compounds, including cyclic nucleotides, prostaglandins, folate, neurotransmitter-metabolites, and hormone-conjugates (reviewed in Sweet et al., 2001
; Russel et al., 2002).
The results of numerous studies have led to the following picture of this pathway (Fig. 1). Organic anion entry across the basolateral membrane of the proximal tubule occurs through an antiporter in exchange for dicarboxylates (in particular, 
-ketoglutarate, an intermediate in the Krebs cycle). The latter are maintained at high intracellular concentrations by a Na+-dicarboxylate cotransporter, which is, in turn, driven by the trans-membrane Na+ gradient generated by the Na+/K+ ATPase. Accordingly, basolateral uptake is referred to as "tertiary" active transport (Sweet et al., 2001; Dantzler, 2002). After uptake, organic anions may be concentrated in cytoplasmic vesicles that move toward the apical surface along the microtubular network (Miller et al., 1993; Miller and Pritchard, 1994). Finally, apical (luminal) efflux (i.e., into urine) occurs through mechanisms that are less well understood but that probably include anion exchange, albeit in a Na+-independent manner (Sweet et al., 2001; Dantzler, 2002). Although this pathway has been studied as a physiological process for more than a century, only within the last several years, with the cloning of multiple related organic anion transporter (OAT) genes, have its molecular underpinnings begun to be explored. Several excellent and detailed recent reviews have addressed substrates, regulation, physiology, and clinical correlates of the cloned OATs (Berkhin and Humphreys, 2001; Dresser et al., 2001; Sweet et al., 2001; Dantzler, 2002; Russel et al., 2002; You, 2002; Eraly et al., 2003a; Terlouw et al., 2003). Here, we focus on the molecular biology and pharmacology of OATs, particularly in relation to genomic location, transcriptional regulation, protein structure, ontogeny, knockouts, toxicology, and pharmacogenetics.
|
|
The Organic Anion Transporter Family of Genes |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
, 1997; Sekine et al., 1997; Sweet et al., 1997), OAT2 (slc22a7, originally cloned as NLT) (Simonson et al., 1994), OAT3 (slc22a8, originally cloned as ROCT) (Brady et al., 1999; Kusuhara et al., 1999), OAT4 (slc22a11) (Cha et al., 2000), and RST (slc22a12) (Mori et al., 1997). In addition, UST1 (Schomig et al., 1998), UST3 (GenBank accession number AB062418
[GenBank]
) (Sun et al., 2001), and OAT5 (Sun et al., 2001; Eraly and Nigam, 2002), although not proven to transport organic anions, are predicted to do so on the basis of sequence homology. The recently identified tubular urate transporter URAT1 (Enomoto et al., 2002a) seems to be the human ortholog of murine RST [although, as in the case of murine NKT (Lopez-Nieto et al., 1997) and rat OAT1 (Sekine et al., 1997), the prior identification of RST was not noted in the report on the cloning of URAT1]. URAT1 and RST are 74% identical and 81% similar at the amino acid level, map to syntenic regions of the mouse and human genomes, and have (to the extent characterized) identical tissue distributions (both are found in the proximal tubule of the kidney and are absent from multiple other tissues examined). Interestingly, the multispecificity of the organic anion transport system resides not in the availability of multiple transporters, but is, in fact, a property of individual transporters, which each transport multiple substrates of diverse structures. However, whereas the substrate specificities of individual OATs overlap substantially, there are some distinct differences (reviewed in Dresser et al., 2001; Russel et al., 2002). This suggests the possibility of "affinity maturation" (Sweet et al., 2001), whereby the constitutive expression of multispecific transporters permits an adequate response to short-term exposure to any particular substrate, whereas exposure in the longer term leads to the "induction" (through increased transcription, message, or protein stability, alternative splicing, or covalent modification that affects activity or sorting) of the more selective OAT(s). Now that all (or nearly all) family members have been identified, it should be possible to test this hypothesis.
Among the aforementioned transporters, OAT1 and OAT3 have been localized to the basolateral surface of the renal proximal tubule (Kojima et al., 2002; Motohashi et al., 2002), and OAT4 and URAT1 to its apical surface (Babu et al., 2002a; Enomoto et al., 2002a). Furthermore, the functional properties of OAT1 and OAT3 on the one hand and OAT4 and URAT1 on the other are consistent with what is known about the mechanisms of basolateral and apical organic anion transport, respectively, in this structure (Fig. 1): OAT1 couples organic anion influx to dicarboxylate efflux (Sekine et al., 1997; Sweet et al., 1997); OAT3, originally described as a facilitated diffusion carrier (Kusuhara et al., 1999; Cha et al., 2001), has also now been demonstrated to function as an organic anion/dicarboxylate exchanger (Sweet et al., 2003); finally, OAT4 and URAT1 mediate transport in a Na+-independent manner (Cha et al., 2000; Enomoto et al., 2002a). Therefore, it would seem that OAT1/OAT3 and OAT4/URAT1 underlie, at least in part, the basolateral and apical steps, respectively, of the classic pathway of renal organic anion secretion. However, it should be noted that other (phylogenetically unrelated) organic anion-transporting proteins, such as the OATPs/OAT-Ks, and MDRs (Dean et al., 2001; Russel et al., 2002; Hagenbuch and Meier, 2003), also seem to contribute to the apical secretion of some OAT substrates.
The OATs are listed in Table 1 along with their alternate designations and sequence accession numbers. As can be seen, the rapid proliferation of cloned transporters has resulted in an unsystematic nomenclature, with designations often reflecting historical rather than phylogenetic relationships, and a revised nomenclature may be in order once all the substrate specificities are determined. Interestingly, the nearest phylogenetic relations of the OATs (as revealed by sequence similarity) are transporters with the opposite charge selectivity—organic cation transporters, OCTs (Sweet and Pritchard, 1999; Burckhardt and Wolff, 2000) and OCTNs (Tamai et al., 2000). The other close relations of the OATs are the ORCTLs (Nishiwaki et al., 1998; Eraly et al., 2003b) and the recently described fly-like putative transporters (Enomoto et al., 2002c; Eraly and Nigam, 2002), which are of unknown specificity. Conversely, despite their functional similarity, there is no significant sequence homology between OATs, OATPs, and MDRs, and there do not seem to be even any common structural motifs among these various protein families, at least at the level of primary structure. For example, the characteristic OAT motifs of STIVTEWD/NLVC and ELYPT (Schomig et al., 1998) are absent from the other anion transporters, which instead possess lineage-specific motifs of their own, such as the nucleotide-binding fold of the MDRs (Dean et al., 2001) and the zinc finger-like motif of the OATPs (Hagenbuch and Meier, 2003). Conceivably, structural similarity might exist between these protein families at the secondary, tertiary, or quaternary levels.
|
All the OATs are expressed in kidney and/or liver, the two major excretory organs of the body; individual family members are also expressed in diverse barrier epithelia (discussed below), including placenta and choroid plexus. OAT function in the placenta is interesting because of its possible contribution to the excretion of organic anions from the fetal to maternal circulation (Cha et al., 2000). Similarly, OAT function in choroid plexus [which seems to be caused by OAT1 and OAT3 (Pritchard et al., 1999; Nagata et al., 2002; Sweet et al., 2002)] is interesting because of its likely role in regulating the availability of organic anions of physiological or pharmacological importance in the cerebrospinal fluid. Not only would this be important for the pharmacology of such drugs as methotrexate and -lactam antibiotics, which partition between blood and cerebrospinal fluid, but it might also have significant implications for neuropsychiatric disorders and their treatments.
|
Structure and Function |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
), are thought to comprise 12 membrane-spanning -helices (Sweet and Pritchard, 1999; Burckhardt and Wolff, 2000; You, 2002) (Fig. 2). The segments connecting these helices are relatively short (around 10 amino acids or fewer) with the exception of the large interconnecting loops between helices 1 and 2 and helices 6 and 7. The first of these loops is extracellular and contains multiple consensus N-linked glycosylation sites. Glycosylation has been demonstrated to be necessary for the proper trafficking of OAT1 to the membrane (Kuze et al., 1999), although the role of these particular sites has not been specifically established. The second of the large loops is intracellular and has several canonical protein kinase C (PKC) phosphorylation sites (Sweet et al., 2001; You, 2002). However, although PKC is known to suppress OAT-mediated transport (reviewed in Berkhin and Humphreys, 2001; You, 2002; Terlouw et al., 2003), these canonical PKC sites do not seem to be involved in this process: PKC down-regulation of OAT1 function was not accompanied by OAT1 phosphorylation (You et al., 2000), and, more definitively, down-regulation was unaffected by mutation of the PKC sites (Wolff et al., 2003). It is interesting that the OATs (like other MFS proteins) manifest subtle, but significant, sequence homology (and thus presumed structural similarity) between their N- and C-terminal halves [trans-membrane domains (TMD) 1-6 and 7-12] (Saier et al., 1999; Burckhardt and Wolff, 2000). This feature has been interpreted as indicating the origin of MFS proteins from the tandem duplication of an ancestor with six membrane-spanning helices.
|
OATs exhibit broad specificity for small molecules and interact with a large number of compounds, often with disparate biochemical (and pharmacologic) properties. Numerous studies have investigated the structural requirements for OAT substrates and indicate that substrate recognition is based on physiochemical characteristics such as hydrophobicity, the presence of one or more hydrogen-bonding sites, and an ionized or partial negative charge distribution, rather than on specific atomic details (Ullrich, 1997). By contrast, beyond the general features noted above, little is currently known about the structure-function relationships of the transporters themselves. It is presumed that the various predicted trans-membrane helices of the OATs are mutually positioned to form a channel for the permeation of substrates. The amino acids lining such a channel (deriving from the inwardly oriented faces of the various helices) must provide the appropriate physical environment for the substrates, which, as noted above, usually possess anionic, polar, and organic components. However, the exact location and detailed characteristics of the OAT active site are unknown because the tertiary structure of an OAT protein has not been solved; even the proposed secondary structure is speculative at this point. In this regard, the recent elucidation of the crystal structures of two different MFS proteins [the Escherichia coli lactose permease and glycerol-3-phosphate transporter, each of which reveals the expected 12 membrane-spanning helices organized into two symmetric domains; (Abramson et al., 2003; Huang et al., 2003)] is likely to provide significant insight into the probable nature of an OAT structure.
Although a solved structure for an OAT does not exist, the availability of molecular clones has made mutagenesis studies possible, from which functional, and thus, indirectly, structural, inferences can be drawn. Such studies have been initiated (Feng et al., 2001, 2002; Wolff et al., 2001), so far targeting amino acids based upon their degree of evolutionary conservation, on the principle that highly conserved residues are likely to prove critical to protein function. These studies have demonstrated the contribution to OAT activity of conserved aromatic as well as basic residues, which are hypothesized to interact with the organic and anionic moieties, respectively, of the substrates. For example, of nine aromatic residues conserved among the OATs, four located in TMD 7 (two tyrosines, a tryptophan, and a phenylalanine) and one located in TMD 8 (a phenylalanine) were found to be required for optimum transport of the prototypic organic anion substrate para-aminohippurate (PAH), as assessed by expression in Xenopus laevis oocytes (Feng et al., 2002) (Fig. 2). Similarly, OATs have three conserved basic residues at positions that are occupied by acidic or neutral residues in their cation-transporting homologs, the OCTs: These are a histidine in TMD 1, a lysine in TMD 8, and an arginine in TMD 11 (Fig. 2). Mutation of any of these residues resulted in decreased PAH transport (Feng et al., 2001; Wolff et al., 2001). Remarkably, substitution of the conserved lysine and arginine by one neutral and one acidic residue (the double mutant R454DK370A) resulted in preferential transport of cationic instead of anionic species; in this case, modification of the electrostatic environment was sufficient to effect a switch in charge selectivity (Feng et al., 2001). It is worth emphasizing here that nominally cationic substrates might be uncharged or even anionic in vivo and might therefore serve as substrates for the OATs, OCTs, and OCTNs as multispecific organic ion transporters with overlapping specificities, rather than specifically as anionic or cationic transporters.
|
Pairing and Tissue Distribution |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
) (Fig. 3A). Specifically, we found that six of the eight known OATs occur as three pairs in the human genome (located on adjacent segments of chromosome 11q12.3 to 11q13.2); OAT1 and OAT3, OAT4 and URAT1, and UST3 and OAT5. [Similarly, OCT1 and OCT2 are paired (on chromosome 6q26), as are OCTN1 and OCTN2 (chromosome 5q23) and ORCTL3 and ORCTL4 (chromosome 3p22).] These physical pairs are also phylogenetic pairs: pair members fall on neighboring branches of the dendrogram of the OAT family, suggesting that they are one another's nearest relations. We have inspected the human genome to determine how prevalent pairing is among other transporters. We find that less than 10% of the approximately 200 other human genes formally designated as solute carriers (having the prefix "slc") are paired or clustered (J. C. Monte, S. A. Eraly, S. K. Nigam, unpublished observations). Furthermore, although the pairing of OATs and OCTs is preserved in mouse and (to the extent verifiable) in Fugu (puffer-fish), it is absent from Drosophila melanogaster and Caenorhabditis elegans (S. A. Eraly, S. K. Nigam, unpublished observations), suggesting that it might be unique to the vertebrate lineage.
|
What evolutionary mechanisms could have resulted in the recurrent pairing of OATs (and OCTs and OCTNs)? Successive duplication of an ancestral gene pair seems unlikely, because such a mechanism (unless accompanied by recurrent gene conversion as well) would have produced pair-members that were distant rather than close relations. An alternative explanation is the presence of shared regulatory elements mediating the coordinated expression (coregulation) of pair members (Fig. 3B). This would lead to selective pressure to hold genes together in a pair, after their origin from, say, a tandem duplication event. In support of this interpretation, we have found that pair members do indeed have similar tissue distributions ((Eraly et al., 2003b) (Fig. 3A). OAT1 and OAT3 are found in the kidney and brain (expression in the latter tissue is presumed to be largely in choroid plexus); OAT4 and URAT1 (RST) are also both expressed in the kidney, but are absent from brain, with OAT4 present in placenta as well; and OAT5 and UST3 are liver-specific. Moreover, within the kidney, the tubular and membrane localization of OATs is also concordant with the coexpression of pair members, with OAT1 and OAT3 immunolocalized to the basolateral surface of the proximal tubule (Kojima et al., 2002; Motohashi et al., 2002) and OAT4 and URAT1 to its apical surface (Babu et al., 2002a; Enomoto et al., 2002a), as mentioned above.
If pairing exists to facilitate the coregulation of pair-members through utilization of shared regulatory elements, the further (ultimate rather than proximate) question arises then of the advantage conferred by such coregulation. The fact that individual pair-members have independent transport capacity, and for overlapping rather than complementary classes of substrates, argues against functional interdependence (as exists for instance between OAT1 and the Na+-dicarboxylate cotransporter) as a rationale for coregulation. The apparent preservation of OAT1-mediated transport in OAT3 knockout mice (discussed below) (Sweet et al., 2002) also argues against functional interdependence of pair members. Similarly, it is unlikely that coexpression is required to accomplish successive steps in vectorial transport of solutes (basolateral uptake and apical efflux), because pair-members (where investigated) have been localized to the same membrane (either apical or basolateral). Conversely, although coordinated expression of functionally similar transporters confers the advantage of redundancy, as well as the potential (as noted above) for affinity maturation, it is not clear why such coregulation should persistently occur in pairs rather than larger groupings.
More satisfying teleological explanations for coregulation in pairs might emerge from investigation of the ontogeny and the evolutionary history of the OATs. For example, we have found (unexpectedly) that OAT1-3 manifest transient embryonic expression in a variety of disparate tissues (discussed below), suggesting possible OAT activity in organogenesis (Pavlova et al., 2000). Similarly, characterization of OAT orthologs in evolutionarily distant taxa might suggest additional, possibly nontransport, functions performed by these genes (although, as noted above, pairing might be relatively specific to the vertebrate lineage). We have identified several OAT-like sequences in the genome of C. elegans (as well as D. melanogaster; S. A. Eraly, S. K. Nigam, unpublished observations); the ready availability of RNA interference-null mutations (Kamath et al., 2003) should facilitate the functional analysis of these putative worm OATs.
|
Ontogeny and Morphogenesis |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
; Horster and Lewy, 1970; Kim et al., 1972; Hook and Hewitt, 1977). This neonatal increase seems to be specifically caused by the maturation of the transport system rather than by the growth and development of the kidney (Hook and Hewitt, 1977). Interestingly, OA transport is inducible by substrate during a limited period that roughly coincides with the phase of postnatal maturation (Hirsch and Hook, 1969, 1970; Stopp et al., 1978), suggesting that similar mechanisms might be involved in both these processes. These increases in transport are prevented when protein synthesis is inhibited by cycloheximide, indicating that they are probably the result of the biosynthesis of OATs or of other proteins involved in OA transport. Because, as described above, renal OA uptake at the basolateral membrane is energized by gradients generated by the Na+/K+ ATPase and Na+-dicarboxylate cotransporter, increased uptake could be indirectly caused by increased expression of these other transporter proteins or indeed by enhanced expression of mitochondrial enzymes or other components of the respiratory cascade that generate the ATP and -ketoglutarate required for the overall process.
With the identification of specific OAT genes, it has become possible to investigate the maturation of OA transport at the molecular level. In the original description of OAT1 (NKT), it was demonstrated that expression (in mouse) increased as the kidney developed (Lopez-Nieto et al., 1997). After this, another study of the ontogeny of OAT1 (this time in rat) determined that kidney expression increased through birth, peaked postpartum, and then declined to adult levels (Nakajima et al., 2000), approximately correlating with the changes in OA transport previously observed in physiological studies. More recently, the postnatal expression of OAT1, OAT2, and OAT3 was examined in greater detail in neonatal rat kidneys (Buist et al., 2002). For each of these OATs, expression levels generally increased over the period examined (birth to 45 days postpartum), but there were some salient differences: OAT1 mRNA levels increased progressively in male rats, but seemed to peak at postpartum day 30 in female rats with a subsequent decline, so that by day 45, levels were significantly lower than in male rats. OAT2, manifested minimal expression in either gender for the first 30 days of postnatal development, then increased in female rats only, through day 45. Finally, OAT3 message increased progressively over the observed course of postnatal development in both male and female rats. Taken together, these results suggest that the postnatal maturation of renal OA transport is caused, at least in part, by increased expression of OAT1-3.
We have also investigated the expression of murine OAT1, OAT2, and OAT3 in the entire embryo (rather than just the kidney), and at earlier developmental stages, using in situ hybridization and northern blotting (Pavlova et al., 2000). Within the kidney, we found onset of OAT1-3 expression to be approximately contemporaneous at embryonic days 14-15 (e14-15), suggesting the existence of a common transcriptional regulatory pathway for these genes. Intriguingly, we also detected transient OAT expression in several extrarenal tissues: OAT1 in choroid plexus, dura mater, and spinal cord early in development, disappearing by e16; OAT2 in fetal liver, lung, stomach, intestine, skin, and bone, with expression still detectable in liver, stomach, and skin at 5 days postpartum; OAT3 in fetal liver and brain by e12, in both cases peaking at e14, with only very low expression levels remaining in adult. Expression during embryogenesis in these extrarenal sites suggests the possibility of a developmental role for the OATs. Conceivably, OATs might transport organic anions with morphogenetic activity (such as, for example, folate), requiring their expression during specific developmental periods, with expression down-regulated at the end of those periods. On the other hand, they may serve a transport-independent function.
|
Knockouts |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
). The resulting mutant mice manifest significantly impaired organic anion transport in kidney and choroid plexus, confirming the in vivo activity of OAT3 in these organs. For example, inhibitorsensitive uptake of PAH in renal slices from knockout animals was less than half that in slices from wild-type animals, whereas transport of the fluorescent OAT substrate, fluorescein, was approximately three quarters less in knockout than in wild-type choroid plexus as quantified by the fluorescence intensity of confocal microscopic images (Sweet et al., 2002). The residual transporter activity in both cases seems to have been caused largely by OAT1. Besides defective organic anion secretion however, the knockout mice seemed grossly physiologically and morphologically normal, without any discernible developmental phenotype. Nevertheless, given the possibility of functional redundancy conferred by other OATs (particularly by the paired and coexpressed gene, OAT1), this finding does not represent compelling evidence against a role for OAT3 in development. It might be necessary to knock out multiple OATs (and possibly OCTs), or at least both members of an OAT pair, to effectively abrogate broader OAT function.
In this regard, it is worth noting that knocking out both proximal tubular basolateral transporters (OAT1 and OAT3), or both apical transporters (OAT4 and RST/URAT1) would be particularly likely to unmask phenotypes relating to substrate accretion or wasting (Eraly et al., 2003a). Conceivably, for instance, knocking out both apical transporters might result in substrates accumulating in the proximal tubule because of the "unopposed" action of the basolateral transporters. Where substrates are potential toxins (e.g., nephrotoxic drugs, see below), this might result in an animal model for substrate-induced nephrotoxicity. Conversely, knockout of basolateral OATs could lead to delayed clearance, possibly creating a model for any extrarenal toxicity of OAT substrates though protecting against nephrotoxicity. Thus, generation of double knockouts could yield crucial insights into the pharmacology as well as the fundamental biology of OATs.
|
Transcriptional Regulation |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
; Terlouw et al., 2003). More recently, the availability of molecular probes for individual OATs has revealed striking gender differences in the expression of OAT2 (expressed at much greater levels in the kidneys of female rats than in those of male rats) and OAT3 (expressed in liver in male rats only, although expressed in kidney in either gender) (Buist et al., 2002, 2003; Kobayashi et al., 2002a,b; Kudo et al., 2002), findings with potentially highly significant clinical implications for drug efficacy and toxicity in the genders. However, the molecular mechanisms underlying many of these regulatory responses remain unclear. In particular, investigations of the transcriptional regulation of OATs have yet to be described. Although such studies have traditionally been labor-intensive, in the present postgenomic era, computational approaches can be employed to predict likely regulatory elements that can then be prioritized for experimental testing (Frech et al., 1997; Fickett and Wasserman, 2000; Hardison, 2000; Pennacchio and Rubin, 2001). We have adapted such approaches to the analysis of the murine and human OAT1/OAT3 locus (Eraly et al., 2003b), and, promisingly, we have detected binding sites for several factors of demonstrated importance in kidney development, including PAX1, PBX, WT1, TCF, and HNF1 (Pontoglio, 2000; Barasch, 2001; Schnabel et al., 2001). Experimental testing of these predicted regulatory motifs might result in the discovery of the shared control elements hinted at by the pairing of OAT1 and OAT3 (see above).
As discussed above, inception of OAT1-3 expression occurs at e14-15 in mice. This period roughly coincides with the differentiation of the proximal tubule, raising the possibility that OAT gene expression might be under the control of "master" factors that are key regulators of proximal tubulogenesis. In other words, factors implicated in OAT transcriptional regulation might also be critical developmental regulators. Among the factors listed above, HNF1 is a plausible candidate for such a "master" regulator. HNF1 induces the transcription of other renal transporters—including the Naphosphate cotransporter (NaPi; Soumounou et al., 2001) and the type II Na-glucose cotransporter (SGLT2; Pontoglio et al., 2000)—and HNF1 knockout mice are a model of Fanconi syndrome (proximal tubular wasting of glucose, amino acids, and phosphate; Pontoglio et al., 1996). Examination of OAT gene expression (and organic anion secretion) in these mice might prove instructive. Furthermore, comparison of embryonic kidney development in wild-type and HNF1 knockout mice might help dissect the regulatory steps involved in the differentiation and maturation of the proximal tubule.
|
Pharmacokinetics and Toxicology |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
; Tsuda et al., 1999; Jung et al., 2001; Babu et al., 2002a), cephaloridine (Takeda et al., 1999, 2002a; Jung et al., 2002; Khamdang et al., 2003), tetracycline (Babu et al., 2002b), mercuric conjugates (Koh et al., 2002; Zalups and Barfuss, 2002; Aslamkhan et al., 2003), the antivirals adefovir and cidofovir (Cihlar et al., 1999; Ho et al., 2000), nephrotoxic cysteine conjugates (Groves et al., 2003), and uremic toxins, such as indoxyl sulfate (Deguchi et al., 2002; Enomoto et al., 2002b; Motojima et al., 2002). Thus, nephrotoxicity could frequently be caused precisely by the avidity of the basolateral OATs, which leads to accumulation of potential toxins within the proximal tubular cell. In vitro experiments with the cloned OATs support this conclusion. Numerous investigators have found that transfection of proximal tubular as well as heterologous cell cultures with OAT cDNAs confers susceptibility to the toxicity of the substances noted above (as indicated by decreased cell viability or proliferation): ochratoxin A (Tsuda et al., 1999), cephaloridine (Jung et al., 2002; Khamdang et al., 2003), mercuric thiol conjugates (Aslamkhan et al., 2003), adefovir and cidofovir (Ho et al., 2000), and indoxyl sulfate (Enomoto et al., 2002b; Motojima et al., 2002). Such susceptibility was generally reversible with administration of an innocuous competitor substrate (for example, probenecid or PAH), further substantiating the specific role of the OATs in mediating toxicity.
As might be expected, OAT-substrate drugs can compete with one another for the transporter to mutually decrease renal secretion and thus delay the clearance and prolong the duration of action of each compound. Such interactions have the potential to bring about critical adverse outcomes—for example, the severe myelosuppression that can result when the OAT substrate, methotrexate, is coadministered with other substrates, such as NSAIDs, penicillins, or probenecid (reviewed in Takeda et al., 2002b). On the other hand, clinicians sometimes employ competition for OAT transport to their advantage, as exemplified by the common practice of coadministering probenecid to prolong the action of -lactam antibiotics. Similarly, competitive interactions can also be beneficial when they lead to decreased proximal tubular uptake of nephrotoxins, which is the presumptive explanation for the nephroprotective actions of probenecid and NSAIDs against toxicity from adefovir and cidofovir (Lacy et al., 1998; Mulato et al., 2000), cephaloridine (Tune, 1997), ochratoxin A (Groves et al., 1998), and mercury (Aslamkhan et al., 2003). However, it is clear that the multiplicity of genes in the OAT family and their complex regulation warrant a careful examination of facile explanations of renal drug handling.
Finally, it is noteworthy that the -ketoglutarate that is discharged to the extracellular space by OAT-mediated exchange for organic anions (Fig. 1) is (as a Krebs cycle intermediate) a key potential energy source for the proximal tubule, because this structure relies almost exclusively on aerobic metabolism in adult life (Ross et al., 1986; Epstein, 1997). Thus OAT uptake of toxins is accompanied by the equimolar loss of a vital nutrient, compromising metabolic reserves when they might be most needed (Eraly et al., 2003a). Such a process could explain some of the vulnerability of the proximal tubule to toxic injury. Indeed, it is conceivable that OAT uptake of even inoffensive substrates could be deleterious during periods of decreased energy availability—which would have important implications for the use of OAT-substrate drugs in the common clinical scenario of renal ischemia. However, whether or not OATs impact renal susceptibility to ischemia remains to be experimentally examined.
|
Medical Anthropology and Pharmacogenetics |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
) such predictions could soon be tested and the exact nature of sequence variation among OAT genes clarified.
Given the importance of OAT activity to drug excretion, interactions, and toxicity, any degree of genetic variation in OAT genes might be a significant determinant of interindividual differences in drug-response. This suggests the possibility of determining the "OAT-genotype" of a patient to individualize his or her pharmacologic therapy. However, although the potential of such genetic profiling is intriguing, it is unclear, a priori, whether it will prove useful and cost-effective. After all, drug response is determined by multiple genes (and polymorphisms in those genes) coding for the transcription, regulation, or structure of proteins that are involved in drug metabolism and excretion (pharmacokinetics), as well as those involved in the action of drugs at their target sites (pharmacodynamics). Furthermore, the use of genetic tests will also be limited if the polymorphisms and/or the outcomes in question are rare (Johnson and Evans, 2002). Nevertheless, the pharmacological importance of OATs would seem to merit association studies that explore correlations between OAT variants (Iida et al., 2001; Nishizato et al., 2003) and particular drug-response phenotypes. Variants/polymorphisms can be prioritized for such analyses based on whether or not they alter critical residues in OAT proteins. These, in turn, can be identified through mutational studies, such as those described above (Feng et al., 2001, 2002; Wolff et al., 2001), or by structural modeling. Alternatively, the importance of particular residues to OAT function can reliably be estimated from their degree of evolutionary conservation (Simon et al., 2002; Blouin et al., 2003). The applicability of this principle has recently been demonstrated by a study of polymorphisms in OCT2 [a member of the OAT-related family of organic cation transporters (Sweet and Pritchard, 1999; Burckhardt and Wolff, 2000)], wherein the only variants that resulted in decreased function were those that altered conserved residues (Shu et al., 2003).
|
Conclusion |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
|
Acknowledgements |
|---|
|
Footnotes |
|---|
ABBREVIATIONS: OAT, organic anion transporter; ACE, angiotensin-converting enzyme; NSAID, nonsteroidal anti-inflammatory drug; OCT, organic cation transporter; MFS, major facilitator superfamily; PKC, protein kinase C; TMD, trans-membrane domain; PAH, para-aminohippurate; OA, organic anion.
Address correspondence to: Sanjay K. Nigam, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, E-mail: snigam{at}ucsd.edu
|
References |
|---|
|
TopAbstractThe Organic Anion Transporter...Structure and FunctionPairing and Tissue DistributionOntogeny and MorphogenesisKnockoutsTranscriptional RegulationPharmacokinetics and ToxicologyMedical Anthropology and...ConclusionReferences |
|---|
Aslamkhan AG, Han Y-H, Yang X-P, Zalups RK, and Pritchard JB (2003) Human renal organic anion transporter 1-dependent uptake and toxicity of mercuric-thiol conjugates in Madin-Darby canine kidney cells. Mol Pharmacol 63: 590-596.
Babu E, Takeda M, Narikawa S, Kobayashi Y, Enomoto A, Tojo A, Cha SH, Sekine T, Sakthisekaran D, and Endou H (2002a) Role of human organic anion transporter 4 in the transport of ochratoxin A. Biochim Biophys Acta 1590: 64-75.[Medline]
Babu E, Takeda M, Narikawa S, Kobayashi Y, Yamamoto T, Cha SH, Sekine T, Sakthisekaran D, and Endou H (2002b) Human organic anion transporters mediate the transport of tetracycline. Jpn J Pharmacol 88: 69-76.[CrossRef][Medline]
Barasch J (2001) Genes and proteins involved in mesenchymal to epithelial transition. Curr Opin Nephrol Hypertens 10: 429-436.[CrossRef][Medline]
Barnett HL, McNamara H, and Schultz S (1949) Renal clearances of sodium penicillin G, procaine penicillin G and inulin in infants and children. Pediatrics 3: 418.
Berkhin EB and Humphreys MH (2001) Regulation of renal tubular secretion of organic compounds. Kidney Int 59: 17-30.[CrossRef][Medline]
Blouin C, Boucher Y, and Roger AJ (2003) Inferring functional constraints and divergence in protein families using 3D mapping of phylogenetic information. Nucleic Acids Res 31: 790-797.
Brady KP, Dushkin H, Fornzler D, Koike T, Magner F, Her H, Gullans S, Segre GV, Green RM, and Beier DR (1999) A novel putative transporter maps to the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse. Genomics 56: 254-261.[CrossRef][Medline]
Buist SC, Cherrington NJ, Choudhuri S, Hartley DP, and Klaassen CD (2002) Gender-specific and developmental influences on the expression of rat organic anion transporters. J Pharmacol Exp Ther 301: 145-151.
Buist SC, Cherrington NJ, and Klaassen CD (2003) Endocrine regulation of rat organic anion transporters. Drug Metab Dispos 31: 559-564.
Burckhardt G and Wolff NA (2000) Structure of renal organic anion and cation transporters. Am J Physiol 278: F853-F866.
Cha SH, Sekine T, Fukushima J-I, Kanai Y, Kobayashi Y, Goya T, and Endou H (2001) Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol 59: 1277-1286.
Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, and Endou H (2000) Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem 275: 4507-4512.
Cihlar T, Lin DC, Pritchard JB, Fuller MD, Mendel DB, and Sweet DH (1999) The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol 56: 570-580.
Dantzler WH (2002) Renal organic anion transport: a comparative and cellular perspective. Biochim Biophys Acta 1566: 169-181.[Medline]
Dean M, Rzhetsky A, and Allikmets R (2001) The human ATP-binding cassette (ABC) transporter superfamily. Genome Res 11: 1156-1166.
Deguchi T, Ohtsuki S, Otagiri M, Takanaga H, Asaba H, Mori S, and Terasaki T (2002) Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int 61: 1760-1768.[CrossRef][Medline]
Dresser MJ, Leabman MK, and Giacomini KM (2001) Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci 90: 397-421.[CrossRef][Medline]
Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, et al. (2002a) Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature (Lond) 417: 447-452.[Medline]
Enomoto A, Takeda M, Tojo A, Sekine T, Cha SH, Khamdang S, Takayama F, Aoyama I, Nakamura S, Endou H, et al. (2002b) Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J Am Soc Nephrol 13: 1711-1720.
Enomoto A, Wempe MF, Tsuchida H, Shin HJ, Cha SH, Anzai N, Goto A, Sakamoto A, Niwa T, Kanai Y, et al. (2002c) Molecular identification of a novel carnitine transporter specific to human testis: insights into the mechanism of carnitine recognition. J Biol Chem 277: 36262-36271.
Epstein FH (1997) Oxygen and renal metabolism. Kidney Int 51: 381-385.[Medline]
Eraly SA, Blantz RC, Bhatnagar V, and Nigam SK (2003a) Novel aspects of renal organic anion transporters. Curr Opin Nephrol Hypertens 12: 551-558.[Medline]
Eraly SA, Hamilton BA, and Nigam SK (2003b) Organic anion and cation transporters occur in pairs of similar and similarly expressed genes. Biochem Biophys Res Commun 300: 333-342.[CrossRef][Medline]
Eraly SA and Nigam SK (2002) Novel human cDNAs homologous to Drosophila Orct and mammalian carnitine transporters. Biochem Biophys Res Commun 297: 1159-1166.[CrossRef][Medline]
Feng B, Dresser MJ, Shu Y, Johns SJ, and Giacomini KM (2001) Arginine 454 and lysine 370 are essential for the anion specificity of the organic anion transporter, rOAT3. Biochemistry 40: 5511-5520.[CrossRef][Medline]
Feng B, Shu Y, and Giacomini KM (2002) Role of aromatic transmembrane residues of the organic anion transporter, rOAT3, in substrate recognition. Biochemistry 41: 8941-8947.[CrossRef][Medline]
Fickett JW and Wasserman WW (2000) Discovery and modeling of transcriptional regulatory regions. Curr Opin Biotechnol 11: 19-24.[CrossRef][Medline]
Frech K, Quandt K, and Werner T (1997) Finding protein-binding sites in DNA sequences: the next generation. Trends Biochem Sci 22: 103-104.[CrossRef][Medline]
Groves CE, Morales M, and Wright SH (1998) Peritubular transport of ochratoxin a in rabbit renal proximal tubules. J Pharmacol Exp Ther 284: 943-948.
Groves CE, Munoz L, Bahn A, Burckhardt G, and Wright SH (2003) Interaction of cysteine conjugates with human and rabbit organic anion transporter 1. J Pharmacol Exp Ther 304: 560-566.
Hagenbuch B and Meier PJ (2003) The superfamily of organic anion transporting polypeptides. Biochim Biophys Acta 1609: 1-18.[Medline]
Hardison RC (2000) Conserved noncoding sequences are reliable guides to regulatory elements. Trends Genet 16: 369-372.[CrossRef][Medline]
Hirsch GH and Hook JB (1969) Maturation of renal organic acid transport: substrate stimulation by penicillin. Science (Wash DC) 165: 909-910.
Hirsch GH and Hook JB (1970) Maturation of renal organic acid transport: substrate stimulation by penicillin and p-aminohippurate (PAH). J Pharmacol Exp Ther 171: 103-108.
Ho ES, Lin DC, Mendel DB, and Cihlar T (2000) Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol 11: 383-393.
Hook JB and Hewitt WR (1977) Development of mechanisms for drug excretion. Am J Med 62: 497-506.[CrossRef][Medline]
Horster M and Lewy JE (1970) Filtration fraction and extraction of PAH during neonatal period in the rat. Am J Physiol 219: 106-119.
Huang Y, Lemieux MJ, Song J, Auer M, and Wang D-N (2003) Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science (Wash DC) 301: 616-620.
Iida A, Saito S, Sekine A, Mishima C, Kondo K, Kitamura Y, Harigae S, Osawa S, and Nakamura Y (2001) Catalog of 258 single-nucleotide polymorphisms (SNPs) in genes encoding three organic anion transporters, three organic anion-transporting polypeptides and three NADH:ubiquinone oxidoreductase flavoproteins. J Hum Genet 46: 668-683.[CrossRef][Medline]
Johnson JA and Evans WE (2002) Molecular diagnostics as a predictive tool: genetics of drug efficacy and toxicity. Trends Mol Med 8: 300-305.[CrossRef][Medline]
Jung KY, Takeda M, Kim DK, Tojo A, Narikawa S, Yoo BS, Hosoyamada M, Cha SH, Sekine T, and Endou H (2001) Characterization of ochratoxin A transport by human organic anion transporters. Life Sci 69: 2123-2135.[CrossRef][Medline]
Jung KY, Takeda M, Shimoda M, Narikawa S, Tojo A, Kim do K, Chairoungdua A, Choi BK, Kusuhara H, Sugiyama Y, et al. (2002) Involvement of rat organic anion transporter 3 (rOAT3) in cephaloridine-induced nephrotoxicity: in comparison with rOAT1. Life Sci 70: 1861-1874.[CrossRef][Medline]
Kamath RS, Fraser AG, Dong Y, Poulin G, Durbin R, Gotta M, Kanapin A, Le Bot N, Moreno S, Sohrmann M, et al. (2003) Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature (Lond) 421: 231-237.[CrossRef][Medline]
Khamdang S, Takeda M, Babu E, Noshiro R, Onozato ML, Tojo A, Enomoto A, Huang XL, Narikawa S, Anzai N, et al. (2003) Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics. Eur J Pharmacol 465: 1-7.[CrossRef][Medline]
Kim JK, Hirsch GH, and Hook JB (1972) In vitro analysis of organic ion transport in renal cortex of the newborn rat. Pediatr Res 6: 600-605.
Kobayashi Y, Hirokawa N, Ohshiro N, Sekine T, Sasaki T, Tokuyama S, Endou H, and Yamamoto T (2002a) Differential gene expression of organic anion transporters in male and female rats. Biochem Biophys Res Commun 290: 482-487.[CrossRef][Medline]
Kobayashi Y, Ohshiro N, Shibusawa A, Sasaki T, Tokuyama S, Sekine T, Endou H, and Yamamoto T (2002b) Isolation, characterization and differential gene expression of multispecific organic anion transporter 2 in mice. Mol Pharmacol 62: 7-14.
Koh AS, Simmons-Willis TA, Pritchard JB, Grassl SM, and Ballatori N (2002) Identification of a mechanism by which the methylmercury antidotes N-acetylcysteine and dimercaptopropanesulfonate enhance urinary metal excretion: transport by the renal organic anion transporter-1. Mol Pharmacol 62: 921-926.
Kojima R, Sekine T, Kawachi M, Cha SH, Suzuki Y, and Endou H (2002) Immuno-localization of multispecific organic anion transporters, OAT1, OAT2 and OAT3, in rat kidney. J Am Soc Nephrol 13: 848-857.
Kudo N, Katakura M, Sato Y, and Kawashima Y (2002) Sex hormone-regulated renal transport of perfluorooctanoic acid. Chem Biol Interact 139: 301-316.[CrossRef][Medline]
Kusuhara H, Sekine T, Utsunomiya-Tate N, Tsuda M, Kojima R, Cha SH, Sugiyama Y, Kanai Y, and Endou H (1999) Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem 274: 13675-13680.
Kuze K, Graves P, Leahy A, Wilson P, Stuhlmann H, and You G (1999) Heterologous expression and functional characterization of a mouse renal organic anion transporter in mammalian cells. J Biol Chem 274: 1519-1524.
Lacy SA, Hitchcock MJM, Lee WA, Tellier P, and Cundy KC (1998) Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys. Toxicol Sci 44: 97-106.
Lopez-Nieto CE, You G, Barros EJG, Beier DR, and Nigam SK (1996) Molecular cloning and characterization of a novel transport protein with very high expression in the kidney (Abstract). J Am Soc Nephrol 7: 130119.
Lopez-Nieto CE, You G, Bush KT, Barros EJG, Beier DR, and Nigam SK (1997) 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.
Miller DS and Pritchard JB (1994) Nocodazole inhibition of organic anion secretion in teleost renal proximal tubules. Am J Physiol 267: R695-R704.
Miller DS, Stewart DE, and Pritchard JB (1993) Intracellular compartmentation of organic anions within renal cells. Am J Physiol 264: R882-R890.
Mori K, Ogawa Y, Ebihara K, Aoki T, Tamura N, Sugawara A, Kuwahara T, Ozaki S, Mukoyama M, and Tashiro K (1997) Kidney-specific expression of a novel mouse organic cation transporter-like protein. FEBS Lett 417: 371-374.[CrossRef][Medline]
Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, Fukatsu A, Ogawa O, and Inui K (2002) Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13: 866-874.
Motojima M, Hosokawa A, Yamato H, Muraki T, and Yoshioka T (2002) Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake. Br J Pharmacol 135: 555-563.[CrossRef][Medline]
Mulato AS, Ho ES, and Cihlar T (2000) Nonsteroidal anti-inflammatory drugs efficiently reduce the transport and cytotoxicity of adefovir mediated by the human renal organic anion transporter 1. J Pharmacol Exp Ther 295: 10-15.
Nagata Y, Kusuhara H, Endou H, and Sugiyama Y (2002) Expression and functional characterization of rat organic anion transporter 3 (rOat3) in the choroid plexus. Mol Pharmacol 61: 982-988.
Nakajima N, Sekine T, Cha SH, Tojo A, Hosoyamada M, Kanai Y, Yan K, Awa S, and Endou H (2000) Developmental changes in multispecific organic anion transporter 1 expression in the rat kidney. Kidney Int 57: 1608-1616.[CrossRef][Medline]
Nishiwaki T, Daigo Y, Tamari M, Fujii Y, and Nakamura Y (1998) Molecular cloning, mapping and characterization of two novel human genes, ORCTL3 and ORCTL4, bearing homology to organic-cation transporters. Cytogenet Cell Genet 83: 251-255.[Medline]
Nishizato Y, Ieiri I, Suzuki H, Kimura M, Kawabata K, Hirota T, Takane H, Irie S, Kusuhara H, and Urasaki Y (2003) Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther 73: 554-565.[CrossRef][Medline]
Pavlova A, Sakurai H, Leclercq B, Beier DR, Yu ASL, and Nigam SK (2000) Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2) and Roct. Am J Physiol 278: F635-F643.
Pennacchio LA and Rubin EM (2001) Genomic strategies to identify mammalian regulatory sequences. Nat Rev Genet 2: 100-109.[CrossRef][Medline]
Pontoglio M (2000) Hepatocyte Nuclear factor 1, a transcription factor at the crossroads of glucose homeostasis. J Am Soc Nephrol 11: S140-S143.
Pontoglio M, Barra J, Hadchouel M, Doyen A, Kress C, Bach JP, Babinet C, and Yaniv M (1996) Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria and renal Fanconi syndrome. Cell 84: 575-585.[CrossRef][Medline]
Pontoglio M, Prie D, Cheret C, Doyen A, Leroy C, Froguel P, Velho G, Yaniv M, and Friedlander G (2000) HNF1 controls renal glucose reabsorption in mouse and man. EMBO (Eur Mol Biol Organ) Reports 1: 359-365.
Pritchard JB, Sweet DH, Miller DS, and Walden R (1999) Mechanism of organic anion transport across the apical membrane of choroid plexus. J Biol Chem 274: 33382-33387.
Ross BD, Espinal J, and Silva P (1986) Glucose metabolism in renal tubular function. Kidney Int 29: 54-67.[Medline]
Russel FGM, Masereeuw R, and van Aubel RAMH (2002) Molecular aspects of renal anionic drug transport. Annu Rev Physiol 64: 563-594.[CrossRef][Medline]
Saier MH Jr, Beatty JT, Goffeau A, Harley KT, Heijne WH, Huang SC, Jack DL, Jahn PS, Lew K, Liu J, et al. (1999) The major facilitator superfamily. J Mol Microbiol Biotechnol 1: 257-279.[Medline]
Schnabel CA, Selleri L, Jacobs Y, Warnke R, and Cleary ML (2001) Expression of Pbx1b during mammalian organogenesis. Mech Dev 100: 131-135.[CrossRef][Medline]
Schomig E, Spitzenberger F, Engelhardt M, Martel F, Ording N, and Grundemann D (1998) Molecular cloning and characterization of two novel transport proteins from rat kidney. FEBS Lett 425: 79-86.[CrossRef][Medline]
Sekine T, Watanabe N, Hosoyamada M, Kanai Y, and Endou H (1997) Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem 272: 18526-18529.
Shu Y, Leabman MK, Feng B, Mangravite LM, Huang CC, Stryke D, Kawamoto M, Johns SJ, DeYoung J, Carlson E, et al. (2003) Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc Natl Acad Sci USA 100: 5902-5907.
Simon AL, Stone EA, and Sidow A (2002) Inference of functional regions in proteins by quantification of evolutionary constraints. Proc Natl Acad Sci USA 99: 2912-2917.
Simonson G, Vincent A, Roberg K, Huang Y, and Iwanij V (1994) Molecular cloning and characterization of a novel liver-specific transport protein. J Cell Sci 107: 1065-1072.[Abstract]
Soumounou Y, Gauthier C, and Tenenhouse HS (2001) Murine and human type I Na-phosphate cotransporter genes: structure and promoter activity. Am J Physiol 281: F1082-F1091.
Stopp M, Hartwich R, and Braunlich H (1978) Enhancement of p-aminohippurate accumulation in renal cortical slices after repeated administrations of various organic anionic drugs to rats of different ages. Experientia 34: 1493-1494.[CrossRef][Medline]
Sun W, Wu RR, van Poelje PD, and Erion MD (2001) Isolation of a family of organic anion transporters from human liver and kidney. Biochem Biophys Res Commun 283: 417-422.[CrossRef][Medline]
Sweet DH, Bush KT, and Nigam SK (2001) The organic anion transporter family: from physiology to ontogeny and the clinic. Am J Physiol 281: F197-F205.
Sweet DH, Chan LM, Walden R, Yang XP, Miller DS, and Pritchard JB (2003) Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+ gradient. Am J Physiol 284: F763-F769.
Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, and Nigam SK (2002) Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 [Slc22a8]) knockout mice. J Biol Chem 277: 26934-26943.
Sweet DH and Pritchard JB (1999) The molecular biology of renal organic anion and organic cation transporters. Cell Biochem Biophys 31: 89-118.[CrossRef][Medline]
Sweet DH, Wolff NA, and Pritchard JB (1997) Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J Biol Chem 272: 30088-30095.
Syvanen AC (2001) Accessing genetic variation: genotyping single nucleotide polymorphisms. Nat Rev Genet 2: 930-942.[CrossRef][Medline]
Takeda M, Tojo A, Sekine T, Hosoyamada M, Kanai Y, and Endou H (1999) Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity. Kidney Int 56: 2128-2136.[CrossRef][Medline]
Takeda M, Babu E, Narikawa S, and Endou H (2002a) Interaction of human organic anion transporters with various cephalosporin antibiotics. Eur J Pharmacol 438: 137-142.[CrossRef][Medline]
Takeda M, Khamdang S, Narikawa S, Kimura H, Hosoyamada M, Cha SH, Sekine T, and Endou H (2002b) Characterization of methotrexate transport and its drug interactions with human organic anion transporters. J Pharmacol Exp Ther 302: 666-671.
Tamai I, Ohashi R, Nezu J-I, Sai Y, Kobayashi D, Oku A, Shimane M, and Tsuji A (2000) Molecular and functional characterization of organic cation/carnitine transporter family in mice. J Biol Chem 275: 40064-40072.
Terlouw SA, Masereeuw R, and Russel FGM (2003) Modulatory effects of hormones, drugs and toxic events on renal organic anion transport. Biochem Pharmacol 65: 1393-1405.[CrossRef][Medline]
Tsuda M, Sekine T, Takeda M, Cha SH, Kanai Y, Kimura M, and Endou H (1999) Transport of ochratoxin A by renal multispecific organic anion transporter 1. J Pharmacol Exp Ther 289: 1301-1305.
Tune BM (1997) Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention. Pediatr Nephrol 11: 768-772.[CrossRef][Medline]
Ullrich KJ (1997) Renal transporters for organic anions and organic cations. Structural requirements for substrates. J Membr Biol 158: 95-107.[CrossRef][Medline]
Wolff NA, Grunwald B, Friedrich B, Lang F, Godehardt S, and Burckhardt G (2001) Cationic amino acids involved in dicarboxylate binding of the flounder renal organic anion transporter. J Am Soc Nephrol 12: 2012-2018.
Wolff NA, Thies K, Kuhnke N, Reid G, Friedrich B, Lang F, and Burckhardt G (2003) Protein kinase C activation downregulates human organic anion transporter 1-mediated transport through carrier internalization. J Am Soc Nephrol 14: 1959-1968.
You G, Kuze K, Kohanski RA, Amsler K, and Henderson S (2000) Regulation of mOAT-mediated organic anion transport by okadaic acid and protein kinase C in LLC-PK1 cells. J Biol Chem 275: 10278-10284.
You G (2002) Structure, function and regulation of renal organic anion transporters. Med Res Rev 22: 602-616.[CrossRef][Medline]
Zalups RK and Barfuss DW (2002) Renal organic anion transport system: a mechanism for the basolateral uptake of mercury-thiol conjugates along the pars recta of the proximal tubule. Toxicol Appl Pharmacol 182: 234-243.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  V. Vallon, S. A. Eraly, W. R. Wikoff, T. Rieg, G. Kaler, D. M. Truong, S.-Y. Ahn, N. R. Mahapatra, S. K. Mahata, J. A. Gangoiti, et al. Organic Anion Transporter 3 Contributes to the Regulation of Blood Pressure J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1732 - 1740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Vallon, T. Rieg, S. Y. Ahn, W. Wu, S. A. Eraly, and S. K. Nigam Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics Am J Physiol Renal Physiol, April 1, 2008; 294(4): F867 - F873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Eraly, V. Vallon, T. Rieg, J. A. Gangoiti, W. R. Wikoff, G. Siuzdak, B. A. Barshop, and S. K. Nigam Multiple organic anion transporters contribute to net renal excretion of uric acid Physiol Genomics, April 1, 2008; 33(2): 180 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Truong, G. Kaler, A. Khandelwal, P. W. Swaan, and S. K. Nigam Multi-level Analysis of Organic Anion Transporters 1, 3, and 6 Reveals Major Differences in Structural Determinants of Antiviral Discrimination J. Biol. Chem., March 28, 2008; 283(13): 8654 - 8663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Kaler, D. M. Truong, A. Khandelwal, M. Nagle, S. A. Eraly, P. W. Swaan, and S. K. Nigam Structural Variation Governs Substrate Specificity for Organic Anion Transporter (OAT) Homologs: POTENTIAL REMOTE SENSING BY OAT FAMILY MEMBERS J. Biol. Chem., August 17, 2007; 282(33): 23841 - 23853. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Zhou, M. Hong, and G. You Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E57 - E61. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hong, F. Zhou, K. Lee, and G. You The Putative Transmembrane Segment 7 of Human Organic Anion Transporter hOAT1 Dictates Transporter Substrate Binding and Stability J. Pharmacol. Exp. Ther., March 1, 2007; 320(3): 1209 - 1215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Perry, N. Dembla-Rajpal, L. A. Hall, and J. B. Pritchard A Three-dimensional Model of Human Organic Anion Transporter 1: AROMATIC AMINO ACIDS REQUIRED FOR SUBSTRATE TRANSPORT J. Biol. Chem., December 8, 2006; 281(49): 38071 - 38079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Eraly, V. Vallon, D. A. Vaughn, J. A. Gangoiti, K. Richter, M. Nagle, J. C. Monte, T. Rieg, D. M. Truong, J. M. Long, et al. Decreased Renal Organic Anion Secretion and Plasma Accumulation of Endogenous Organic Anions in OAT1 Knock-out Mice J. Biol. Chem., February 24, 2006; 281(8): 5072 - 5083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sekine, H. Miyazaki, and H. Endou Molecular physiology of renal organic anion transporters Am J Physiol Renal Physiol, February 1, 2006; 290(2): F251 - F261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Eraly, J. C. Monte, and S. K. Nigam Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters Physiol Genomics, June 17, 2004; 18(1): 12 - 24. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
