Associate editor: K. -I. InuiDrug transport by Organic Anion Transporters (OATs)
Introduction
Organic Anion Transporters (OATs) play a pivotal role in renal excretion of water-soluble, negatively charged organic compounds including endogenous waste products, numerous drugs and drug metabolites. OATs are located in the plasma membranes of epithelial cells of proximal tubules, the site of efficient renal organic anion secretion. Selected OATs are present also outside the kidneys, e.g. in liver, placenta, nasal epithelium, and liquor-brain barrier, where they serve special functions.
Together with transporters for organic cations and zwitterions, the OATs are members of the Solute Carrier Family 22 [SLC22; (Koepsell and Endou, 2004, Jacobsson et al., 2007)]. This review will deal only with those OATs for which transport of organic anions has been shown experimentally, i.e. OATs1–4, OAT7, OAT10, and URAT1 in humans (upper case lettering), as well as Oats1–3, Oat5, Oat6, Oat8, Oat9, and Urat1/Rst in rodents (lower case lettering). Table 1 provides a summary of the OATs dealt with here. For a complete survey over all presently known SLC22 family members in humans, rats and mice see Jacobsson et al. (2007).
For each characterized OAT/Oat, cloning and protein features, tissue distribution of mRNA, subcellular localization of the OAT/Oat protein, abundance of OAT/Oat protein, function and endogenous substrates, interaction with drug classes, drug–drug interactions and single nucleotide polymorphisms are described. The interaction of OATs/Oats with exogenous and endogenous toxins is not a subject of this review.
In Chapter #6, the interaction of OAT1, OAT2, and OAT3, all located in the basolateral membrane of human renal proximal tubule cells, with selected drug classes is compared to point out which of these three transporters may be involved in the handling of antihypertensive agents, cephalosporins and nonsteroidal anti-inflammatory drugs. Such a comparison is possible because these three drug classes have been tested under similar experimental conditions with heterologously expressed OATs. For other drugs, a straightforward comparison of literature data is not possible due to the use of different expression systems (oocytes, HEK cells, immortalized mouse S2 segments, and others) and different radiolabeled or fluorescent test anions.
Section snippets
Relationships
The genetic relationship between OATs1–10 and URAT1 is shown in Fig. 1. There are two major branches that divided up early in evolution with OAT1/Oat1 and OAT3/Oat3 on the one side (A in Fig. 1), and OAT6/Oat6 on the other (B). A third branch (C) diverged into 1) the group of OAT2/Oat2 and OAT10/Oat10 (D), 2) a cluster consisting of OATs5, 7, 8, and 9 (E), and 3) the OAT4 and URAT1/Urat1 group (F). The genes for human OAT1 (SLC22A6) and OAT3 (SLC22A8) are paired on chromosome 11q12.3, and those
Cloning and protein features
As shown in Table 1, OAT1/Oat1 was cloned and functionally characterized from man, monkey, pig, rabbit, rat, and mouse. Oat1 sequences derived from many more species are deposited in gene banks, but functional studies were not reported. Four splice variants of human OAT1 occur in kidneys, the longer two of them (OAT1-1; OAT1-2) having identical transport functions and the shorter two (OAT1-3; OAT1-4) lacking transport capability (Bahn et al., 2000, Bahn et al., 2004). Human OAT1-2 is composed
Cloning and protein features
As shown in Table 1, OAT2/Oat2 was cloned from man, rat and mouse (Simonson et al., 1994, Sekine et al., 1998, Sun et al., 2001, Kobayashi et al., 2002). OAT2/Oat2 proteins consist of 535 (rat), 540 (mouse) or 546/548 (man) amino acids. The shorter splice variant of human OAT2 (546 aa) lacking a serine and a glutamine in the large extracellular loop can be functionally expressed whereas the 548 aa variant turned out to be non-functional (Cropp et al., 2008). The gene for human OAT2 is located
Cloning and protein features
As shown in Table 1, OAT3/Oat3 was cloned from man, monkey, pig, rabbit, rat, and mouse. Functionally not yet characterized Oat3 sequences were deposited for additional species in the gene bank. The respective OAT3/Oat3 proteins have 536–542 amino acids. By site-directed mutagenesis of rat Oat3, amino acid residues in TMHs 7, 8, and 11 were found to be involved in substrate binding (Feng et al., 2001, Feng et al., 2002). The gene for human OAT3, SLC22A8, is located on chromosome 11q12.3, in
Interactions of OAT1, OAT2, and OAT3 with selected drug classes
In human kidneys, these three transporters are located in the basolateral membrane of proximal tubule cells and thus are likely instrumental in the uptake of drugs from the blood into proximal tubule cells. Drug uptake through OAT1 and OAT3 is driven by the efflux of α-ketoglutarate (dic2− in Fig. 2). In case of OAT2, succinate (or fumarate) drives drug uptake. α-Ketoglutarate and succinate are substrates of the sodium-dicarboxylate cotransporter 3 (NaDC3 or NaC3) and intermediate products of
Cloning and protein features
OAT4 was cloned from a human kidney library (Cha et al., 2000). There is no ortholog in rodents. A monkey OAT4 is deposited in the gene bank. The human OAT4 protein consists of 550 amino acids. N-linked glycosylation at residues in the large extracellular loop is required for targeting of OAT4 to the membrane and proper transport function (Zhou et al., 2005). Through its C-terminal PDZ motif OAT4 interacts with the scaffolding proteins PDZK1 and NHERF1, and expression of these proteins
Cloning and protein features of human OAT5
This transporter was cloned from human liver, the only organ in which OAT5 is expressed (Sun et al., 2001, Eraly and Nigam, 2002). The protein consists of 541 amino acids. The expression was trans-activated by HNF-1α and, in human liver biopsies, expression levels of HNF-1α and OAT5 correlated positively (Klein et al., 2010). The gene coding for human OAT5, SLC22A10, is located on chromosome 11q12.3 (Jacobsson et al., 2007). There is no rodent homologue of OAT5. The function of OAT5 is unknown.
Cloning and protein features of Oat5
As shown in Table 1, Oat5 was cloned from rat and mouse (Youngblood and Sweet, 2004, Anzai et al., 2005). Rat Oat5 has 551 amino acids. The gene, Slc22a19, is located on chromosome 1q43 in rat and on 19qA in mouse (Jacobsson et al., 2007). Rodent Oat5 (Slc22a19) is not homologous to human OAT5 (SLC22A10).
Tissue distribution and location of Oat5
In rats and mice, this transporter is restricted to the kidneys where it is expressed in the apical membrane of late proximal tubule cells (Youngblood and Sweet, 2004, Anzai et al., 2005, Kwak
Cloning and protein features
Oat6 was cloned from mouse (Monte et al., 2004, Schnabolk et al., 2006). The protein has 556 amino acids. The gene, Slc22a20, is located on chromosome 19qA. In rats, a homologous gene was found on chromosome 1q43 (Jacobsson et al., 2007). A human OAT6 is deposited in the gene bank, but has not been functionally characterized.
Tissue distribution and location of Oat6
Messenger RNA for murine Oat6 was detected in nasal olfactory mucosa and, to a smaller extent, in testis; no expression was found in kidneys and liver (Monte et al., 2004,
Cloning, protein features, and tissue distribution
Previously known as UST3 or OAT4, OAT7 has been cloned from a human liver library (Shin et al., 2007). OAT7 is a 553 amino acid protein and is restricted to the liver where it is located in the sinusoidal membrane. The expression of OAT7 was trans-activated by HNF-1α (Klein et al., 2010). The gene, SLC22A9, is located on human chromosome 11q12.3 (Jacobsson et al., 2007).
Function of OAT7 and endogenous substrates
OAT7 transported ES (Km 8.7 μM) and DHEAS (Km 2.2 μM) with high affinity. Unlike other OATs, OAT7 did not interact with
Cloning, protein features, and tissue distribution
Previously cloned as Ust1, functional expression revealed the ability to transport organic anions. Hence, the transporter was renamed as rat Oat8 (Yokoyama et al., 2008). Oat8 mRNA occurred in kidneys, but not in liver. Immunoreactivity was found in the intercalated cells of collecting ducts. In acid-secreting intercalated cells (type A), Oat8 was detected in the apical cell membrane. In acid-absorbing (bicarbonate-secreting) type B cells, Oat8 occurred at the basolateral cell side. Thus, Oat8
Cloning, protein features, and tissue distribution
Two clones, one coding for a long form (Oat9L) and one for a short form (Oat9S) of Oat9 were obtained from mouse. The long Oat9 protein consists of 551 amino acids with the usual 12 transmembrane helices. The short Oat9 protein is lacking transmembrane helices 3–6. The mRNA occurred predominantly in the kidneys and, more weakly, in the liver. Immunohistochemistry with antibodies reacting with both isoforms located Oat9 to the apical membrane of proximal tubule cells (segments S1 and S2) and to
Cloning, protein features, and tissue distribution
Previously cloned as “organic cation transporter like 3 (ORCTL3)” this transporter turned out to be an organic anion transporter and was renamed OAT10. The mRNA for full length OAT10 and splice variants was predominantly expressed in kidneys and – to a weaker extent – in brain, heart and colon. In the kidneys, the highest amount of mRNA was found in proximal tubules and less in collecting ducts. Western blot studies on isolated membranes indicated that the OAT10 protein is expressed in the
Cloning and protein features
Originally cloned as “renal specific transporter (Rst)”, the human homolog transported urate and therefore was named “Urate Transporter 1 (URAT1)” (Enomoto et al., 2002a). For the functional mouse clone (Hosoyamada et al., 2004, Imaoka et al., 2004), either Rst or Urat1 are used as names. URAT1 protein has 555 amino acids, Urat1/Rst 553 amino acids. The gene for human URAT1, SLC22A12, is located on chromosome 11q13.1, in close neighborhood to the gene SLC22A11 coding for OAT4 (Eraly et al.,
Pharmacological role of OATs 1–3
Organic Anion Transporters 1–3 in humans and Oat1 and Oat3 in rodents are located in the basolateral membrane of renal proximal tubule cells (Fig. 10). This in vivo location and the in vitro interaction of OATs1–3 with various drug classes strongly suggest their involvement in drug uptake from the blood into proximal tubule cells. Uptake across the basolateral membrane is the first step in transcellular drug secretion and is likely energized by the release of dicarboxylates from the cell to the
References (248)
- et al.
Interaction of organic cations with organic anion transporters
J Biol Chem
(2009) - et al.
Renal xenobiotic transporters are differentially expressed in mice following cisplatin treatment
Toxicology
(2008) - et al.
The multivalent PDZ domain-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C terminus
J Biol Chem
(2004) - et al.
Role of human organic anion transporter 4 in the transport of ochratoxin A
Biochim Biophys Acta
(2002) - et al.
Human organic anion transporters mediate the transport of tetracycline
Jpn J Pharmacol
(2002) - et al.
Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13)
J Biol Chem
(2008) - et al.
Genomic structure and in vivo expression of the human organic anion transporter 1 (hOAT1) gene
Biochem Biophys Res Commun
(2000) - et al.
Activation of protein kinase Cζ increases OAT1 (SLC22A6)- and OAT3 (SLC22A8)-mediated transport
J Biol Chem
(2009) - et al.
A novel putative transporter maps top the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse
Genomics
(1999) - et al.
Renal elimination of p-aminohippurate (PAH) in response to three days of biliary obstruction in the rat. The role of OAT1 and OAT3
Biochim Biophys Acta
(2006)
Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta
J Biol Chem
Fluorescence-based assay for the interaction of small molecules with the human renal organic anion transporter 1
Anal Biochem
Characterization of uremic toxin transport by organic anion transporters in the kidney
Kidney Int
Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules
J Pharmacol Sci
Interactions of human organic anion as well as cation transporters with indoxyl sulfate
Eur J Pharmacol
Organic anion and cation transporters occur in pairs of similar and similarly expressed genes
Biochem Biophys Res Commun
Novel human cDNAs homologous to Drosophila Orct and mammalian carnitine transporters
Biochem Biophys Res Commun
Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knockout mice
J Biol Chem
Expression of slc5a8 in kidney and its role in Na+-coupled transport of lactate
J Biol Chem
Restored expression and activity of organic ion transporters rOAT1, rOAT3 and rOCT2 after hyperuricemia in the rat kidney
Biochem Pharmacol
Functional expression of pig renal organic anion transporter 3 (pOAT3)
Biochimie
COX-2 inhibition attenuates endotoxin-induced downregulation of organic anion transporters in the renal cortex
Kidney Int
Urate transport via human PAH transporter hOAT1 and its gene structure
Kidney Int
Identification of six putative human transporters with structural similarity to the drug transporter SLC22 family
Genomics
Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy
Kidney Int
Characterization of ochratoxin A transport by human organic anion transporters
Life Sci
Involvement of rat organic anion transporter 3 (rOAT3) in cephaloridine-induced nephrotoxicity: in comparison with rOAT1
Life Sci
Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate
J Biol Chem
Structural variation governs substrate specificity for organic anion transporter (OAT) homologs. Potential remote sensing by OAT family members
J Biol Chem
The interaction between methotrexate and probenecid in man
Br J Pharmacol
Expression of human organic anion transporter in the choroid plexus and their interactions with neurotransmitter metabolites
J Pharmacol Sci
Functional characterization of rat organic anion transporter 5 (Slc22a19) at the apical membrane of renal proximal tubules
J Pharmacol Exp Ther
Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes
Mol Pharmacol
Presence of organic anion transporters 3 (OAT3) and 4 (OAT4) in human adrenocortical cells
Pflügers Arch. - Eur J Physiol
Xenobiotic and endobiotic transporter mRNA expression in the blood–testis barrier
Drug Metab Dispos
Expression studies and functional characterization of renal human organic anion transporter 1 isoforms
Drug Metab Dispos
Interaction of the metal chelator 2,3-dimercapto-1-propane sulfonate with the rabbit multispecific organic anion transporter 1 (rbOAT1)
Mol Pharmacol
Murine renal organic anion transporters mOAT1 and mOAT3 facilitate the transport of neuroactive tryptophan metabolites
Am J Physiol Cell Physiol
Human organic anion transporter 3 (hOAT3) can operate as an exchanger accepting urate as a substrate
Cell Physiol Biochem
Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition
Xenobiotica
Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6)
J Pharmacol Exp Ther
The impact of plasma protein binding on the renal transport of organic anions
J Pharmacol Exp Ther
Compensation increase in organic anion excretion in rats with acute biliary obstruction: role of the renal organic anion transporter 1
Pharmacology
Expression of rat renal cortical OAT1 and OAT3 in response to acute biliary obstruction
Hepatology
Gender-specific and developmental influences on the expression of rat organic anion transporters
J Pharmacol Exp Ther
Endocrine regulation of rat organic anion transporters
Drug Metab Dispos
Rat and mouse differences in gender-predominant expression of organic anion transporter (OAT1-3, SLC22A6-8) mRNA levels
Drug Metab Dispos
Transport of cimetidine by flounder and human renal organic anion transporter 1
Am J Physiol Renal Physiol
Transport of organic anions across the basolateral membrane of proximal tubule cells
Rev Physiol Biochem Pharmacol
In vitro and in vivo evidence of the importance of organic anion transporters (OATs) in drug therapy
Cited by (280)
When the same treatment has different response: The role of pharmacogenomics in statin therapy
2024, Biomedicine and Pharmacotherapy