Update on the molecular physiology of organic anion transporters

Current Opinion in Nephrology and Hypertension

Volumn 17, Issue 5, 2008, Pages 499-505

  Ahn, Sun Young ^a   Bhatnagar, Vibha ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b VA SAN DIEGO HEALTHCARE SYSTEM   (United States)

Author keywords

Ischemia; Nephrotoxicity; OAT; Organic anion transporter; Pharmacogenetics

Indexed keywords

ADEFOVIR; CIDOFOVIR; FLAVONOID; GEMFIBROZIL; METHOTREXATE; MYCOPHENOLIC ACID; MYCOTOXIN; NONSTEROID ANTIINFLAMMATORY AGENT; NORPHENAZONE; ORGANIC ANION TRANSPORTER; PENICILLIN G; POLYCYCLIC AROMATIC HYDROCARBON; PRAVASTATIN; PROBENECID; QUINOLINE DERIVED ANTIINFECTIVE AGENT; ROSUVASTATIN; SALICYLIC ACID; TENOFOVIR;

BLOOD PRESSURE REGULATION; BRAIN INFARCTION; DNA POLYMORPHISM; DRUG DESIGN; DRUG ELIMINATION; DRUG TOXICITY; ENZYME SPECIFICITY; HUMAN; KIDNEY ISCHEMIA; KIDNEY TUBULE ABSORPTION; MUSCLE DISEASE; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DETERMINATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; PROTEIN TRANSPORT; REVIEW; TREATMENT RESPONSE; URINARY EXCRETION; ANIMAL; GENETICS; ISCHEMIA; KIDNEY; METABOLISM; PATHOPHYSIOLOGY; PHYSIOLOGY; VASCULARIZATION;

ANIMALS; HUMANS; ISCHEMIA; KIDNEY; ORGANIC ANION TRANSPORTERS; SUBSTRATE SPECIFICITY;

EID: 58149357521     PISSN: 10624821     EISSN: None     Source Type: Journal    
DOI: 10.1097/MNH.0b013e32830b5d5d     Document Type: Review

References (91)

1. Dresser MJ, Leabman MK, Giacomini KM. Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J Pharm Sci 2001; 90:397-421.
2. Eraly SA, Monte JC, Nigam SK. Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters. Physiol Genomics 2004; 18:12-24.
3. Eraly SA, Nigam SK. Novel human cDNAs homologous to Drosophila Orct and mammalian carnitine transporters. Biochem Biophys Res Commun 2002; 297:1159-1166.
4. Koepsell H. Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol Sci 2004; 25:375-381.
5. Sweet DH, Bush KT, Nigam SK. The organic anion transporter family: from physiology to ontogeny and the clinic. Am J Physiol Renal Physiol 2001; 281:F197-F205.
6. Lopez-Nieto CE, You G, Bush KT, et al. Molecular cloning and characterization of NKT, a gene product related to the organic cation transporterfamily that is almost exclusively expressed in the kidney. J Biol Chem 1997; 272:6471 -6478.
7. Kojima R, Sekine T, Kawachi M, et al. Immunolocalization of multispecific organic anion transporters, OAT1, OAT2, and OAT3, in rat kidney. J Am Soc Nephrol 2002; 13:848-857.
8. Motohashi H, Sakurai Y, Saito H, et al. Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 2002; 13:866-874.
9. Sweet DH, Wolff NA, Pritchard JB. Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J Biol Chem 1997; 272:30088-30095.
10. Sweet DH, Miller DS, Pritchard JB, et al. Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem 2002; 277:26934-26943.
11. Rizwan AN, Burckhardt G. Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharm Res 2007; 24:450-470. This is an excellent review that provides a comprehensive overview of the interaction of human OATs with drugs.
12. Russel FG, Masereeuw R, van Aubel RA. Molecular aspects of renal anionic drug transport. Annu Rev Physiol 2002; 64:563-594.
13. Burckhardt BC, Burckhardt G. Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol 2003; 146:95-158.
14. Eraly SA, Bush KT, Sampogna RV, et al. The molecular pharmacology of organic anion transporters: from DNA to FDA? Mol Pharmacol 2004; 65:479-487.
15. Robertson EE, Rankin GO. Human renal organic anion transporters: characteristics and contributions to drug and drug metabolite excretion. Pharmacol Ther 2006; 109:399-412.
16. VanwertAL, Bailey RM, Sweet DH. Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G. Am J Physiol Renal Physiol 2007; 293:F1332-F1341.
17. Vanwert AL, Srimaroeng C, Sweet DH. Organic anion transporter 3 (Oat3/ Slc22a8) interacts with carboxyfluoroquinolones and deletion increases systemic exposure to ciprofloxacin. Mol Pharmacol 2008;1 Apr [Epub ahead of print].
18. Uwai Y, IdaH,Tsuji Y, et al. Renal transport of adefovir, cidofovir, and tenofovir by SLC22A family members (hOAT1, hOAT3, and hOCT2). Pharm Res 2007; 24:811.
19. Windass AS, Lowes S, Wang Y, Brown CD. The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther 2007; 322:1221 -1227.
20. Wolff NA, Burckhardt BC, Burckhardt G, et al. Mycophenolic acid (MPA) and its glucuronide metabolites interact with transport systems responsible for excretion of organic anions in the basolateral membrane of the human kidney. Nephrol Dial Transplant 2007; 22:2497-2503.
21. Uwai Y, Motohashi H, Tsuji Y, et al. Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3. Biochem Pharmacol 2007; 74:161 -168.
22. Mizuno N, Takahashi T, Iwase Y, et al. Human organic anion transporters 1 (hOAT1/SLC22A6) and 3 (hOAT3/SLC22A8) transport edaravone (MCI-186; 3-methyl-1-phenyl-2-pyrazolin-5-one) and its sulfate conjugate. Drug Metab Dispos 2007; 35:1429-1434.
23. Hong SS, Seo K, Lim SC, Han HK. Interaction characteristics of flavonoids with human organic anion transporter 1 (hOAT1) and 3 (hOAT3). Pharmacol Res 2007; 56:468-473.
24. Tachampa K, Takeda M, Khamdang S, et al. Interactions of organic anion transporters and organic cation transporters with mycotoxins. J Pharmacol Sci 2008; 106:435-443.
25. Gwak HS, Oh JH, Han HK. Effects of nonsteroidal anti-inflammatory drugs on the pharmacokinetics and elimination of aciclovir in rats. J Pharm Pharmacol 2005; 57:393-398.
26. Hedaya MA, Elmquist WF, Sawchuk RJ. Probenecid inhibits the metabolic and renal clearances of zidovudine (AZT) in human volunteers. Pharm Res 1990; 7:411 -417.
27. Overbosch D, Van Gulpen C, Hermans J, Mattie H. The effect of probenecid on the renal tubular excretion of benzylpenicillin. Br J Clin Pharmacol 1988; 25:51 -58.
28. Nozaki Y, Kusuhara H, Endou H, Sugiyama Y. 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 2004; 309:226-234.
29. Nierenberg DW. Competitive inhibition of methotrexate accumulation in rabbit kidney slices by nonsteroidal anti-inflammatory drugs. J Pharmacol Exp Ther 1983; 226:1 -6.
30. Liegler DG, Henderson ES, Hahn MA, Oliverio VT. The effect of organic acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 1969; 10:849-857.
31. Bourke RS, Chheda G, Bremer A, et al. Inhibition of renal tubular transport of methotrexate by probenecid. Cancer Res 1975; 35:110-116.
32. Nakagomi-Hagihara R, Nakai D, Tokui T. Inhibition of human organic anion transporter 3 mediated pravastatin transport by gemfibrozil and the metabolites in humans. Xenobiotica 2007; 37:416-426.
33. Ullrich KJ, Rumrich G, Kloss S. Contraluminal para-aminohippurate (PAH) transport in the proximal tubule of the rat kidney. IV. Specificity: mono- and polysubstituted benzene analogs. Pflugers Arch 1988; 413:134-146.
34. Kaler G, Truong DM, Khandelwal A, et al. Structural variation governs substrate specificity for organic anion transporter (OAT) homologs: potential remote sensing by OAT family members. J Biol Chem 2007; 282:23841-23853.
35. Truong DM, Kaler G, Khandelwal A, et al. Multilevel analysis of organic anion transporters 1,3, and 6 reveals major differences in structural determinants of antiviral discrimination. J Biol Chem 2008; 283:8654-8663.
36. Eraly SA, Vallon V, Vaughn DA, et al. Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J Biol Chem 2006; 281:5072-5083.
37. Hagos Y, Krick W, Braulke T, et al. Organic anion transporters OAT1 and OAT4 mediate the high affinity transport of glutarate derivatives accumulating in patients with glutaric acidurias. Pflugers Arch 2008; 265 Mar [Epub ahead of print].
38. Islam R, Anzai N, Ahmed N, et al. Mouse organic anion transporter 2 (mOat2) mediates the transport of short chain fatty acid propionate. J Pharmacol Sci 2008; 106:525-528.
39. Nilwarangkoon S, Anzai N, Shiraya K, et al. Role of mouse organic anion transporter 3 (mOat3) as a basolateral prostaglandin E2 transport pathway. J Pharmacol Sci 2007; 103:48-55.
40. Mount DB. Molecular physiology and the four-component model of renal urate transport. Curr Opin Nephrol Hypertens 2005; 14:460-463.
41. Nakagawa T, Kang DH, Feig D, et al. Unearthing uric acid: an ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int 2006; 69:1722-1725.
42. Eraly SA, Vallon V, Rieg T, et al. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol Genomics 2008; 33:180-192.
43. Anzai N, Kanai Y, Endou H. New insights into renal transport of urate. Curr Opin Rheumatol 2007; 19:151-157.
44. Bahn A, Hagos Y, Reuter S, et al. Identification of a new urate and high affinity nicotinate transporter: human organic anion transporter 10 (hOAT10, SLC22A13. J Biol Chem 2008; 283:16332-16341.
45. Vitart V, Rudan I, Hayward C, et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 2008; 40:437-442.
46. Komatsuda A, Iwamoto K, Wakui H, et al. Analysis of mutations in the urate transporter 1 (URAT1) gene of Japanese patients with hypouricemia in northern Japan and review of the literature. Ren Fail 2006; 28:223-227.
47. Doring A, Gieger C, Mehta D, et al. SLC2A9 influences uric acid concentrations with pronounced sex-specific effects. Nat Genet 2008; 40:430-436.
48. Li S, Sanna S, Maschio A, et al. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLoS Genet 2007; 3:e1 94.
49. Wallace C, Newhouse SJ, Braund P, et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet 2008; 82:139-149.
50. Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417:447-452.
51. Vazquez-MelladoJ, Alvarado-Romano V, Burgos-Vargas R, et al. Homozygous frameshift mutation in the SLC22A12 gene in a patient with primary gout and high levels of serum uric acid. J Clin Pathol 2007; 60:947-948.
52. Vallon V, Eraly SA, Wikoff WR, et al. Organic anion transporter 3 contributes to the regulation of blood pressure. J Am Soc Nephrol 2008; May [Epub ahead of print].
53. Sekine T, Miyazaki H, Endou H. Molecular physiology of renal organic anion transporters. Am J Physiol Renal Physiol 2006; 290:F251 -F261.
54. Nigam SK, Bush KT, Bhatnagar V. Drug and toxicant handling by the OAT organic anion transporters in the kidney and other tissues. Nat Clin Pract Nephrol 2007; 3:443-448.
55. Koepsell H, Endou H. The SLC22 drug transporter family. Pflugers Arch 2004; 447:666-676.
56. Shin HJ, Anzai N, Enomoto A, et al. Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate. Hepatology 2007; 45:1046-1055.
57. Zhou F, You G. Molecular insights into the structure-function relationship of organic anion transporters OATs. Pharm Res 2007; 24:28-36.
58. Monte JC, Nagle MA, Eraly SA, Nigam SK. Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa. Biochem Biophys Res Commun 2004; 323:429-436.
59. Kaler G, Truong DM, Sweeney DE, et al. Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions. Biochem Biophys Res Commun 2006; 351:872-876.
60. Sekine T, Cha SH, Tsuda M, et al. Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett 1998; 429:1 79-182.
61. Brown AJ, Goldsworthy SM, Barnes AA, et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 2003; 278:11312-11319.
62. Xiong Y, Miyamoto N, Shibata K, et al. Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41. Proc Natl Acad Sci USA 2004; 101:1045-1050.
63. Cropp CD, Komori T, Shima JE, et al. Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Mol Pharmacol 2008; 73:1151 -1158.
64. Barasch J. Genes and proteins involved in mesenchymal to epithelial transition. Curr Opin Nephrol Hypertens 2001; 10:429-436.
65. Pontoglio M. Hepatocyte nuclear factor 1, a transcription factor at the crossroads of glucose homeostasis. J Am Soc Nephrol 2000; 11 (Suppl 16):S140-S143.
66. Eraly SA, Hamilton BA, Nigam SK. Organic anion and cation transporters occur in pairs of similar and similarly expressed genes. Biochem Biophys Res Commun 2003; 300:333-342.
67. Eraly SA, Blantz RC, Bhatnagar V, Nigam SK. Novel aspects of renal organic anion transporters. Curr Opin Nephrol Hypertens 2003; 12:551 -558.
68. Pontoglio M, Prie D, Cheret C, et al. HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO Rep 2000; 1:359-365.
69. Maher JM, Slitt AL, Callaghan TN, et al. Alterations in transporter expression in liver, kidney, and duodenum after targeted disruption of the transcription factor HNF1alpha. Biochem Pharmacol 2006; 72:512-522.
70. OgasawaraK,TeradaT, AsakaJ, et al. Hepatocyte nuclearfactor-4a regulates the human organic anion transporter 1 gene in the kidney. Am J Physiol Renal Physiol 2007; 292:F1819-F1826.
71. Saji T, Kikuchi R, Kusuhara H, et al. Transcriptional regulation of human and mouse organic anion transporter 1 by hepatocyte nuclear factor 1 alpha/beta. J Pharmacol Exp Ther 2008; 324:784-790.
72. Kikuchi R, Kusuhara H, Hattori N, et al. Regulation of tissue-specific expres-sion of the human and mouse urate transporter 1 gene by hepatocyte nuclear factor 1 alpha/beta and DNA methylation. Mol Pharmacol 2007; 72:1619-1625.
73. Kikuchi R, Kusuhara H, Hattori N, et al. Regulation of the expression of human organic anion transporter 3 by hepatocyte nuclear factor 1alpha/beta and DNA methylation. Mol Pharmacol 2006; 70:887-896.
74. Buist SC, Klaassen CD. Rat and mouse differences in gender-predominant expression of organic anion transporter (Oat1-3; Slc22a6-8) mRNA levels. Drug Metab Dispos 2004; 32:620-625.
75. Kobayashi Y, Hirokawa N, Ohshiro N, et al. Differential gene expression of organic anion transporters in male and female rats. Biochem Biophys Res Commun 2002; 290:482-487.
76. Kudo N, Katakura M, Sato Y, Kawashima Y. Sex hormone-regulated renal transport of perfluorooctanoic acid. Chem Biol Interact 2002; 139:301 -31 6.
77. Ljubojevic M, Balen D, Breljak D, et al. Renal expression of organic anion transporter OAT2 in rats and mice is regulated by sex hormones. Am J Physiol Renal Physiol 2007; 292:F361-F372.
78. Zhou F, Hong M, You G. Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells. Am J Physiol Endocrinol Metab 2007; 293:E57-E61.
79. Brone B, Eggermont J. PDZ proteins retain and regulate membrane transporters in polarized epithelial cell membranes. Am J Physiol Cell Physiol 2005; 288:C20-C29.
80. Zhou F, Xu W, Tanaka K, You G. Comparison of the interaction of human organic anion transporter hOAT4 with PDZ proteins between kidney cells and placental cells. Pharm Res 2008; 25:475-480.
81. Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med 1996; 334:1448-1460.
82. Kwon O, Hong SM, Blouch K. Alteration in renal organic anion transporter 1 after ischemia/reperfusion in cadaveric renal allografts. J Histochem Cyto-chem 2007; 55:575-584.
83. Matsuzaki T, Watanabe H, Yoshitome K, et al. Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure. Kidney Int 2007; 71:539-547.
84. Schneider R, Sauvant C, Betz B, et al. Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats. Am J Physiol Renal Physiol 2007; 292:F1599-F1605.
85. Di Giusto G, Anzai N, Endou H, Torres AM. Elimination of organic anions in response to an early stage of renal ischemia-reperfusion in the rat: role of basolateral plasma membrane transporters and cortical renal blood flow. Pharmacology 2008; 81:127-136.
86. Ogasawara K, Terada T, Motohashi H, et al. Analysis of regulatory polymorphisms in organic ion transporter genes (SLC22A) in the kidney. J Hum Genet 2008; 15 Apr [Epub ahead of print].
87. Fujita T, Brown C, Carlson EJ, et al. Functional analysis of polymorphisms in the organic anion transporter, SLC22A6 (OAT1). Pharmacogenet Genomics 2005; 15:201 -209.
88. Huang RS, Duan S, Shukla SJ, et al. Identification of genetic variants contributing to cisplatin-induced cytotoxicity by use of a genomewide approach. Am J Hum Genet 2007; 81:427-437.
89. Huang RS, Duan S, Bleibel WK, et al. A genome-wide approach to identify genetic variants that contribute to etoposide-induced cytotoxicity. Proc Natl Acad Sci USA 2007; 104:9758-9763.
90. Ranganathan P, Culverhouse R, Marsh S, et al. Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in caucasian and African American patients with rheumatoid arthritis. J Rheumatol 2008; 35:572-579.
91. Zhang W, Bleibel WK, Roe CA, et al. Gender-specific differences in expression in human lymphoblastoid cell lines. Pharmacogenet Genomics 2007; 17:447-450.