Abstract
Organic anion transporters (OATs) translocate drugs as well as endogenous substances and toxins. The prototype, OAT1 (SLC22A6), first identified as NKT in 1996, is the best-studied member of the OAT subgroup of the SLC22 transporter family, which also includes OCTs (organic cation transporters), OCTNs (organic cation transporters of carnitine) and Flipts (fly-like putative transporters). The SLC22 family is evolutionarily conserved, with members expressed in fly and worm. An unusual feature of many SLC22A genes is a tendency to exist in pairs or clusters in the genome. Much of the early research in the field focused on the role of OATs and other SLC22 family members in renal drug transport. OATs have now been localized to other epithelial tissues, including placenta (OAT4) and mouse olfactory mucosa (Oat6). Although findings from in vivo physiological studies in mice lacking OATs (e.g. Oat1 and Oat3) have generally been consistent with in vitro transport data from Xenopus oocytes and transfected cells, these in vivo data are helping to clarify the relative contributions of individual OATs to the renal excretion of particular organic anions and drugs. Moreover, in mutant mice, certain endogenous anions accumulate, suggesting the physiological roles of the proteins encoded by the mutant genes. It has been proposed that the presence of OATs and other SLC22-family members in multiple tissue compartments might enable a 'remote sensing' mechanism by allowing communication between organs, and possibly individuals, through organic ions. Variability of human drug responses and susceptibility to drug toxicity might, in part, be explained by variations in the coding and promoter regions of these genes. Computational biological studies are likely to not only shed light on molecular mechanisms of transport for compounds of clinical and toxicological interest, but also aid in drug design.
Key Points
-
Organic anion transporters (OATs) translocate drugs (e.g. antibiotics, diuretics, nonsteroidal anti-inflammatory agents, antiviral agents), endogenous substances (e.g. folate) and nephrotoxins (e.g. ochratoxin A and mercurials)
-
Seven OATs—all members of the SLC22 family—have been identified
-
OATs are antiporters, linked to the sodium–dicarboxylate cotransporter and the sodium–potassium ATPase
-
OAT1 and OAT3 are expressed in the basolateral membranes of tubule cells
-
Study of OAT single nucleotide polymorphisms might facilitate prediction of drug response and toxicity in individual patients
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
You G (2002) Structure, function, and regulation of renal organic anion transporters. Med Res Rev 22: 602–616
Sweet DH et al. (2001) The organic anion transporter family: from physiology to ontogeny and the clinic. Am J Physiol Renal Physiol 281: F197–F205
Wright SH and Dantzler WH (2004) Molecular and cellular physiology of renal organic cation and anion transport. Physiol Rev 84: 987–1049
Eraly SA et al. (2004) The molecular pharmacology of organic anion transporters: from DNA to FDA? Mol Pharmacol 65: 479–487
Moller JV and Sheikh MI (1982) Renal organic anion transport system: pharmacological, physiological, and biochemical aspects. Pharmacol Rev 34: 315–358
Miyazaki H et al. (2004) The multispecific organic anion transporter family: properties and pharmacological significance. Trends Pharmacol Sci 25: 654–662
Lopez-Nieto CE et al. (online 29 March 1997) Mus musculus kidney-specific transport protein mRNA, complete cds. GenBank accession number: U52842 [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nuccore&id=1293671] (accessed 11 June 2007)
Lopez-Nieto CE et al. (1996) Molecular cloning and characterization of a novel transport protein with very high expression in the kidney [abstract]. J Am Soc Nephrol 7: a1301
Lopez-Nieto CE et al. (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
Pavlova A et al. (1999) Evolution of gene expression patterns in a model of branching morphogenesis. Am J Physiol Renal Physiol 277: F650–F663
Sekine T et al. (1997) Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem 272: 18526–18529
Sweet DH et al. (1997) Expression cloning and characterization of ROAT1: the basolateral organic anion transporter in rat kidney. J Biol Chem 272: 30088–30095
Wolff NA et al. (1997) Expression cloning and characterization of a renal organic anion transporter from winter flounder. FEBS Lett 417: 287–291
Grundemann D et al. (1994) Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372: 549–552
Eraly SA and Nigam SK (2002) Novel human cDNAs homologous to Drosophila Orct and mammalian carnitine transporters. Biochem Biophys Res Commun 297: 1159–1166
Eraly SA et al. (2004) Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters. Physiol Genomics 18: 12–24
Van Aubel RAMH et al. (2000) Molecular pharmacology of renal organic anion transporters. Am J Physiol Renal Physiol 279: F216–F232
Dresser MJ et al. (2001) Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci 90: 397–421
Sweet DH (2005) Organic anion transporter (Slc22a) family members as mediators of toxicity. Toxicol Appl Pharmacol 204: 198–215
Brady KP et al. (1999) A novel putative transporter maps to the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse. Genomics 56: 254–261
Burckhardt BC and Burckhardt G (2003) Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol 146: 95–158
Schnabolk GW et al. (2006) Transport of estrone sulfate by the novel organic anion transporter Oat6 (Slc22a20). Am J Physiol Renal Physiol 291: F314–F321
Hong M et al. (2005) Human organic anion transporter hOAT1 forms homooligomers. J Biol Chem 280: 32285–32290
Tanaka K et al. (2004) Role of glycosylation in the organic anion transporter OAT1. J Biol Chem 279: 14961–14966
You G et al. (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
Bow DA et al. (2006) The impact of plasma protein binding on the renal transport of organic anions. J Pharmacol Exp Ther 316: 349–355
Brater DC et al. (1983) Bumetanide and furosemide. Clin Pharmacol Ther 34: 207–213
Kim GH (2004) Long-term adaptation of renal ion transporters to chronic diuretic treatment. Am J Nephrol 24: 595–605
Eraly SA et al. (2006) Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J Biol Chem 281: 5072–5083
Sweet DH et al. (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
Eraly SA et al. (2003) Organic anion and cation transporters occur in pairs of similar and similarly expressed genes. Biochem Biophys Res Commun 300: 333–342
Groves CE et al. (1998) Peritubular transport of ochratoxin A in rabbit renal proximal tubules. J Pharmacol Exp Ther 284: 943–948
Aslamkhan AG et al. (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
Bahn A et al. (2002) Interaction of the metal chelator 2,3-dimercapto-1-propanesulfonate with the rabbit multispecific organic anion transporter 1 (rbOAT1). Mol Pharmacol 62: 1128–1136
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 Applied Pharmacol 182: 234–243
Ho ES et al. (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
Shitara Y et al. (2005) Evaluation of drug–drug interaction in the hepatobiliary and renal transport of drugs. Annu Rev Pharmacol Toxicol 45: 689–723
Nozaki Y et al. (2004) Quantitative evaluation of the drug–drug interactions between methotrexate and nonsteroidal anti-inflammatory drugs in the renal uptake process based on the contribution of organic anion transporters and reduced folate carrier. J Pharmacol Exp Ther 309: 226–234
Buist SC et al. (2003) Endocrine regulation of rat organic anion transporters. Drug Metab Dispos 31: 559–564
Buist SCN and Klaassen CD (2004) Rat and mouse differences in gender-predominant expression of organic anion transporter (oat1-3; slc22a6-8) mRNA levels. Drug Metab Dispos 32: 620–625
Ljubojevic M et al. (2004) Rat renal cortical OAT1 and OAT3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition. Am J Physiol Renal Physiol 287: F124–F138
Cerrutti JA et al. (2002) Sex differences in p-aminohippuric acid transport in rat kidney: role of membrane fluidity and expression of OAT1. Mol Cell Biochem 233: 175–179
Xu G et al. (2005) Analyses of coding region polymorphisms in apical and basolateral human organic anion transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT (RST)]. Kidney Int 68: 1491–1499
Bleasby K et al. (2005) Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6). J Pharmacol Exp Ther 314: 923–931
Fujita T et al. (2005) Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1). Pharmacogenet Genomics 15: 201–209
Bhatnagar V et al. (2006) Analyses of 5′ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3). J Hum Genet 51: 575–580
Pavlova A et al. (2000) Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct. Am J Physiol Renal Physiol 278: F635–F643
Sweet DH et al. (2006) Organic anion and cation transporter expression and function during embryonic kidney development and in organ culture models. Kidney Int 69: 837–845
Nakajima N et al. (2000) Developmental changes in multispecific organic anion transporter 1 expression in the rat kidney. Kidney Int 57: 1608–1616
Sekine T et al. (2006) Molecular physiology of renal organic anion transporters. Am J Physiol Renal Physiol 290: F251–F261
Kaler G et al. (2006) Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions. Biochem Biophys Res Commun 351: 872–876
Monte JC et al. (2004) Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa. Biochem Biophys Res Commun 323: 429–436
Schnabolk GW et al. (2006) Transport of estrone sulfate by the novel organic anion transporter Oat6 (Slc22a20). Am J Physiol Renal Physiol 291: F314–F321
Kusuhara H and Sugiyama Y (2005) Active efflux across the blood–brain barrier: role of the solute carrier family. NeuroRx 2: 73–85
Cha SH et al. (2000) Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem 275: 4507–4512
Nagata Y et al. (2002) Expression and functional characterization of rat organic anion transporter 3 (rOat3) in the choroid plexus. Mol Pharmacol 61: 982–988
Sekine T et al. (1998) Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett 429: 179–182
Simonson G et al. (1994) Molecular cloning and characterization of a novel liver-specific transport protein. J Cell Sci 107: 1065–1072
Eraly SA et al. (2003) Novel aspects of renal organic anion transporters. Curr Opin Nephrol Hypertens 12: 551–558
Kaler G et al. (2007) Structural variation governs substrate specificity for organic anion transporters (oat) homologs: potential remote sensing by oat family members. J Biol Chem [doi:10.1074/jbc.M703467200]
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Nigam, S., Bush, K. & Bhatnagar, V. Drug and toxicant handling by the OAT organic anion transporters in the kidney and other tissues. Nat Rev Nephrol 3, 443–448 (2007). https://doi.org/10.1038/ncpneph0558
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ncpneph0558
This article is cited by
-
Susceptibility genes of hyperuricemia and gout
Hereditas (2022)
-
Genome-wide methylation profiling of the different stages of hepatitis B virus-related hepatocellular carcinoma development in plasma cell-free DNA reveals potential biomarkers for early detection and high-risk monitoring of hepatocellular carcinoma
Clinical Epigenetics (2014)
-
Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy
Kidney International (2012)
-
Quercetin regulates organic ion transporter and uromodulin expression and improves renal function in hyperuricemic mice
European Journal of Nutrition (2012)
-
Membrane transporters in drug development
Nature Reviews Drug Discovery (2010)