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Abstract

The SLC22 transporter family consists of more than two dozen members, which are expressed in the kidney, the liver, and other tissues. Evolutionary analysis indicates that SLC22 transporters fall into at least six subfamilies: OAT (organic anion transporter), OAT-like, OAT-related, OCT (organic cation transporter), OCTN (organic cation/carnitine transporter), and OCT/OCTN-related. Some—including OAT1 [SLC22A6 or NKT (novel kidney transporter)] and OAT3 (SLC22A8), as well as OCT1 (SLC22A1) and OCT2 (SLC22A2)—are widely studied drug transporters. Nevertheless, analyses of knockout mice and other data indicate that SLC22 transporters regulate key metabolic pathways and levels of signaling molecules (e.g., gut microbiome products, bile acids, tricarboxylic acid cycle intermediates, dietary flavonoids and other nutrients, prostaglandins, vitamins, short-chain fatty acids, urate, and ergothioneine), as well as uremic toxins associated with chronic kidney disease. Certain SLC22 transporters—such as URAT1 (SLC22A12) and OCTN2 (SLC22A5)—are mutated in inherited metabolic diseases. A new systems biology view of transporters is emerging. As proposed in the remote sensing and signaling hypothesis, SLC22 transporters, together with other SLC and ABC transporters, have key roles in interorgan and interorganism small-molecule communication and, together with the neuroendocrine, growth factor–cytokine, and other homeostatic systems, regulate local and whole-body homeostasis.

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2018-01-06
2024-03-29
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Literature Cited

  1. Nigam SK. 1.  2015. What do drug transporters really do?. Nat. Rev. Drug Discov. 14:29–44 [Google Scholar]
  2. Rizwan AN, Burckhardt G. 2.  2007. Organic anion transporters of the SLC22 family: biopharmaceutical, physiological, and pathological roles. Pharm. Res. 24:450–70 [Google Scholar]
  3. Pelis RM, Wright SH. 3.  2014. SLC22, SLC44, and SLC47 transporters—organic anion and cation transporters: molecular and cellular properties. Curr. Top. Membr. 73:233–61 [Google Scholar]
  4. Saito H. 4.  2010. Pathophysiological regulation of renal SLC22A organic ion transporters in acute kidney injury: pharmacological and toxicological implications. Pharmacol. Ther. 125:79–91 [Google Scholar]
  5. VanWert AL, Gionfriddo MR, Sweet DH. 5.  2010. Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology. Biopharm. Drug Dispos. 31:1–71 [Google Scholar]
  6. Wang L, Sweet DH. 6.  2013. Renal organic anion transporters (SLC22 family): expression, regulation, roles in toxicity, and impact on injury and disease. AAPS J 15:53–69 [Google Scholar]
  7. You GF, Morris ME. 7.  2014. Drug Transporters: Molecular Characterization and Role in Drug Disposition Hoboken, NJ: Wiley, 2nd ed.. [Google Scholar]
  8. Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, Nigam SK. 8.  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. 272:6471–78 [Google Scholar]
  9. Simonson G, Vincent A, Roberg K, Huang Y, Iwanij V. 9.  1994. Molecular cloning and characterization of a novel liver-specific transport protein. J. Cell Sci. 107:1065–72 [Google Scholar]
  10. Grundemann D, Gorboulev V, Gambaryan S, Veyhl M, Koepsell H. 10.  1994. Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549–52 [Google Scholar]
  11. Zhu C, Nigam KB, Date RC, Bush KT, Springer SA. 11.  et al. 2015. Evolutionary analysis and classification of OATs, OCTs, OCTNs, and other SLC22 transporters: structure–function implications and analysis of sequence motifs. PLOS ONE 10:e0140569 [Google Scholar]
  12. Ahn SY, Nigam SK. 12.  2009. Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis. Mol. Pharmacol. 76:481–90 [Google Scholar]
  13. Cesar-Razquin A, Snijder B, Frappier-Brinton T, Isserlin R, Gyimesi G. 13.  et al. 2015. A call for systematic research on solute carriers. Cell 162:478–87 [Google Scholar]
  14. Brouwer KL, Aleksunes LM, Brandys B, Giacoia GP, Knipp G. 14.  et al. 2015. Human ontogeny of drug transporters: review and recommendations of the Pediatric Transporter Working Group. Clin. Pharmacol. Ther. 98:266–87 [Google Scholar]
  15. Pavlova A, Sakurai H, Leclercq B, Beier DR, Yu AS, Nigam SK. 15.  2000. Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct. Am. J. Physiol. Renal Physiol. 278:F635–43 [Google Scholar]
  16. Kaler G, Truong DM, Khandelwal A, Nagle M, Eraly SA. 16.  et al. 2007. Structural variation governs substrate specificity for organic anion transporter (OAT) homologs: potential remote sensing by OAT family members. J. Biol. Chem. 282:23841–53 [Google Scholar]
  17. Koepsell H. 17.  2013. Polyspecific organic cation transporters and their biomedical relevance in kidney. Curr. Opin. Nephrol. Hypertens. 22:533–38 [Google Scholar]
  18. Nigam SK, Bush KT, Martovetsky G, Ahn SY, Liu HC. 18.  et al. 2015. The organic anion transporter (OAT) family: a systems biology perspective. Physiol. Rev. 95:83–123 [Google Scholar]
  19. Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M. 19.  et al. 2004. Clinical and molecular analysis of patients with renal hypouricemia in Japan—influence of URAT1 gene on urinary urate excretion. J. Am. Soc. Nephrol. 15:164–73 [Google Scholar]
  20. Seth P, Wu X, Huang W, Leibach FH, Ganapathy V. 20.  1999. Mutations in novel organic cation transporter (OCTN2), an organic cation/carnitine transporter, with differential effects on the organic cation transport function and the carnitine transport function. J. Biol. Chem. 274:33388–92 [Google Scholar]
  21. Ahn SY, Jamshidi N, Mo ML, Wu W, Eraly SA. 21.  et al. 2011. Linkage of organic anion transporter-1 to metabolic pathways through integrated “omics”-driven network and functional analysis. J. Biol. Chem. 286:31522–31 [Google Scholar]
  22. Eraly SA, Vallon V, Vaughn DA, Gangoiti JA, Richter K. 22.  et al. 2006. Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice. J. Biol. Chem. 281:5072–83 [Google Scholar]
  23. Wikoff WR, Nagle MA, Kouznetsova VL, Tsigelny IF, Nigam SK. 23.  2011. Untargeted metabolomics identifies enterobiome metabolites and putative uremic toxins as substrates of organic anion transporter 1 (Oat1). J. Proteome Res. 10:2842–51 [Google Scholar]
  24. Wu W, Jamshidi N, Eraly SA, Liu HC, Bush KT. 24.  et al. 2013. Multispecific drug transporter Slc22a8 (Oat3) regulates multiple metabolic and signaling pathways. Drug Metab. Dispos. 41:1825–34 [Google Scholar]
  25. Wu W, Bush KT, Nigam SK. 25.  2017. Key role for the organic anion transporters, OAT1 and OAT3, in the in vivo handling of uremic toxins and solutes. Sci. Rep. 7:4939 [Google Scholar]
  26. Bush KT, Wu W, Lun C, Nigam SK. 26.  2017. The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut-liver-kidney axis. J. Biol. Chem. 292:15789–803 [Google Scholar]
  27. Wu W, Dnyanmote AV, Nigam SK. 27.  2011. Remote communication through solute carriers and ATP binding cassette drug transporter pathways: an update on the Remote Sensing and Signaling Hypothesis. Mol. Pharmacol. 79:795–805 [Google Scholar]
  28. Grundemann D. 28.  2012. The ergothioneine transporter controls and indicates ergothioneine activity—a review. Prev. Med. 54:Suppl.S71–74 [Google Scholar]
  29. Kaler G, Truong DM, Sweeney DE, Logan DW, Nagle M. 29.  et al. 2006. Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions. Biochem. Biophys. Res. Commun. 351:872–76 [Google Scholar]
  30. Monte JC, Nagle MA, Eraly SA, Nigam SK. 30.  2004. Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa. Biochem. Biophys. Res. Commun. 323:429–36 [Google Scholar]
  31. Shiraya K, Hirata T, Hatano R, Nagamori S, Wiriyasermkul P. 31.  et al. 2010. A novel transporter of SLC22 family specifically transports prostaglandins and co-localizes with 15-hydroxyprostaglandin dehydrogenase in renal proximal tubules. J. Biol. Chem. 285:22141–51 [Google Scholar]
  32. 32. US FDA (Food Drug Adm.). 2012. Guidance for Industry: Drug Interaction Studies—Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations Silver Spring, MD: US FDA
  33. 33. Eur. Med. Agency. 2012. Guideline on the Investigation of Drug Interactions London: Eur. Med. Agency
  34. 34. MHLW Res. Group. 2014. Drug Interaction Guideline for Drug Development and Labeling Recommendations Tokyo: Minist. Health Labour Welf.
  35. Bhatnagar V, Richard EL, Wu W, Nievergelt CM, Lipkowitz MS. 35.  et al. 2016. Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling. Clin. Kidney J. 9:444–53 [Google Scholar]
  36. Brandoni A, Hazelhoff MH, Bulacio RP, Torres AM. 36.  2012. Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis. World J. Gastroenterol. 18:6387–97 [Google Scholar]
  37. Di Giusto G, Anzai N, Endou H, Torres AM. 37.  2008. 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 81:127–36 [Google Scholar]
  38. Di Giusto G, Anzai N, Ruiz ML, Endou H, Torres AM. 38.  2009. Expression and function of Oat1 and Oat3 in rat kidney exposed to mercuric chloride. Arch. Toxicol. 83:887–97 [Google Scholar]
  39. Torres AM, Dnyanmote AV, Bush KT, Wu W, Nigam SK. 39.  2011. Deletion of multispecific organic anion transporter Oat1/Slc22a6 protects against mercury-induced kidney injury. J. Biol. Chem. 286:26391–95 [Google Scholar]
  40. Liu HC, Jamshidi N, Chen Y, Eraly SA, Cho SY. 40.  et al. 2016. An organic anion transporter 1 (OAT1)–centered metabolic network. J. Biol. Chem. 291:19474–86 [Google Scholar]
  41. Lu H, Klaassen C. 41.  2008. Gender differences in mRNA expression of ATP-binding cassette efflux and bile acid transporters in kidney, liver, and intestine of 5/6 nephrectomized rats. Drug Metab. Dispos. 36:16–23 [Google Scholar]
  42. Yano H, Tamura Y, Kobayashi K, Tanemoto M, Uchida S. 42.  2014. Uric acid transporter ABCG2 is increased in the intestine of the 5/6 nephrectomy rat model of chronic kidney disease. Clin. Exp. Nephrol. 18:50–55 [Google Scholar]
  43. Lopez-Nieto CE, You G, Barros EJG, Beier DR, Nigam SK. 43.  1996. Molecular cloning and characterization of a novel transport protein with very high expression in the kidney. J. Am. Soc. Nephrol. 7:1301 (Abstr.) [Google Scholar]
  44. Eraly SA, Monte JC, Nigam SK. 44.  2004. Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transporters. Physiol. Genom. 18:12–24 [Google Scholar]
  45. Wu W, Baker ME, Eraly SA, Bush KT, Nigam SK. 45.  2009. Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members. Physiol. Genom. 38:116–24 [Google Scholar]
  46. Emami Riedmaier A, Nies AT, Schaeffeler E, Schwab M. 46.  2012. Organic anion transporters and their implications in pharmacotherapy. Pharmacol. Rev. 64:421–49 [Google Scholar]
  47. Nigam SK, Wu W, Bush KT, Hoenig MP, Blantz RC, Bhatnagar V. 47.  2015. Handling of drugs, metabolites, and uremic toxins by kidney proximal tubule drug transporters. Clin. J. Am. Soc. Nephrol. 10:2039–49 [Google Scholar]
  48. Ahn SY, Eraly SA, Tsigelny I, Nigam SK. 48.  2009. Interaction of organic cations with organic anion transporters. J. Biol. Chem. 284:31422–30 [Google Scholar]
  49. Liu HC, Goldenberg A, Chen Y, Lun C, Wu W. 49.  et al. 2016. Analysis of molecular properties of drugs interacting with SLC22 transporters OAT1, OAT3, OCT1, and OCT2: a machine-learning approach. J. Pharmacol. Exp. Ther. 359:215–29 [Google Scholar]
  50. Mori K, Ogawa Y, Ebihara K, Aoki T, Tamura N. 50.  et al. 1997. Kidney-specific expression of a novel mouse organic cation transporter-like protein. FEBS Lett 417:371–74 [Google Scholar]
  51. Sakurai H. 51.  2013. Urate transporters in the genomic era. Curr. Opin. Nephrol. Hypertens. 22:545–50 [Google Scholar]
  52. Shen H, Lai Y, Rodrigues AD. 52.  2017. Organic anion transporter 2: an enigmatic human solute carrier. Drug Metab. Dispos. 45:228–36 [Google Scholar]
  53. Cropp CD, Komori T, Shima JE, Urban TJ, Yee SW. 53.  et al. 2008. Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Mol. Pharmacol. 73:1151–8 [Google Scholar]
  54. Russel FG, Koenderink JB, Masereeuw R. 54.  2008. Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol. Sci. 29:200–7 [Google Scholar]
  55. Schnabolk GW, Youngblood GL, Sweet DH. 55.  2006. Transport of estrone sulfate by the novel organic anion transporter Oat6 (Slc22a20). Am. J. Physiol. Renal. Physiol. 291:F314–21 [Google Scholar]
  56. Wu W, Bush KT, Liu HC, Zhu C, Abagyan R, Nigam SK. 56.  2015. Shared ligands between organic anion transporters (OAT1 and OAT6) and odorant receptors. Drug Metab. Dispos. 43:1855–63 [Google Scholar]
  57. Schnabolk GW, Gupta B, Mulgaonkar A, Kulkarni M, Sweet DH. 57.  2010. Organic anion transporter 6 (Slc22a20) specificity and Sertoli cell–specific expression provide new insight on potential endogenous roles. J. Pharmacol. Exp. Ther. 334:927–35 [Google Scholar]
  58. AbuAli G, Grimm S. 58.  2014. Isolation and characterization of the anticancer gene organic cation transporter like-3 (ORCTL3). Anticancer Genes: Advances in Experimental Medicine and Biology 818 S Grimm 213–27 London: Springer-Verlag [Google Scholar]
  59. Bahn A, Hagos Y, Reuter S, Balen D, Brzica H. 59.  et al. 2008. Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13). J. Biol. Chem. 283:16332–41 [Google Scholar]
  60. Nagle MA, Wu W, Eraly SA, Nigam SK. 60.  2013. Organic anion transport pathways in antiviral handling in choroid plexus in Oat1 (Slc22a6) and Oat3 (Slc22a8) deficient tissue. Neurosci. Lett. 534:133–38 [Google Scholar]
  61. Devireddy LR, Gazin C, Zhu X, Green MR. 61.  2005. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 123:1293–305 [Google Scholar]
  62. Ciarimboli G, Gautron S, Schlatter E. 62.  2016. Organic Cation Transporters: Integration of Physiology, Pathology and Pharmacology Cham, Switz.: Springer [Google Scholar]
  63. Koepsell H. 63.  2004. Polyspecific organic cation transporters: their functions and interactions with drugs. Trends Pharmacol. Sci. 25:375–81 [Google Scholar]
  64. Duan H, Wang J. 64.  2010. Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J. Pharmacol. Exp. Ther. 335:743–53 [Google Scholar]
  65. Koepsell H, Schmitt BM, Gorboulev V. 65.  2003. Organic cation transporters. Rev. Physiol. Biochem. Pharmacol. 150:36–90 [Google Scholar]
  66. Wu X, Prasad PD, Leibach FH, Ganapathy V. 66.  1998. cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem. Biophys. Res. Commun. 246:589–95 [Google Scholar]
  67. Eraly SA, Nigam SK. 67.  2002. Novel human cDNAs homologous to Drosophila Orct and mammalian carnitine transporters. Biochem. Biophys. Res. Commun. 297:1159–66 [Google Scholar]
  68. Enomoto A, Wempe MF, Tsuchida H, Shin HJ, Cha SH. 68.  et al. 2002. Molecular identification of a novel carnitine transporter specific to human testis: insights into the mechanism of carnitine recognition. J. Biol. Chem. 277:36262–71 [Google Scholar]
  69. Aouida M, Poulin R, Ramotar D. 69.  2010. The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine analogue bleomycin-A5. J. Biol. Chem. 285:6275–84 [Google Scholar]
  70. Bacq A, Balasse L, Biala G, Guiard B, Gardier AM. 70.  et al. 2012. Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol. Psychiatry 17:926–39 [Google Scholar]
  71. Eraly SA, Vallon V, Rieg T, Gangoiti JA, Wikoff WR. 71.  et al. 2008. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol. Genom. 33:180–92 [Google Scholar]
  72. Franke RM, Kosloske AM, Lancaster CS, Filipski KK, Hu C. 72.  et al. 2010. Influence of Oct1/Oct2-deficiency on cisplatin-induced changes in urinary N-acetyl-β-d-glucosaminidase. Clin. Cancer Res. 16:4198–206 [Google Scholar]
  73. Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H. 73.  et al. 2001. Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol. Cell. Biol. 21:5471–77 [Google Scholar]
  74. Jonker JW, Wagenaar E, Van Eijl S, Schinkel AH. 74.  2003. Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol. Cell. Biol. 23:7902–8 [Google Scholar]
  75. Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK. 75.  2002. Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 [Slc22a8]) knockout mice. J. Biol. Chem. 277:26934–43 [Google Scholar]
  76. Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. 76.  2002. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther. 302:510–15 [Google Scholar]
  77. Wultsch T, Grimberg G, Schmitt A, Painsipp E, Wetzstein H. 77.  et al. 2009. Decreased anxiety in mice lacking the organic cation transporter 3. J. Neural. Transm. 116:689–97 [Google Scholar]
  78. Vallon V, Rieg T, Ahn SY, Wu W, Eraly SA, Nigam SK. 78.  2008. 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. 294:F867–73 [Google Scholar]
  79. Nagle MA, Truong DM, Dnyanmote AV, Ahn SY, Eraly SA. 79.  et al. 2011. Analysis of three-dimensional systems for developing and mature kidneys clarifies the role of OAT1 and OAT3 in antiviral handling. J. Biol. Chem. 286:243–51 [Google Scholar]
  80. Truong DM, Kaler G, Khandelwal A, Swaan PW, Nigam SK. 80.  2008. Multi-level analysis of organic anion transporters 1, 3, and 6 reveals major differences in structural determinants of antiviral discrimination. J. Biol. Chem. 283:8654–63 [Google Scholar]
  81. Vanwert AL, Bailey RM, Sweet DH. 81.  2007. Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G. Am. J. Physiol. Renal. Physiol. 293:F1332–41 [Google Scholar]
  82. Vanwert AL, Srimaroeng C, Sweet DH. 82.  2008. Organic anion transporter 3 (Oat3/Slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin. Mol. Pharmacol. 74:122–31 [Google Scholar]
  83. Mori S, Takanaga H, Ohtsuki S, Deguchi T, Kang YS. 83.  et al. 2003. Rat organic anion transporter 3 (rOAT3) is responsible for brain-to-blood efflux of homovanillic acid at the abluminal membrane of brain capillary endothelial cells. J. Cereb. Blood Flow Metab. 23:432–40 [Google Scholar]
  84. Mori S, Ohtsuki S, Takanaga H, Kikkawa T, Kang YS, Terasaki T. 84.  2004. Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J. Neurochem. 90:931–41 [Google Scholar]
  85. Ose A, Ito M, Kusuhara H, Yamatsugu K, Kanai M. 85.  et al. 2009. Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64–0802), a pharmacologically active form of oseltamivir, by active efflux across the blood–brain barrier mediated by organic anion transporter 3 (Oat3/Slc22a8) and multidrug resistance–associated protein 4 (Mrp4/Abcc4). Drug Metab. Dispos. 37:315–21 [Google Scholar]
  86. Zalups RK, Ahmad S. 86.  2005. Handling of cysteine S-conjugates of methylmercury in MDCK cells expressing human OAT1. Kidney Int 68:1684–99 [Google Scholar]
  87. Stiborova M, Arlt VM, Schmeiser HH. 87.  2016. Balkan endemic nephropathy: an update on its aetiology. Arch. Toxicol. 90:2595–615 [Google Scholar]
  88. Bakhiya N, Arlt VM, Bahn A, Burckhardt G, Phillips DH, Glatt H. 88.  2009. Molecular evidence for an involvement of organic anion transporters (OATs) in aristolochic acid nephropathy. Toxicology 264:74–79 [Google Scholar]
  89. Xue X, Gong LK, Maeda K, Luan Y, Qi XM. 89.  et al. 2011. Critical role of organic anion transporters 1 and 3 in kidney accumulation and toxicity of aristolochic acid I. Mol. Pharm. 8:2183–92 [Google Scholar]
  90. Li S, Sanna S, Maschio A, Busonero F, Usala G. 90.  et al. 2007. The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. PLOS Genet 3:e194 [Google Scholar]
  91. Woodward OM, Kottgen A, Coresh J, Boerwinkle E, Guggino WB, Kottgen M. 91.  2009. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. PNAS 106:10338–42 [Google Scholar]
  92. Togawa N, Juge N, Miyaji T, Hiasa M, Omote H, Moriyama Y. 92.  2015. Wide expression of type I Na+-phosphate cotransporter 3 (NPT3/SLC17A2), a membrane potential–driven organic anion transporter. Am. J. Physiol. Cell Physiol. 309:C71–80 [Google Scholar]
  93. Reimer RJ. 93.  2013. SLC17: a functionally diverse family of organic anion transporters. Mol. Asp. Med. 34:350–59 [Google Scholar]
  94. Farthing CA, Sweet DH. 94.  2014. Expression and function of organic cation and anion transporters (SLC22 family) in the CNS. Curr. Pharm. Des. 20:1472–86 [Google Scholar]
  95. Chen L, Shu Y, Liang X, Chen EC, Yee SW. 95.  et al. 2014. OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. PNAS 111:9983–88 [Google Scholar]
  96. Aurich MK, Thiele I. 96.  2016. Computational modeling of human metabolism and its application to systems biomedicine. Methods Mol. Biol. 1386:253–81 [Google Scholar]
  97. Szallasi Z, Stelling J, Periwal V. 97.  2006. System Modeling in Cell Biology: From Concepts to Nuts and Bolts Cambridge, MA: MIT Press
  98. Hewitt WR, Wagner PA, Bostwick EF, Hook JB. 98.  1977. Transport ontogeny and selective substrate stimulation as models for identification of multiple renal organic anion transport systems. J. Pharmacol. Exp. Ther. 202:711–23 [Google Scholar]
  99. Gallegos TF, Martovetsky G, Kouznetsova V, Bush KT, Nigam SK. 99.  2012. Organic anion and cation SLC22 “drug” transporter (Oat1, Oat3, and Oct1) regulation during development and maturation of the kidney proximal tubule. PLOS ONE 7:e40796 [Google Scholar]
  100. Martovetsky G, Bush KT, Nigam SK. 100.  2016. Kidney versus liver specification of SLC and ABC drug transporters, tight junction molecules, and biomarkers. Drug Metab. Dispos. 44:1050–60 [Google Scholar]
  101. Martovetsky G, Tee JB, Nigam SK. 101.  2013. Hepatocyte nuclear factors 4α and 1α regulate kidney developmental expression of drug-metabolizing enzymes and drug transporters. Mol. Pharmacol. 84:808–23 [Google Scholar]
  102. Yuan X, Ta TC, Lin M, Evans JR, Dong Y. 102.  et al. 2009. Identification of an endogenous ligand bound to a native orphan nuclear receptor. PLOS ONE 4:e5609 [Google Scholar]
  103. Rosines E, Sampogna RV, Johkura K, Vaughn DA, Choi Y. 103.  et al. 2007. Staged in vitro reconstitution and implantation of engineered rat kidney tissue. PNAS 104:20938–43 [Google Scholar]
  104. Sweeney DE, Vallon V, Rieg T, Wu W, Gallegos TF, Nigam SK. 104.  2011. Functional maturation of drug transporters in the developing, neonatal, and postnatal kidney. Mol. Pharmacol. 80:147–54 [Google Scholar]
  105. Sweet DH, Eraly SA, Vaughn DA, Bush KT, Nigam SK. 105.  2006. Organic anion and cation transporter expression and function during embryonic kidney development and in organ culture models. Kidney Int 69:837–45 [Google Scholar]
  106. Habu Y, Yano I, Okuda M, Fukatsu A, Inui K. 106.  2005. Restored expression and activity of organic ion transporters rOAT1, rOAT3 and rOCT2 after hyperuricemia in the rat kidney. Biochem. Pharmacol. 69:993–99 [Google Scholar]
  107. Preising C, Schneider R, Bucher M, Gekle M, Sauvant C. 107.  2015. Regulation of expression of renal organic anion transporters OAT1 and OAT3 in a model of ischemia/reperfusion injury. Cell. Physiol. Biochem. 37:1–13 [Google Scholar]
  108. Bulacio RP, Anzai N, Ouchi M, Torres AM. 108.  2015. Organic anion transporter 5 (Oat5) urinary excretion is a specific biomarker of kidney injury: evaluation of urinary excretion of exosomal Oat5 after N-acetylcysteine prevention of cisplatin induced nephrotoxicity. Chem. Res. Toxicol. 28:1595–602 [Google Scholar]
  109. Cocucci E, Kim JY, Bai Y, Pabla N. 109.  2017. Role of passive diffusion, transporters, and membrane trafficking–mediated processes in cellular drug transport. Clin. Pharmacol. Ther. 101:121–29 [Google Scholar]
  110. Xu D, Wang H, You G. 110.  2016. Posttranslational regulation of organic anion transporters by ubiquitination: known and novel. Med. Res. Rev. 36:964–79 [Google Scholar]
  111. Sprowl JA, Ong SS, Gibson AA, Hu S, Du G. 111.  et al. 2016. A phosphotyrosine switch regulates organic cation transporters. Nat. Commun. 7:10880 [Google Scholar]
  112. Zhang Q, Hong M, Duan P, Pan Z, Ma J, You G. 112.  2008. Organic anion transporter OAT1 undergoes constitutive and protein kinase C–regulated trafficking through a dynamin- and clathrin-dependent pathway. J. Biol. Chem. 283:32570–79 [Google Scholar]
  113. Zhang Q, Suh W, Pan Z, You G. 113.  2012. Short-term and long-term effects of protein kinase C on the trafficking and stability of human organic anion transporter 3. Int. J. Biochem. Mol. Biol. 3:242–49 [Google Scholar]
  114. Xu D, Wang H, Zhang Q, You G. 114.  2016. Nedd4-2 but not Nedd4-1 is critical for protein kinase C–regulated ubiquitination, expression, and transport activity of human organic anion transporter 1. Am. J. Physiol. Renal. Physiol. 310:F821–31 [Google Scholar]
  115. Anzai N, Miyazaki H, Noshiro R, Khamdang S, Chairoungdua A. 115.  et al. 2004. The multivalent PDZ domain–containing protein PDZK1 regulates transport activity of renal urate–anion exchanger URAT1 via its C terminus. J. Biol. Chem. 279:45942–50 [Google Scholar]
  116. Merriman TR. 116.  2015. An update on the genetic architecture of hyperuricemia and gout. Arthritis Res. Ther. 17:98 [Google Scholar]
  117. Xu G, Bhatnagar V, Wen G, Hamilton BA, Eraly SA, Nigam SK. 117.  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 68:1491–99 [Google Scholar]
  118. Bhatnagar V, Xu G, Hamilton BA, Truong DM, Eraly SA. 118.  et al. 2006. Analyses of 5′ regulatory region polymorphisms in human SLC22A6 (OAT1) and SLC22A8 (OAT3). J. Hum. Genet. 51:575–80 [Google Scholar]
  119. Engstrom K, Ameer S, Bernaudat L, Drasch G, Baeuml J. 119.  et al. 2012. Polymorphisms in genes encoding potential mercury transporters and urine mercury concentrations in populations exposed to mercury vapor from gold mining. Environ. Health Perspect. 121:85–91 [Google Scholar]
  120. Han YF, Fan XH, Wang XJ, Sun K, Xue H. 120.  et al. 2011. Association of intergenic polymorphism of organic anion transporter 1 and 3 genes with hypertension and blood pressure response to hydrochlorothiazide. Am. J. Hypertens. 24:340–46 [Google Scholar]
  121. Yee SW, Nguyen AN, Brown C, Savic RM, Zhang YC. 121.  et al. 2013. Reduced renal clearance of cefotaxime in Asians with a low-frequency polymorphism of OAT3 (SLC22A8). J. Pharm. Sci. 102:3451–57 [Google Scholar]
  122. Tanaka M, Itoh K, Matsushita K, Matsushita K, Wakita N. 122.  et al. 2003. Two male siblings with hereditary renal hypouricemia and exercise-induced ARF. Am. J. Kidney Dis. 42:1287–92 [Google Scholar]
  123. Mount DB. 123.  2013. The kidney in hyperuricemia and gout. Curr. Opin. Nephrol. Hypertens. 22:216–23 [Google Scholar]
  124. Sharma K, Karl B, Mathew AV, Gangoiti JA, Wassel CL. 124.  et al. 2013. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J. Am. Soc. Nephrol. 24:1901–12 [Google Scholar]
  125. Prentice KJ, Luu L, Allister EM, Liu Y, Jun LS. 125.  et al. 2014. The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. Cell Metab 19:653–66 [Google Scholar]
  126. Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H. 126.  et al. 1999. Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion–dependent carnitine transporter. Nat. Genet. 21:91–94 [Google Scholar]
  127. El-Hattab AW, Scaglia F. 127.  2015. Disorders of carnitine biosynthesis and transport. Mol. Genet. Metab. 116:107–12 [Google Scholar]
  128. Peltekova VD, Wintle RF, Rubin LA, Amos CI, Huang Q. 128.  et al. 2004. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat. Genet. 11:11 [Google Scholar]
  129. Tamai I. 129.  2013. Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm. Drug Dispos. 34:29–44 [Google Scholar]
  130. Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y. 130.  et al. 2003. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat. Genet. 35:341–48 [Google Scholar]
  131. Malir F, Ostry V, Pfohl-Leszkowicz A, Malir J, Toman J. 131.  2016. Ochratoxin A: 50 years of research. Toxins 8:191 [Google Scholar]
  132. Stefanovic V, Polenakovic M. 132.  2009. Fifty years of research in Balkan endemic nephropathy: Where are we now?. Nephron Clin. Pract. 112:c51–56 [Google Scholar]
  133. Masereeuw R, Mutsaers HA, Toyohara T, Abe T, Jhawar S. 133.  et al. 2014. The kidney and uremic toxin removal: glomerulus or tubule?. Semin. Nephrol. 34:191–208 [Google Scholar]
  134. Tang WH, Hazen SL. 134.  2017. Microbiome, trimethylamine N-oxide, and cardiometabolic disease. Transl. Res. 179:108–15 [Google Scholar]
  135. Leong SC, Sirich TL. 135.  2016. Indoxyl sulfate—review of toxicity and therapeutic strategies. Toxins 8:358 [Google Scholar]
  136. Yamaguchi J, Tanaka T, Inagi R. 136.  2017. Effect of AST-120 in chronic kidney disease treatment: Still a controversy?. Nephron 135:201–6 [Google Scholar]
  137. Kennedy PJ, Cryan JF, Dinan TG, Clarke G. 137.  2017. Kynurenine pathway metabolism and the microbiota–gut–brain axis. Neuropharmacology 112:399–412 [Google Scholar]
  138. Lowenstein J, Grantham JJ. 138.  2016. The rebirth of interest in renal tubular function. Am. J. Physiol. Renal Physiol. 310:F1351–55 [Google Scholar]
  139. Lowenstein J, Grantham JJ. 139.  2017. Residual renal function: a paradigm shift. Kidney Int 91:561–65 [Google Scholar]
  140. Imamura Y, Murayama N, Okudaira N, Kurihara A, Okazaki O. 140.  et al. 2011. Prediction of fluoroquinolone-induced elevation in serum creatinine levels: a case of drug–endogenous substance interaction involving the inhibition of renal secretion. Clin. Pharmacol. Ther. 89:81–88 [Google Scholar]
  141. Reznichenko A, Sinkeler SJ, Snieder H, van den Born J, de Borst MH. 141.  et al. 2013. SLC22A2 is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation. Physiol. Genom. 45:201–9 [Google Scholar]
  142. Shen H, Liu T, Morse BL, Zhao Y, Zhang Y. 142.  et al. 2015. Characterization of organic anion transporter 2 (SLC22A7): a highly efficient transporter for creatinine and species-dependent renal tubular expression. Drug Metab. Dispos. 43:984–93 [Google Scholar]
  143. Vallon V, Eraly SA, Rao SR, Gerasimova M, Rose M. 143.  et al. 2012. A role for the organic anion transporter OAT3 in renal creatinine secretion in mice. Am. J. Physiol. Renal Physiol. 302:F1293–99 [Google Scholar]
  144. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET. 144.  et al. 2008. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin. Pharmacol. Ther. 83:273–80 [Google Scholar]
  145. Wu X, Kekuda R, Huang W, Fei YJ, Leibach FH. 145.  et al. 1998. Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J. Biol. Chem. 273:32776–86 [Google Scholar]
  146. Eraly SA, Bush KT, Sampogna RV, Bhatnagar V, Nigam SK. 146.  2004. The molecular pharmacology of organic anion transporters: from DNA to FDA?. Mol. Pharmacol. 65:479–87 [Google Scholar]
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