Pharmaceutical Research

, Volume 24, Issue 7, pp 1227–1251 | Cite as

Polyspecific Organic Cation Transporters: Structure, Function, Physiological Roles, and Biopharmaceutical Implications

Expert Review


The body is equipped with broad-specificity transporters for the excretion and distribution of endogeneous organic cations and for the uptake, elimination and distribution of cationic drugs, toxins and environmental waste products. This group of transporters consists of the electrogenic cation transporters OCT1-3 (SLC22A1-3), the cation and carnitine transporters OCTN1 (SLC22A4), OCTN2 (SLC22A5) and OCT6 (SLC22A16), and the proton/cation antiporters MATE1, MATE2-K and MATE2-B. The transporters show broadly overlapping sites of expression in many tissues such as small intestine, liver, kidney, heart, skeletal muscle, placenta, lung, brain, cells of the immune system, and tumors. In epithelial cells they may be located in the basolateral or luminal membranes. Transcellular cation movement in small intestine, kidney and liver is mediated by the combined action of electrogenic OCT-type uptake systems and MATE-type efflux transporters that operate as cation/proton antiporters. Recent data showed that OCT-type transporters participate in the regulation of extracellular concentrations of neurotransmitters in brain, mediate the release of acetylcholine in non-neuronal cholinergic reactions, and are critically involved in the regulation of histamine release from basophils. The recent identification of polymorphisms in human OCTs and OCTNs allows the identification of patients with an increased risk for adverse drug reactions. Transport studies with expressed OCTs will help to optimize pharmacokinetics during development of new drugs.

Key words

drug transporters MATE1 OCT1 OCT2 OCT3 OCT6 OCTN1 OCTN2 organic cation transport polyspecific transporters 


  1. 1.
    A. H. Schinkel and J. W. Jonker. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv. Drug Deliv. Rev. 55:3–29 (2003).PubMedCrossRefGoogle Scholar
  2. 2.
    H. Daniel and G. Kottra. The proton oligopeptide cotransporter family SLC15 in physiology and pharmacology. Pflugers Arch. 447:610–618 (2004).PubMedCrossRefGoogle Scholar
  3. 3.
    B. Hagenbuch and P. J. Meier. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch. 447:653–665 (2004).PubMedCrossRefGoogle Scholar
  4. 4.
    J. E. van Montfoort, B. Hagenbuch, G. M. M. Groothuis, H. Koepsell, P. J. Meier, and D. K. F. Meijer. Drug uptake systems in liver and kidney. Curr. Drug Metab. 4:185–211 (2003).PubMedCrossRefGoogle Scholar
  5. 5.
    H. Koepsell and H. Endou. The SLC22 drug transporter family. Pflugers Arch. 447:666–676 (2004).PubMedCrossRefGoogle Scholar
  6. 6.
    H. Koepsell, B. M. Schmitt, and V. Gorboulev. Organic cation transporters. Rev. Physiol. Biochem. Pharmacol. 150:36–90 (2003).PubMedCrossRefGoogle Scholar
  7. 7.
    M. Otsuka, T. Matsumoto, R. Morimoto, S. Arioka, H. Omote, and Y. Moriyama. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc. Natl. Acad. Sci. U.S.A. 102:17923–17928 (2005).PubMedCrossRefGoogle Scholar
  8. 8.
    H. Koepsell. Organic cation transporters in intestine, kidney, liver, and brain. Annu. Rev. Physiol. 60:243–266 (1998).PubMedCrossRefGoogle Scholar
  9. 9.
    H. Koepsell. Polyspecific organic cation transporters: their functions and interactions with drugs. TIPS 25:375–381 (2004).PubMedGoogle Scholar
  10. 10.
    S. H. Wright and W. H. Dantzler. Molecular and cellular physiology of renal organic cation and anion transport. Physiol. Rev. 84:987–1049 (2004).PubMedCrossRefGoogle Scholar
  11. 11.
    M. J. Dresser, M. K. Leabman, and K. M. Giacomini. Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters. J. Pharm. Sci. 90:397–421 (2001).PubMedCrossRefGoogle Scholar
  12. 12.
    S. S. Pao, I. T. Paulsen, and M. H. Saier, Jr. Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 62:1–34 (1998).PubMedGoogle Scholar
  13. 13.
    D. Gründemann, V. Gorboulev, S. Gambaryan, M. Veyhl, and H. Koepsell. Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549–552 (1994).PubMedCrossRefGoogle Scholar
  14. 14.
    L. Zhang, M. J. Dresser, A. T. Gray, S. C. Yost, S. Terashita, and K. M. Giacomini. Cloning and functional expression of a human liver organic cation transporter. Mol. Pharmacol. 51:913–921 (1997).PubMedGoogle Scholar
  15. 15.
    V. Gorboulev, J. C. Ulzheimer, A. Akhoundova, I. Ulzheimer-Teuber, U. Karbach, S. Quester, C. Baumann, F. Lang, A. E. Busch, and H. Koepsell. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 16:871–881 (1997).PubMedGoogle Scholar
  16. 16.
    S. Terashita, M. J. Dresser, L. Zhang, A. T. Gray, S. C. Yost, and K. M. Giacomini. Molecular cloning and functional expression of a rabbit renal organic cation transporter. Biochim. Biophys. Acta 1369:1–6 (1998).PubMedCrossRefGoogle Scholar
  17. 17.
    R. M. Green, K. Lo, C. Sterritt, and D. R. Beier. Cloning and functional expression of a mouse liver organic cation transporter. Hepatology 29:1556–1562 (1999).PubMedCrossRefGoogle Scholar
  18. 18.
    M. Okuda, H. Saito, Y. Urakami, M. Takano, and K. Inui. cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem. Biophys. Res. Commun. 224:500–507 (1996).PubMedCrossRefGoogle Scholar
  19. 19.
    K. A. Mooslehner and N. D. Allen. Cloning of the mouse organic cation transporter 2 gene, Slc22a2, from an enhancer-trap transgene integration locus. Mamm. Genome 10:218–224 (1999).PubMedCrossRefGoogle Scholar
  20. 20.
    D. Gründemann, J. Babin-Ebell, F. Martel, N. Örding, A. Schmidt, and E. Schömig. Primary structure and functional expression of the apical organic cation transporter from kidney epithelial LLC-PK1 cells. J. Biol. Chem. 272:10408–10413 (1997).PubMedCrossRefGoogle Scholar
  21. 21.
    D. Gründemann, B. Schechinger, G. A. Rappold, and E. Schömig. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat. Neurosci. 1:349–351 (1998).PubMedCrossRefGoogle Scholar
  22. 22.
    R. Kekuda, P. D. Prasad, X. Wu, H. Wang, Y.-J. Fei, F. H. Leibach, and V. Ganapathy. Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J. Biol. Chem. 273:15971–15979 (1998).PubMedCrossRefGoogle Scholar
  23. 23.
    X. Wu, W. Huang, M. E. Ganapathy, H. Wang, R. Kekuda, S. J. Conway, F. H. Leibach, and V. Ganapathy. Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney. Am. J. Physiol. Renal Physiol. 279:F449–F458 (2000).PubMedGoogle Scholar
  24. 24.
    L. Zhang, M. J. Dresser, J. K. Chun, P. C. Babbitt, and K. M. Giacomini. Cloning and functional characterization of a rat renal organic cation transporter isoform (rOCT1A). J. Biol. Chem. 272:16548–16554 (1997).PubMedCrossRefGoogle Scholar
  25. 25.
    Y. Urakami, M. Akazawa, H. Saito, M. Okuda, and K.-I. Inui. cDNA cloning, functional characterization, and tissue distribution of an alternatively spliced variant of organic cation transporter hOCT2 predominantly expressed in the human kidney. J. Am. Soc. Nephrol. 13:1703–1710 (2002).PubMedCrossRefGoogle Scholar
  26. 26.
    M. R. Koehler, B. Wissinger, V. Gorboulev, H. Koepsell, and M. Schmid. The two human organic cation transporter genes SLC22A1 and SLC22A2 are located on chromosome 6q26. Cytogenet. Cell Genet. 79:198–200 (1997).PubMedGoogle Scholar
  27. 27.
    D. Gründemann and E. Schömig. Gene structures of the human non-neuronal monoamine transporters EMT and OCT2. Hum. Genet. 106:627–635 (2000).PubMedCrossRefGoogle Scholar
  28. 28.
    M. Hayer, H. Bönisch, and M. Bruss. Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann. Hum. Genet. 63:473–482 (1999).PubMedCrossRefGoogle Scholar
  29. 29.
    S. Verhaagh, N. Schweifer, D. P. Barlow, and R. Zwart. Cloning of the mouse and human solute carrier 22a3 (Slc22a3/SLC22A3) identifies a conserved cluster of three organic cation transporters on mouse chromosome 17 and human 6q26–q27. Genomics 55:209–218 (1999).PubMedCrossRefGoogle Scholar
  30. 30.
    X. Wu, R. L. George, W. Huang, H. Wang, S. J. Conway, F. H. Leibach, and V. Ganapathy. Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim. Biophys. Acta 1466:315–327 (2000).PubMedCrossRefGoogle Scholar
  31. 31.
    I. Tamai, H. Yabuuchi, J. Nezu, Y. Sai, A. Oku, M. Shimane, and A. Tsuji. Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett. 419:107–111 (1997).PubMedCrossRefGoogle Scholar
  32. 32.
    I. Tamai, R. Ohashi, J. Nezu, Y. Sai, D. Kobayashi, A. Oku, M. Shimane, and A. Tsuji. Molecular and functional characterization of organic cation/carnitine transporter family in mice. J. Biol. Chem. 275:40064–40072 (2000).PubMedCrossRefGoogle Scholar
  33. 33.
    X. Wu, P. D. Prasad, F. H. Leibach, and V. Ganapathy. cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem. Biophys. Res. Commun. 246:589–595 (1998).PubMedCrossRefGoogle Scholar
  34. 34.
    T. Sekine, H. Kusuhara, N. Utsunomiya-Tate, M. Tsuda, Y. Sugiyama, Y. Kanai, and H. Endou. Molecular cloning and characterization of high-affinity carnitine transporter from rat intestine. Biochem. Biophys. Res. Commun. 251:586–591 (1998).PubMedCrossRefGoogle Scholar
  35. 35.
    E. Schömig, F. Spitzenberger, M. Engelhardt, F. Martel, N. Örding, and D. Gründemann. Molecular cloning and characterization of two novel transport proteins from rat kidney. FEBS Lett. 425:79–86 (1998).PubMedCrossRefGoogle Scholar
  36. 36.
    V. D. Peltekova, R. F. Wintle, L. A. Rubin, C. I. Amos, Q. Huang, X. Gu, B. Newman, M. Van Oene, D. Cescon, G. Greenberg, A. M. Griffiths, P. H. St. George-Hyslop, and K. A. Siminovitch. Functional variants of OCTN cation transporter genes are associated with Crohn disease. Nat. Genet. 36:471–475 (2004).PubMedCrossRefGoogle Scholar
  37. 37.
    A. Enomoto, M. F. Wempe, H. Tsuchida, H. J. Shin, S. H. Cha, N. Anzai, A. Goto, A. Sakamoto, T. Niwa, Y. Kanai, M. W. Anders, and H. Endou. Molecular identification of a novel carnitine transporter specific to human testis: Insights into the mechanism of carnitine recognition. J. Biol. Chem. 277:36262–36271 (2002).PubMedCrossRefGoogle Scholar
  38. 38.
    S. Gong, X. Lu, Y. Xu, C. F. Swiderski, C. T. Jordan, and J. A. Moscow. Identification of OCT6 as a novel organic cation transporter preferentially expressed in hematopoietic cells and leukemias. Exp. Hematol. 30:1162–1169 (2002).PubMedCrossRefGoogle Scholar
  39. 39.
    M. Hiasa, T. Matsumoto, T. Komatsu, and Y. Moriyama. Wide variety of locations for rodent MATE1, a transporter protein that mediates the final excretion step for toxic organic cations. Am. J. Physiol. Cell Physiol. 291:478–486 (2006).CrossRefGoogle Scholar
  40. 40.
    T. Terada, S. Masuda, J.-i. Asaka, M. Tsuda, T. Katsura, and K.-i. Inui. Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm. Res. 23:1696–1701 (2006).PubMedCrossRefGoogle Scholar
  41. 41.
    K. Y. Ohta, K. Inoue, Y. Hayashi, and H. Yuasa. Molecular identification and functional characterization of rat MATE1 as an organic cation/H+ antiporter in the kidney. Drug Metab. Dispos. 34:1868–1874 (2006).PubMedCrossRefGoogle Scholar
  42. 42.
    S. Masuda, T. Terada, A. Yonezawa, Y. Tanihara, K. Kishimoto, T. Katsura, O. Ogawa, and K.-i. Inui. Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J. Am. Soc. Nephrol. 17:2127–2135 (2006).PubMedCrossRefGoogle Scholar
  43. 43.
    J. J. Chen, Z. Li, H. Pan, D. L. Murphy, H. Tamir, H. Koepsell, and M. D. Gershon. Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: abnormal intestinal motility and the expression of cation transporters. J. Neurosci. 21:6348–6361 (2001).PubMedGoogle Scholar
  44. 44.
    A. Schmitt, R. Mössner, A. Gossmann, I. G. Fischer, V. Gorboulev, D. L. Murphy, H. Koepsell, and K. P. Lesch. Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice. J. Neurosci. Res. 71:701–709 (2003).PubMedCrossRefGoogle Scholar
  45. 45.
    U. Karbach, J. Kricke, F. Meyer-Wentrup, V. Gorboulev, C. Volk, D. Loffing-Cueni, B. Kaissling, S. Bachmann, and H. Koepsell. Localization of organic cation transporters OCT1 and OCT2 in rat kidney. Am. J. Physiol. Renal Physiol. 279:F679–F687 (2000).PubMedGoogle Scholar
  46. 46.
    S. Choudhuri, N. J. Cherrington, N. Li, and C. D. Klaassen. Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metab. Dispos. 31:1337–1345 (2003).PubMedCrossRefGoogle Scholar
  47. 47.
    K. S. Lips, C. Volk, B. M. Schmitt, U. Pfeil, P. Arndt, D. Miska, L. Ermert, W. Kummer, and H. Koepsell. Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium. Am. J. Respir. Cell Mol. Biol. 33:79–88 (2005).PubMedCrossRefGoogle Scholar
  48. 48.
    A. L. Slitt, N. J. Cherrington, D. P. Hartley, T. M. Leazer, and C. D. Klaassen. Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab. Dispos. 30:212–219 (2002).PubMedCrossRefGoogle Scholar
  49. 49.
    Y. Alnouti, J. S. Petrick, and C. D. Klaassen. Tissue distribution and ontogeny of organic cation transporters in mice. Drug Metab. Dispos. 34:477–482 (2006).PubMedGoogle Scholar
  50. 50.
    J. Müller, K. S. Lips, L. Metzner, R. H. H. Neubert, H. Koepsell, and M. Brandsch. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT). Biochem. Pharmacol. 70:1851–1860 (2005).PubMedCrossRefGoogle Scholar
  51. 51.
    J. Alcorn, X. Lu, J. A. Moscow, and P. J. McNamara. Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction. J. Pharmacol. Exp. Ther. 303:487–496 (2002).PubMedCrossRefGoogle Scholar
  52. 52.
    M. Hayer-Zillgen, M. Brüss, and H. Bönisch. Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br. J. Pharmacol. 136:829–836 (2002).PubMedCrossRefGoogle Scholar
  53. 53.
    K. S. Lips, J. Wunsch, S. Zarghooni, T. Bschleipfer, K. Schukowski, W. Weidner, I. Wessler, U. Schwantes, H. Koepsell, and W. Kummer. Acetylcholine and molecular components of its synthesis and release machinery in the urothelium. Eur. Urol. PMID: 17084519 (2006).Google Scholar
  54. 54.
    M. R. Ballestero, M. J. Monte, O. Briz, F. Jimenez, F. Gonzalez-San Martin, and J. J. G. Marin. Expression of transporters potentially involved in the targeting of cytostatic bile acid derivatives to colon cancer and polyps. Biochem. Pharmacol. 72:729–738 (2006).PubMedCrossRefGoogle Scholar
  55. 55.
    S. Zhang, K. S. Lovejoy, J. E. Shima, L. L. Lagpacan, Y. Shu, A. Lapuk, Y. Chen, T. Komori, J. W. Gray, X. Chen, S. J. Lippard, and K. M. Giacomini. Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 66:8847–8857 (2006).PubMedCrossRefGoogle Scholar
  56. 56.
    E. Beéry, P. Middel, A. Bahn, H. S. Willenberg, Y. Hagos, H. Koepsell, S. R. Bornstein, G. A. Müller, G. Burckhardt, and J. Steffgen. Molecular evidence of organic ion transporters in the rat adrenal cortex with adrenocorticotropin-regulated zonal expression. Endocrinology 144:4519–4526 (2003).PubMedCrossRefGoogle Scholar
  57. 57.
    P. M. Gerk, C. Y. Oo, E. W. Paxton, J. A. Moscow, and P. J. McNamara. Interactions between cimetidine, nitrofurantoin, and probenecid active transport into rat milk. J. Pharmacol. Exp. Ther. 296:175–180 (2001).PubMedGoogle Scholar
  58. 58.
    E. Schneider, F. Machavoine, J.-M. Pléau, A.-F. Bertron, R. L. Thurmond, H. Ohtsu, T. Watanabe, A. H. Schinkel, and M. Dy. Organic cation transporter 3 modulates murine basophil functions by controlling intracellular histamine levels. J. Exp. Med. 202:387–393 (2005).PubMedCrossRefGoogle Scholar
  59. 59.
    L. M. Augustine, R. J. Markelewicz, Jr., K. Boekelheide, and N. J. Cherrington. Xenobiotic and endobiotic transporter mRNA expression in the blood-testis barrier. Drug Metab. Dispos. 33:182–189 (2005).PubMedCrossRefGoogle Scholar
  60. 60.
    F. Meyer-Wentrup, U. Karbach, V. Gorboulev, P. Arndt, and H. Koepsell. Membrane localization of the electrogenic cation transporter rOCT1 in rat liver. Biochem. Biophys. Res. Commun. 248:673–678 (1998).PubMedCrossRefGoogle Scholar
  61. 61.
    M. Sugawara-Yokoo, Y. Urakami, H. Koyama, K. Fujikura, S. Masuda, H. Saito, T. Naruse, K.-i. Inui, and K. Takata. Differential localization of organic cation transporters rOCT1 and rOCT2 in the basolateral membrane of rat kidney proximal tubules. Histochem. Cell Biol. 114:175–180 (2000).PubMedGoogle Scholar
  62. 62.
    W. Kummer, S. Wiegand, S. Akinci, I. Wessler, A. H. Schinkel, J. Wess, H. Koepsell, R. V. Haberberger, and K. S. Lips. Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse. Respir. Res. 7:65 (2006).PubMedCrossRefGoogle Scholar
  63. 63.
    A. E. Busch, U. Karbach, D. Miska, V. Gorboulev, A. Akhoundova, C. Volk, P. Arndt, J. C. Ulzheimer, M. S. Sonders, C. Baumann, S. Waldegger, F. Lang, and H. Koepsell. Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol. Pharmacol. 54:342–352 (1998).PubMedGoogle Scholar
  64. 64.
    D. H. Sweet, D. S. Miller, and J. B. Pritchard. Ventricular choline transport: a role for organic cation transporter 2 expressed in choroid plexus. J. Biol. Chem. 276:41611–41619 (2001).PubMedCrossRefGoogle Scholar
  65. 65.
    H. Motohashi, Y. Sakurai, H. Saito, S. Masuda, Y. Urakami, M. Goto, A. Fukatsu, O. Ogawa, and K.- I. Inui. Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J. Am. Soc. Nephrol. 13:866–874 (2002).PubMedGoogle Scholar
  66. 66.
    A. Seithel, J. Karlsson, C. Hilgendorf, A. Björquist, and A. L. Ungell. Variability in mRNA expression of ABC- and SLC-transporters in human intestinal cells: comparison between human segments and Caco-2 cells. Eur. J. Pharm. Sci. 28:291–299 (2006).PubMedCrossRefGoogle Scholar
  67. 67.
    D. Kristufek, W. Rudorfer, C. Pifl, and S. Huck. Organic cation transporter mRNA and function in the rat superior cervical ganglion. J. Physiol. 543:117–134 (2002).PubMedCrossRefGoogle Scholar
  68. 68.
    T. Shang, A. V. Uihlein, J. Van Asten, B. Kalyanaraman, and C. J. Hillard. 1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. J. Neurochem. 85:358–367 (2003).PubMedGoogle Scholar
  69. 69.
    M. Inazu, H. Takeda, and T. Matsumiya. Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes. J. Neurochem. 84:43–52 (2003).PubMedCrossRefGoogle Scholar
  70. 70.
    C. Haag, R. Berkels, D. Gründemann, A. Lazar, D. Taubert, and E. Schömig. The localisation of the extraneuronal monoamine transporter (EMT) in rat brain. J. Neurochem. 88:291–297 (2004).PubMedCrossRefGoogle Scholar
  71. 71.
    R. Sata, H. Ohtani, M. Tsujimoto, H. Murakami, N. Koyabu, T. Nakamura, T. Uchiumi, M. Kuwano, H. Nagata, K. Tsukimori, H. Nakano, and Y. Sawada. Functional analysis of organic cation transporter 3 expressed in human placenta. J. Pharmacol. Exp. Ther. 315:888–895 (2005).PubMedCrossRefGoogle Scholar
  72. 72.
    X. Wu, R. Kekuda, W. Huang, Y.-J. Fei, F. H. Leibach, J. Chen, S. J. Conway, and V. Ganapathy. 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. 273:32776–32786 (1998).PubMedCrossRefGoogle Scholar
  73. 73.
    P. J. Gasser, C. A. Lowry, and M. Orchinik. Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J. Neurosci. 26:8758–8766 (2006).PubMedCrossRefGoogle Scholar
  74. 74.
    V. Vialou, A. Amphoux, R. Zwart, B. Giros, and S. Gautron. Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation. J. Neurosci. 24:2846–2851 (2004).PubMedCrossRefGoogle Scholar
  75. 75.
    S. Tokuhiro, R. Yamada, X. Chang, A. Suzuki, Y. Kochi, T. Sawada, M. Suzuki, M. Nagasaki, M. Ohtsuki, M. Ono, H. Furukawa, M. Nagashima, S. Yoshino, A. Mabuchi, A. Sekine, S. Saito, A. Takahashi, T. Tsunoda, Y. Nakamura, and K. Yamamoto. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat. Genet. 35:341–348 (2003).PubMedCrossRefGoogle Scholar
  76. 76.
    W. Xuan, A.-M. Lamhonwah, C. Librach, K. Jarvi, and I. Tein. Characterization of organic cation/carnitine transporter family in human sperm. Biochem. Biophys. Res. Commun. 306:121–128 (2003).PubMedCrossRefGoogle Scholar
  77. 77.
    A.-M. Lamhonwah and I. Tein. Novel localization of OCTN1, an organic cation/carnitine transporter, to mammalian mitochondria. Biochem. Biophys. Res. Commun. 345:1315–1325 (2006).PubMedCrossRefGoogle Scholar
  78. 78.
    A.-M. Lamhonwah, C. Ackerley, R. Onizuka, A. Tilups, D. Lamhonwah, C. Chung, K. S. Tao, R. Tellier, and I. Tein. Epitope shared by functional variant of organic cation/carnitine transporter, OCTN1, Campylobacter jejuni and Mycobacterium paratuberculosis may underlie susceptibility to Crohn’s disease at 5q31. Biochem. Biophys. Res. Commun. 337:1165–1175 (2005).PubMedGoogle Scholar
  79. 79.
    I. Tamai, T. Nakanishi, D. Kobayashi, K. China, Y. Kosugi, J.-i. Nezu, Y. Sai, and A. Tsuji. Involvement of OCTN1 (SLC22A4) in pH-dependent transport of organic cations. Mol. Pharm. 1:57–66 (2004).PubMedCrossRefGoogle Scholar
  80. 80.
    I. Tamai, R. Ohashi, J. Nezu, H. Yabuuchi, A. Oku, M. Shimane, Y. Sai, and A. Tsuji. Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J. Biol. Chem. 273:20378–20382 (1998).PubMedCrossRefGoogle Scholar
  81. 81.
    T. Terada, Y. Shimada, X. Pan, K. Kishimoto, T. Sakurai, R. Doi, H. Onodera, T. Katsura, M. Imamura, and K.-i. Inui. Expression profiles of various transporters for oligopeptides, amino acids and organic ions along the human digestive tract. Biochem. Pharmacol. 70:1756–1763 (2005).PubMedCrossRefGoogle Scholar
  82. 82.
    M. Inazu, H. Takeda, K. Maehara, K. Miyashita, A. Tomoda, and T. Matsumiya. Functional expression of the organic cation/carnitine transporter 2 in rat astrocytes. J. Neurochem. 97:424–434 (2006).PubMedCrossRefGoogle Scholar
  83. 83.
    I. Tamai, K. China, Y. Sai, D. Kobayashi, J.-i. Nezu, E. Kawahara, and A. Tsuji. Na+-coupled transport of L-carnitine via high-affinity carnitine transporter OCTN2 and its subcellular localization in kidney. Biochim. Biophys. Acta 1512:273–284 (2001).PubMedCrossRefGoogle Scholar
  84. 84.
    K. Yakushiji, S. Kai, M. Yamauchi, M. Kuwajima, Y. Osada, and K. Toshimori. Expression and distribution of OCTN2 in mouse epididymis and its association with obstructive azoospermia in juvenile visceral steatosis mice. Int. J. Urol. 13:420–426 (2006).PubMedCrossRefGoogle Scholar
  85. 85.
    J. M. Durán, M. J. Peral, M. L. Calonge, and A. A. Ilundáin. OCTN3: A Na+-independent L-carnitine transporter in enterocytes basolateral membrane. J. Cell. Physiol. 202:929–935 (2005).PubMedCrossRefGoogle Scholar
  86. 86.
    A.-M. Lamhonwah, J. Skaug, S. W. Scherer, and I. Tein. A third human carnitine/organic cation transporter (OCTN3) as a candidate for the 5q31 Crohn’s disease locus (IBD5). Biochem. Biophys. Res. Commun. 301:98–101 (2003).PubMedCrossRefGoogle Scholar
  87. 87.
    M. Okabe, M. Unno, H. Harigae, M. Kaku, Y. Okitsu, T. Sasaki, T. Mizoi, K. Shiiba, H. Takanaga, T. Terasaki, S. Matsuno, I. Sasaki, S. Ito, and T. Abe. Characterization of the organic cation transporter SLC22A16: a doxorubicin importer. Biochem. Biophys. Res. Commun. 333:754–762 (2005).PubMedCrossRefGoogle Scholar
  88. 88.
    B. M. Schmitt and H. Koepsell. Alkali cation binding and permeation in the rat organic cation transporter rOCT2. J. Biol. Chem. 280:24481–24490 (2005).PubMedCrossRefGoogle Scholar
  89. 89.
    M. Okuda, Y. Urakami, H. Saito, and K.-i. Inui. Molecular mechanisms of organic cation transport in OCT2-expressing Xenopus oocytes. Biochim. Biophys. Acta 1417:224–231 (1999).PubMedCrossRefGoogle Scholar
  90. 90.
    P. Arndt, C. Volk, V. Gorboulev, T. Budiman, C. Popp, I. Ulzheimer-Teuber, A. Akhoundova, S. Koppatz, E. Bamberg, G. Nagel, and H. Koepsell. Interaction of cations, anions, and weak base quinine with rat renal cation transporter rOCT2 compared with rOCT1. Am. J. Physiol. Renal Physiol. 281:F454–F468 (2001).PubMedGoogle Scholar
  91. 91.
    G. Nagel, C. Volk, T. Friedrich, J. C. Ulzheimer, E. Bamberg, and H. Koepsell. A reevaluation of substrate specificity of the rat cation transporter rOCT1. J. Biol. Chem. 272:31953–31956 (1997).PubMedCrossRefGoogle Scholar
  92. 92.
    A. E. Busch, S. Quester, J. C. Ulzheimer, S. Waldegger, V. Gorboulev, P. Arndt, F. Lang, and H. Koepsell. Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCT1. J. Biol. Chem. 271:32599–32604 (1996).PubMedCrossRefGoogle Scholar
  93. 93.
    M. J. Dresser, A. T. Gray, and K. M. Giacomini. Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1). J. Pharmacol. Exp. Ther. 292:1146–1152 (2000).PubMedGoogle Scholar
  94. 94.
    T. Keller, M. Elfeber, V. Gorboulev, H. Reiländer, and H. Koepsell. Purification and functional reconstitution of the rat organic cation transporter OCT1. Biochemistry 44:12253–12263 (2005).PubMedCrossRefGoogle Scholar
  95. 95.
    H. Kimura, M. Takeda, S. Narikawa, A. Enomoto, K. Ichida, and H. Endou. Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J. Pharmacol. Exp. Ther. 301:293–298 (2002).PubMedCrossRefGoogle Scholar
  96. 96.
    S. Harlfinger, C. Fork, A. Lazar, E. Schömig, and D. Gründemann. Are organic cation transporters capable of transporting prostaglandins? Naunyn-Schmiedeberg’s Arch. Pharmacol. 372:125–130 (2005).CrossRefGoogle Scholar
  97. 97.
    C. Volk, V. Gorboulev, T. Budiman, G. Nagel, and H. Koepsell. Different affinities of inhibitors to the outwardly and inwardly directed substrate binding site of organic cation transporter 2. Mol. Pharmacol. 64:1037–1047 (2003).PubMedCrossRefGoogle Scholar
  98. 98.
    T. Budiman, E. Bamberg, H. Koepsell, and G. Nagel. Mechanism of electrogenic cation transport by the cloned organic cation transporter 2 from rat. J. Biol. Chem. 275:29413–29420 (2000).PubMedCrossRefGoogle Scholar
  99. 99.
    R. Ohashi, I. Tamai, H. Yabuuchi, J. -i Nezu, A. Oku, Y. Sai, M. Shimane, and A. Tsuji. Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J. Pharmacol. Exp. Ther. 291:778–784 (1999).PubMedGoogle Scholar
  100. 100.
    X. Wu, W. Huang, P. D. Prasad, P. Seth, D. P. Rajan, F. H. Leibach, J. Chen, S. J. Conway, and V. Ganapathy. Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J. Pharmacol. Exp. Ther. 290:1482–1492 (1999).PubMedGoogle Scholar
  101. 101.
    C. A. Wagner, U. Lükewille, S. Kaltenbach, I. Moschen, A. Bröer, T. Risler, S. Bröer, and F. Lang. Functional and pharmacological characterization of the human Na+/carnitine cotransporter hOCTN2. Am. J. Physiol. Renal Physiol. 279:F584–F591 (2000).PubMedGoogle Scholar
  102. 102.
    H. Yabuuchi, I. Tamai, J. Nezu, K. Sakamoto, A. Oku, M. Shimane, Y. Sai, and A. Tsuji. Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J. Pharmacol. Exp. Ther. 289:768–773 (1999).PubMedGoogle Scholar
  103. 103.
    W. M. Suhre, S. Ekins, C. Chang, P. W. Swaan, and S. H. Wright. Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters hOCT2 and rbOCT2. Mol. Pharmacol. 67:1067–1077 (2005).PubMedCrossRefGoogle Scholar
  104. 104.
    D. Gründemann, G. Liebich, N. Kiefer, S. Köster, and E. Schömig. Selective substrates for non-neuronal monoamine transporters. Mol. Pharmacol. 56:1–10 (1999).PubMedGoogle Scholar
  105. 105.
    A. Amphoux, V. Vialou, E. Drescher, M. Brüss, C. M. La Cour, C. Rochat, M. J. Millan, B. Giros, H. Bönisch, and S. Gautron. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50:941–952 (2006).PubMedCrossRefGoogle Scholar
  106. 106.
    D. Gründemann, S. Köster, N. Kiefer, T. Breidert, M. Engelhardt, F. Spitzenberger, N. Obermüller, and E. Schömig. Transport of monoamine transmitters by the organic cation transporter type 2, OCT2. J. Biol. Chem. 273:30915–30920 (1998).PubMedCrossRefGoogle Scholar
  107. 107.
    L. Zhang, M. E. Schaner, and K. M. Giacomini. Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J. Pharmacol. Exp. Ther. 286:354–361 (1998).PubMedGoogle Scholar
  108. 108.
    D. Gründemann, S. Harlfinger, S. Golz, A. Geerts, A. Lazar, R. Berkels, N. Jung, A. Rubbert, and E. Schömig. Discovery of the ergothioneine transporter. Proc. Natl. Acad. Sci. U. S. A. 102:5256–5261 (2005).PubMedCrossRefGoogle Scholar
  109. 109.
    H. Tahara, H. Kusuhara, H. Endou, H. Koepsell, T. Imaoka, E. Fuse, and Y. Sugiyama. A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J. Pharmacol. Exp. Ther. 315:337–345 (2005).PubMedCrossRefGoogle Scholar
  110. 110.
    M. E. Ganapathy, W. Huang, D. P. Rajan, A. L. Carter, M. Sugawara, K. Iseki, F. H. Leibach, and V. Ganapathy. b-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. J. Biol. Chem. 275:1699–1707 (2000).PubMedCrossRefGoogle Scholar
  111. 111.
    M. Takeda, S. Khamdang, S. Narikawa, H. Kimura, Y. Kobayashi, T. Yamamoto, S. H. Cha, T. Sekine, and H. Endou. Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J. Pharmacol. Exp. Ther. 300:918–924 (2002).PubMedCrossRefGoogle Scholar
  112. 112.
    N. Kimura, S. Masuda, Y. Tanihara, H. Ueo, M. Okuda, T. Katsura, and K.-I. Inui. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab. Pharmacokinet. 20:379–386 (2005).PubMedCrossRefGoogle Scholar
  113. 113.
    L. Zhang, W. Gorset, C. B. Washington, T. F. Blaschke, D. L. Kroetz, and K. M. Giacomini. Interactions of HIV protease inhibitors with a human organic cation transporter in a mammalian expression system. Drug Metab. Dispos. 28:329–334 (2000).PubMedGoogle Scholar
  114. 114.
    G. Ciarimboli, T. Ludwig, D. Lang, H. Pavenstädt, H. Koepsell, H.-J. Piechota, J. Haier, U. Jaehde, J. Zisowsky, and E. Schlatter. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am. J. Pathol. 167:1477–1484 (2005).PubMedGoogle Scholar
  115. 115.
    Q. Li, Y. Sai, Y. Kato, H. Muraoka, I. Tamai, and A. Tsuji. Transporter-mediated renal handling of nafamostat mesilate. J. Pharm. Sci. 93:262–272 (2004).PubMedCrossRefGoogle Scholar
  116. 116.
    D. Gründemann, C. Hahne, R. Berkels, and E. Schömig. Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2). J. Pharmacol. Exp. Ther. 304:810–817 (2003).PubMedCrossRefGoogle Scholar
  117. 117.
    R. Ohashi, I. Tamai, A. Inano, M. Katsura, Y. Sai, J.-I. Nezu, and A. Tsuji. Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein. J. Pharmacol. Exp. Ther. 302:1286–1294 (2002).PubMedCrossRefGoogle Scholar
  118. 118.
    M. J. Dresser, G. Xiao, M. K. Leabman, A. T. Gray, and K. M. Giacomini. Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2). Pharm. Res. 19:1244–1247 (2002).PubMedCrossRefGoogle Scholar
  119. 119.
    A. E. Busch, S. Quester, J. C. Ulzheimer, V. Gorboulev, A. Akhoundova, S. Waldegger, F. Lang, and H. Koepsell. Monoamine neurotransmitter transport mediated by the polyspecific cation transporter rOCT1. FEBS Lett. 395:153–156 (1996).PubMedCrossRefGoogle Scholar
  120. 120.
    M. Kakehi, N. Koyabu, T. Nakamura, T. Uchiumi, M. Kuwano, H. Ohtani, and Y. Sawada. Functional characterization of mouse cation transporter mOCT2 compared with mOCT1. Biochem. Biophys. Res. Commun. 296:644–650 (2002).PubMedCrossRefGoogle Scholar
  121. 121.
    R. Ohashi, I. Tamai, J.-I. Nezu, H. Nikaido, N. Hashimoto, A. Oku, Y. Sai, M. Shimane, and A. Tsuji. Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2. Mol. Pharmacol. 59:358–366 (2001).PubMedGoogle Scholar
  122. 122.
    A. Inano, Y. Sai, Y. Kato, I. Tamai, M. Ishiguro, and A. Tsuji. Functional regions of organic cation/carnitine transporter OCTN2 (SLC22A5): roles in carnitine recognition. Drug Metab. Pharmacokinet. 19:180–189 (2004).PubMedCrossRefGoogle Scholar
  123. 123.
    P. Seth, X. Wu, W. Huang, F. H. Leibach, and V. Ganapathy. 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. 274:33388–33392 (1999).PubMedCrossRefGoogle Scholar
  124. 124.
    S. Berardi, B. Stieger, B. Hagenbuch, E. Carafoli, and S. Krähenbühl. Characterization of L-carnitine transport into rat skeletal muscle plasma membrane vesicles. Eur. J. Biochem. 267:1985–1994 (2000).PubMedCrossRefGoogle Scholar
  125. 125.
    B. Stieger, B. O’Neill, and S. Krähenbühl. Characterization of L-carnitine transport by rat kidney brush-border-membrane vesicles. Biochem. J. 309:643–647 (1995).PubMedGoogle Scholar
  126. 126.
    C. J. Rebouche and D. L. Mack. Sodium gradient-stimulated transport of L-carnitine into renal brush border membrane vesicles: kinetics, specificity, and regulation by dietary carnitine. Arch. Biochem. Biophys. 235:393–402 (1984).PubMedCrossRefGoogle Scholar
  127. 127.
    G. Ciarimboli, K. Struwe, P. Arndt, V. Gorboulev, H. Koepsell, E. Schlatter, and J. R. Hirsch. Regulation of the human organic cation transporter hOCT1. J. Cell. Physiol. 201:420–428 (2004).PubMedCrossRefGoogle Scholar
  128. 128.
    T. Mehrens, S. Lelleck, I. Çetinkaya, M. Knollmann, H. Hohage, V. Gorboulev, P. Bokník, H. Koepsell, and E. Schlatter. The affinity of the organic cation transporter rOCT1 is increased by protein kinase C-dependent phosphorylation. J. Am. Soc. Nephrol. 11:1216–1224 (2000).PubMedGoogle Scholar
  129. 129.
    G. Ciarimboli, H. Koepsell, M. Iordanova, V. Gorboulev, B. Dürner, D. Lang, B. Edemir, R. Schröter, T. Van Le, and E. Schlatter. Individual PKC-phosphorylation sites in organic cation transporter 1 determine substrate selectivity and transport regulation. J. Am. Soc. Nephrol. 16:1562–1570 (2005).PubMedCrossRefGoogle Scholar
  130. 130.
    I. Çetinkaya, G. Ciarimboli, G. Yalcinkaya, T. Mehrens, A. Velic, J. R. Hirsch, V. Gorboulev, H. Koepsell, and E. Schlatter. Regulation of human organic cation transporter hOCT2 by PKA, PI3K, and calmodulin-dependent kinases. Am. J. Physiol. Renal Physiol. 284:F293–F302 (2003).PubMedGoogle Scholar
  131. 131.
    F. Martel, E. Keating, C. Calhau, D. Gründemann, E. Schömig, and I. Azevedo. Regulation of human extraneuronal monoamine transporter (hEMT) expressed in HEK293 cells by intracellular second messenger systems. Naunyn Schmiedeberg’s Arch. Pharmacol. 364:487–495 (2001).CrossRefGoogle Scholar
  132. 132.
    G. Pietig, T. Mehrens, J. R. Hirsch, I. Çetinkaya, H. Piechota, and E. Schlatter. Properties and regulation of organic cation transport in freshly isolated human proximal tubules. J. Biol. Chem. 276:33741–33746 (2001).PubMedCrossRefGoogle Scholar
  133. 133.
    Y. Kato, K. Yoshida, C. Watanabe, Y. Sai, and A. Tsuji. Screening of the interaction between xenobiotic transporters and PDZ proteins. Pharm. Res. 21:1886–1894 (2004).PubMedCrossRefGoogle Scholar
  134. 134.
    Y. Kato, Y. Sai, K. Yoshida, C. Watanabe, T. Hirata, and A. Tsuji. PDZK1 directly regulates the function of organic cation/carnitine transporter OCTN2. Mol. Pharmacol. 67:734–743 (2005).PubMedCrossRefGoogle Scholar
  135. 135.
    E. Schlatter, V. Mönnich, I. Çetinkaya, T. Mehrens, G. Ciarimboli, J. R. Hirsch, C. Popp, and H. Koepsell. The organic cation transporters rOCT1 and hOCT2 are inhibited by cGMP. J. Membr. Biol. 189:237–244 (2002).PubMedCrossRefGoogle Scholar
  136. 136.
    H. M. Bowman and J. B. Hook. Sex differences in organic ion transport by rat kidney. Proc. Soc. Exp. Biol. Med. 141:258–262 (1972).PubMedGoogle Scholar
  137. 137.
    Y. Urakami, N. Nakamura, K. Takahashi, M. Okuda, H. Saito, Y. Hashimoto, and K.-i. Inui. Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett. 461:339–342 (1999).PubMedCrossRefGoogle Scholar
  138. 138.
    Y. Urakami, M. Okuda, H. Saito, and K.-i. Inui. Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett. 473:173–176 (2000).PubMedCrossRefGoogle Scholar
  139. 139.
    Y. Shu, C. L. Bello, L. M. Mangravite, B. Feng, and K. M. Giacomini. Functional characteristics and steroid hormone-mediated regulation of an organic cation transporter in madin-darby canine kidney cells. J. Pharmacol. Exp. Ther. 299:392–398 (2001).PubMedGoogle Scholar
  140. 140.
    J.-i. Asaka, T. Terada, M. Okuda, T. Katsura, and K.-i. Inui. Androgen receptor is responsible for rat organic cation transporter 2 gene regulation but not for rOCT1 and rOCT3. Pharm. Res. 1–8 (2006).Google Scholar
  141. 141.
    C. E. Groves, W. B. Suhre, N. J. Cherrington, and S. H. Wright. Sex differences in the mRNA, protein, and functional expression of organic anion transporter (Oat) 1, Oat3, and organic cation transporter (Oct) 2 in rabbit renal proximal tubules. J. Pharmacol. Exp. Ther. 316:743–752 (2006).PubMedCrossRefGoogle Scholar
  142. 142.
    M. Saborowski, G. A. Kullak-Ublick, and J. J. Eloranta. The human organic cation transporter-1 gene is transactivated by hepatocyte nuclear factor-4a. J. Pharmacol. Exp. Ther. 317:778–785 (2006).PubMedCrossRefGoogle Scholar
  143. 143.
    W. Nie, S. Sweetser, M. Rinella, and R. M. Green. Transcriptional regulation of murine Slc22a1 (Oct1) by peroxisome proliferator agonist receptor-a and -g. Am. J. Physiol. Gastrointest. Liver Physiol. 288:G207–G212 (2005).PubMedCrossRefGoogle Scholar
  144. 144.
    L. Ji, S. Masuda, H. Saito, and K.-I. Inui. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int. 62:514–524 (2002).PubMedCrossRefGoogle Scholar
  145. 145.
    M. C. Thomas, C. Tikellis, W. C. Burns, V. Thallas, J. M. Forbes, Z. Cao, T. M. Osicka, L. M. Russo, G. Jerums, H. Ghabrial, M. E. Cooper, and P. Kantharidis. Reduced tubular cation transport in diabetes: Prevented by ACE inhibition. Kidney Int. 63:2152–2161 (2003).PubMedCrossRefGoogle Scholar
  146. 146.
    M. C. Thomas, C. Tikellis, P. Kantharidis, W. C. Burns, M. E. Cooper, and J. M. Forbes. The role of advanced glycation in reduced organic cation transport associated with experimental diabetes. J. Pharmacol. Exp. Ther. 311:456–466 (2004).Google Scholar
  147. 147.
    B. Grover, C. Auberger, R. Sarangarajan, and W. Cacini. Functional impairment of renal organic cation transport in experimental diabetes. Pharmacol. Toxicol. 90:181–186 (2002).PubMedCrossRefGoogle Scholar
  148. 148.
    Y. Habu, I. Yano, A. Takeuchi, H. Saito, M. Okuda, A. Fukatsu, and K.-i. Inui. Decreased activity of basolateral organic ion transports in hyperuricemic rat kidney: roles of organic ion transporters, rOAT1, rOAT3 and rOCT2. Biochem. Pharmacol. 66:1107–1114 (2003).PubMedCrossRefGoogle Scholar
  149. 149.
    G. U. Denk, C. J. Soroka, A. Mennone, H. Koepsell, U. Beuers, and J. L. Boyer. Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis. Hepatology 39:1382–1389 (2004).PubMedCrossRefGoogle Scholar
  150. 150.
    N. J. Cherrington, A. L. Slitt, N. Li, and C. D. Klaassen. Lipopolysaccharide-mediated regulation of hepatic transporter mRNA levels in rats. Drug Metab. Dispos. 32:734–741 (2004).PubMedCrossRefGoogle Scholar
  151. 151.
    K. Kitaichi, Y. Morishita, Y. Doi, J. Ueyama, M. Matsushima, Y.-L. Zhao, K. Takagi, and T. Hasegawa. Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats. Eur. J. Pharmacol. 464:39–48 (2003).PubMedCrossRefGoogle Scholar
  152. 152.
    T. Maeda, M. Hirayama, D. Kobayashi, and I. Tamai. Regulation of testis-specific carnitine transporter (octn3) gene by proximal cis-acting elements Sp1 in mice. Biochem. Pharmacol. 70:858–868 (2005).PubMedCrossRefGoogle Scholar
  153. 153.
    O. Dransfeld, T. Gehrmann, K. Köhrer, G. Kircheis, C. Holneicher, D. Häussinger, and M. Wettstein. Oligonucleotide microarray analysis of differential transporter regulation in the regenerating rat liver. Liver Int. 25:1243–1258 (2005).PubMedCrossRefGoogle Scholar
  154. 154.
    J. W. Jonker, E. Wagenaar, C. A. A. M. Mol, M. Buitelaar, H. Koepsell, J. W. Smit, and A. H. Schinkel. 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. 21:5471–5477 (2001).PubMedCrossRefGoogle Scholar
  155. 155.
    R. Zwart, S. Verhaagh, M. Buitelaar, C. Popp-Snijders, and D. P. Barlow. Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol. Cell Biol. 21:4188–4196 (2001).PubMedCrossRefGoogle Scholar
  156. 156.
    J. W. Jonker, E. Wagenaar, S. van Eijl, and A. H. Schinkel. Deficiency in the organic cation transporters 1 and 2 (oct1/oct2 [slc22a1/slc22a2]) in mice abolishes renal secretion of organic cations. Mol. Cell Biol. 23:7902–7908 (2003).PubMedCrossRefGoogle Scholar
  157. 157.
    D.-S. Wang, J. W. Jonker, Y. Kato, H. Kusuhara, A. H. Schinkel, and Y. Sugiyama. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther. 302:510–515 (2002).PubMedCrossRefGoogle Scholar
  158. 158.
    K. Yokogawa, M. Yonekawa, I. Tamai, R. Ohashi, Y. Tatsumi, Y. Higashi, M. Nomura, N. Hashimoto, H. Nikaido, J. Hayakawa, J. Nezu, A. Oku, M. Shimane, K. Miyamoto, and A. Tsuji. Loss of wild-type carrier-mediated L-carnitine transport activity in hepatocytes of juvenile visceral steatosis mice. Hepatology 30:997–1001 (1999).PubMedCrossRefGoogle Scholar
  159. 159.
    K.-m. Lu, H. Nishimori, Y. Nakamura, K. Shima, and M. Kuwajima. A missense mutation of mouse OCTN2, a sodium-dependent carnitine cotransporter, in the juvenile visceral steatosis mouse. Biochem. Biophys. Res. Commun. 252:590–594 (1998).PubMedCrossRefGoogle Scholar
  160. 160.
    N. Hashimoto, F. Suzuki, I. Tamai, H. Nikaido, M. Kuwajima, J.-I. Hayakawa, and A. Tsuji. Gene-dose effect on carnitine transport activity in embryonic fibroblasts of JVS mice as a model of human carnitine transporter deficiency. Biochem. Pharmac. 55:1729–1732 (1998).CrossRefGoogle Scholar
  161. 161.
    J. Hayakawa, T. Koizumi, and H. Nikaido. Inheritance of juvenile visceral steatosis found in C3H-H-2o mice. Mouse Genome 86:261 (1990).Google Scholar
  162. 162.
    T. Koizumi, H. Nikaido, J. Hayakawa, A. Nonomura, and T. Yoneda. Infantile disease with microvesicular fatty infiltration of viscera spontaneously occurring in the C3H-H-2° strain of mouse with similarities to Reye’s syndrome. Lab. Anim. 22:83–87 (1988).PubMedCrossRefGoogle Scholar
  163. 163.
    M. Horiuchi, H. Yoshida, K. Kobayashi, K. Kuriwaki, K. Yoshimine, M. Tomomura, T. Koizumi, H. Nikaido, J. Hayakawa, M. Kuwajima, and T. Saheki. Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency. FEBS Lett. 326:267–271 (1993).PubMedCrossRefGoogle Scholar
  164. 164.
    M. Tomomura, Y. Imamura, M. Horiuchi, T. Koizumi, H. Nikaido, J. Hayakawa, and T. Saheki. Abnormal expression of urea cycle enzyme genes in juvenile visceral steatosis (jvs) mice. Biochim. Biophys. Acta 1138:167–171 (1992).PubMedGoogle Scholar
  165. 165.
    K. Toshimori, M. Kuwajima, K. Yoshinaga, T. Wakayama, and K. Shima. Dysfunctions of the epididymis as a result of primary carnitine deficiency in juvenile visceral steatosis mice. FEBS Lett. 446:323–326 (1999).PubMedCrossRefGoogle Scholar
  166. 166.
    R. Kerb, U. Brinkmann, N. Chatskaia, D. Gorbunov, V. Gorboulev, E. Mornhinweg, A. Keil, M. Eichelbaum, and H. Koepsell. Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 12:591–595 (2002).PubMedCrossRefGoogle Scholar
  167. 167.
    Y. Shu, M. K. Leabman, B. Feng, L. M. Mangravite, C. C. Huang, D. Stryke, M. Kawamoto, S. J. Johns, J. DeYoung, E. Carlson, T. E. Ferrin, I. Herskowitz, and K. M. Giacomini, Pharmacogenetics of membrane transporters investigators. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1. Proc. Natl. Acad. Sci.U.S.A. 100:5902–5907 (2003).PubMedCrossRefGoogle Scholar
  168. 168.
    M. Itoda, Y. Saito, K. Maekawa, H. Hichiya, K. Komamura, S. Kamakura, M. Kitakaze, H. Tomoike, K. Ueno, S. Ozawa, and J.-i. Sawada. Seven novel single nucleotide polymorphisms in the human SLC22A1 gene encoding organic cation transporter 1 (OCT1). Drug Metab. Pharmacokinet. 19:308–312 (2004).PubMedCrossRefGoogle Scholar
  169. 169.
    H. Fukushima-Uesaka, K. Maekawa, S. Ozawa, K. Komamura, K. Ueno, M. Shibakawa, S. Kamakura, M. Kitakaze, H. Tomoike, Y. Saito, and J. Sawada. Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2). Drug Metab. Pharmacokin. 19:239–244 (2004).CrossRefGoogle Scholar
  170. 170.
    M. K. Leabman, C. C. Huang, M. Kawamoto, S. J. Johns, D. Stryke, T. E. Ferrin, J. DeYoung, T. Taylor, A. G. Clark, I. Herskowitz, and K. M. Giacomini. Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 12:395–405 (2002).PubMedCrossRefGoogle Scholar
  171. 171.
    T. Fujita, T. J. Urban, M. K. Leabman, K. Fujita, and K. M. Giacomini. Transport of drugs in the kidney by the human organic cation transporter, OCT2 and its genetic variants. J. Pharm. Sci. 95:25–36 (2006).PubMedCrossRefGoogle Scholar
  172. 172.
    A. Takeuchi, H. Motohashi, M. Okuda, and K.-i. Inui. Decreased function of genetic variants, Pro283Leu and Arg287Gly, in human organic cation transporter hOCT1. Drug Metab. Pharmacokin. 18:409–412 (2003).CrossRefGoogle Scholar
  173. 173.
    T. Sakata, N. Anzai, H. J. Shin, R. Noshiro, T. Hirata, H. Yokoyama, Y. Kanai, and H. Endou. Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochem. Biophys. Res. Commun. 313:789–793 (2004).PubMedCrossRefGoogle Scholar
  174. 174.
    A. Koizumi, J.-i. Nozaki, T. Ohura, T. Kayo, Y. Wada, J.-i. Nezu, R. Ohashi, I. Tamai, Y. Shoji, G. Takada, S. Kibira, T. Matsuishi, and A. Tsuji. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum. Mol. Genet. 8:2247–2254 (1999).PubMedCrossRefGoogle Scholar
  175. 175.
    N. L. S. Tang, V. Ganapathy, X. Wu, J. Hui, P. Seth, P. M. P. Yuen, T. F. Fok, and N. M. Hjelm. Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. Hum. Mol. Genet. 8:655–660 (1999).PubMedCrossRefGoogle Scholar
  176. 176.
    Y. Wang, J. Ye, V. Ganapathy, and N. Longo. Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency. Proc. Natl. Acad. Sci. U.S.A. 96:2356–2360 (1999).PubMedCrossRefGoogle Scholar
  177. 177.
    O. Palmieri, A. Latiano, R. Valvano, R. D’Inca, M. Vecchi, G. C. Sturniolo, S. Saibeni, F. Peyvandi, F. Bossa, C. Zagaria, A. Andriulli, M. Devoto, and V. Annese. Variants of OCTN1-2 cation transporter genes are associated with both Crohn’s disease and ulcerative colitis. Aliment. Pharmacol. Ther. 23:497–506 (2006).PubMedCrossRefGoogle Scholar
  178. 178.
    J. D. Rioux, M. J. Daly, M. S. Silverberg, K. Lindblad, H. Steinhart, Z. Cohen, T. Delmonte, K. Kocher, K. Miller, S. Guschwan, E. J. Kulbokas, S. O’Leary, E. Winchester, K. Dewar, T. Green, V. Stone, C. Chow, A. Cohen, D. Langelier, G. Lapointe, D. Gaudet, J. Faith, N. Branco, S. B. Bull, R. S. McLeod, A. M. Griffiths, A. Bitton, G. R. Greenberg, E. S. Lander, K. A. Siminovitch, and T. J. Hudson. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat. Genet. 29:223–228 (2001).PubMedCrossRefGoogle Scholar
  179. 179.
    M. S. Silverberg. OCTNs: Will the real IBD5 gene please stand up? World J. Gastroenterol. 12:3678–3681 (2006).PubMedGoogle Scholar
  180. 180.
    R. K. Russell, H. Drummond, E. Nimmo, N. Anderson, C. Noble, D. Wilson, P. Gillett, P. McGrogan, K. Hassan, L. Weaver, M. Bisset, G. Mahdi, and J. Satsangi. Analysis of the influence of OCTN1/2 variants within the IBD5 locus on disease susceptibility and growth parameters in early-onset inflammatory bowel disease. Gut (2006).Google Scholar
  181. 181.
    A. Lazar, T. Zimmermann, W. Koch, D. Gründemann, A. Schömig, A. Kastrati, and E. Schömig. Lower prevalence of the OCT2 Ser270 allele in patients with essential hypertension. Clin. Exp. Hypertens. 28:645–653 (2006).PubMedCrossRefGoogle Scholar
  182. 182.
    N. Aoyama, N. Takahashi, K. Kitaichi, R. Ishihara, S. Saito, N. Maeno, X. Ji, K. Takagi, Y. Sekine, M. Iyo, M. Harano, T. Komiyama, M. Yamada, I. Sora, H. Ujike, N. Iwata, T. Inada, and N. Ozaki. Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder. Alcohol Clin. Exp. Res. 30:1644–1649 (2006).PubMedCrossRefGoogle Scholar
  183. 183.
    D. Taubert, G. Grimberg, N. Jung, A. Rubbert, and E. Schömig. Functional role of the 503F variant of the organic cation transporter OCTN1 in Crohn’s disease. Gut 54:1505–1506 (2005).PubMedCrossRefGoogle Scholar
  184. 184.
    D. Taubert, A. Lazar, G. Grimberg, N. Jung, A. Rubbert, K.-S. Delank, A. Perniok, E. Erdmann, and E. Schömig. Association of rheumatoid arthritis with ergothioneine levels in red blood cells: a case control study. J. Rheumatol. 33:2139–2145 (2006).PubMedGoogle Scholar
  185. 185.
    S. Vermeire and P. Rutgeerts. Current status of genetics research in inflammatory bowel disease. Genes Immun. 6:637–645 (2005).PubMedGoogle Scholar
  186. 186.
    J. L. Santiago, A. Martinez, H. de la Calle, M. Fernandez-Arquero, M. A. Figueredo, E. G. de la Concha, and E. Urcelay. Evidence for the association of the SLC22A4 and SLC22A5 genes with Type 1 Diabetes: a case control study, BMC. Med. Genet. 7:54 (2006).Google Scholar
  187. 187.
    C. A. Stanley, S. DeLeeuw, P. M. Coates, C. Vianey-Liaud, P. Divry, J. P. Bonnefont, J. M. Saudubray, M. Haymond, F. K. Trefz, and G. N. Breningstall. Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake. Ann. Neurol. 30:709–716 (1991).PubMedCrossRefGoogle Scholar
  188. 188.
    T. J. Urban, R. C. Gallagher, C. Brown, R. A. Castro, L. L. Lagpacan, C. M. Brett, T. R. Taylor, E. J. Carlson, T. E. Ferrin, E. G. Burchard, S. Packman, and K. M. Giacomini. Functional genetic diversity in the high-affinity carnitine transporter OCTN2 (SLC22A5). Mol. Pharmacol. 70:1602–1611 (2006).PubMedCrossRefGoogle Scholar
  189. 189.
    C. Popp, V. Gorboulev, T. D. Müller, D. Gorbunov, N. Shatskaya, and H. Koepsell. Amino acids critical for substrate affinity of rat organic cation transporter 1 line the substrate binding region in a model derived from the tertiary structure of lactose permease. Mol. Pharmacol. 67:1600–1611 (2005).PubMedCrossRefGoogle Scholar
  190. 190.
    V. Gorboulev, N. Shatskaya, C. Volk, and H. Koepsell. Subtype-specific affinity for corticosterone of rat organic cation transporters rOCT1 and rOCT2 depends on three amino acids within the substrate binding region. Mol. Pharmacol. 67:1612–1619 (2005).PubMedCrossRefGoogle Scholar
  191. 191.
    V. Gorboulev, C. Volk, P. Arndt, A. Akhoundova, and H. Koepsell. Selectivity of the polyspecific cation transporter rOCT1 is changed by mutation of aspartate 475 to glutamate. Mol. Pharmacol. 56:1254–1261 (1999).PubMedGoogle Scholar
  192. 192.
    X. Zhang, N. V. Shirahatti, D. Mahadevan, and S. H. Wright. A conserved glutamate residue in transmembrane helix 10 influences substrate specificity of rabbit OCT2 (SLC22A2). J. Biol. Chem. 280:34813–34822 (2005).PubMedCrossRefGoogle Scholar
  193. 193.
    J. Abramson, I. Smirnova, V. Kasho, G. Verner, H. R. Kaback, and S. Iwata. Structure and mechanism of the lactose permease of Escherichia coli. Science 301:610–615 (2003).PubMedCrossRefGoogle Scholar
  194. 194.
    Y. Huang, M. J. Lemieux, J. Song, M. Auer, and D.-N. Wang. Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli. Science 301:616–620 (2003).PubMedCrossRefGoogle Scholar
  195. 195.
    R. M. Pelis, X. Zhang, Y. Danqprapai, and S. H. Wright. Cysteine accessibility in the hydrophilic cleft of the human organic cation transporter 2. J. Biol. Chem. 281:35272–35280 (2006).Google Scholar
  196. 196.
    Y. Wang, S. H. Korman, J. Ye, J. J. Gargus, A. Gutman, F. Taroni, B. Garavaglia, and N. Longo. Phenotype and genotype variation in primary carnitine deficiency. Genet. Med. 3:387–392 (2001).Google Scholar
  197. 197.
    Y. Wang, F. Taroni, B. Garavaglia, and N. Longo. Functional analysis of mutations in the OCTN2 transporter causing primary carnitine deficiency: lack of genotype-phenotype correlation. Hum. Mutat. 16:401–407 (2000).PubMedCrossRefGoogle Scholar
  198. 198.
    A.-M. Lamhonwah, S. E. Olpin, R. J. Pollitt, C. Vianey-Saban, P. Divry, N. Guffon, G. T. N. Besley, R. Onizuka, L. J. De Meirleir, L. Cvitanovic-Sojat, I. Baric, C. Dionisi-Vici, K. Fumic, M. Maradin, and I. Tein. Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy. Am. J. Med. Genet. 111:271–284 (2002).PubMedCrossRefGoogle Scholar
  199. 199.
    B. Burwinkel, J. Kreuder, S. Schweitzer, M. Vorgerd, K. Gempel, K.-D. Gerbitz, and M. W. Kilimann. Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality. Biochem. Biophys. Res. Commun. 261:484–487 (1999).PubMedCrossRefGoogle Scholar
  200. 200.
    F. M. Vaz, H. R. Scholte, J. Ruiter, L. M. Hussaarts-Odijk, R. R. Pereira, S. Schweitzer, J. B. C. de Klerk, H. R. Waterham, and R. J. A. Wanders. Identification of two novel mutations in OCTN2 of three patients with systemic carnitine deficiency. Hum. Genet. 105:157–161 (1999).PubMedCrossRefGoogle Scholar
  201. 201.
    E. Mayatepek, J. Nezu, I. Tamai, A. Oku, M. Katsura, M. Shimane, and A. Tsuji. Two novel missense mutations of the OCTN2 gene (W283R and V446F) in a patient with primary systemic carnitine deficiency. Hum. Mutat. 15:118 (2000).PubMedCrossRefGoogle Scholar
  202. 202.
    Y. Wang, M. A. Kelly, T. M. Cowan, and N. Longo. A missense mutation in the OCTN2 gene associated with residual carnitine transport activity. Hum. Mutat. 15:238–245 (2000).PubMedCrossRefGoogle Scholar
  203. 203.
    Y. Wang, T. A. Meadows, and N. Longo. Abnormal sodium stimulation of carnitine transport in primary carnitine deficiency. J. Biol. Chem. 275:20782–20786 (2000).PubMedCrossRefGoogle Scholar
  204. 204.
    K. Turnheim and F. O. Lauterbach. Absorption and secretion of monoquaternary ammonium compounds by the isolated intestinal mucosa. Biochem. Pharmac. 26:99–108 (1977).CrossRefGoogle Scholar
  205. 205.
    K. Turnheim and F. Lauterbach. Interaction between intestinal absorption and secretion of monoquaternary ammonium compounds in guinea pigs—a concept for the absorption kinetics of organic cations. J. Pharmacol. Exp. Ther. 212:418–424 (1980).PubMedGoogle Scholar
  206. 206.
    M. K. Kim and C.-K. Shim. The transport of organic cations in the small intestine: current knowledge and emerging concepts. Arch. Pharm. Res. 29:605–616 (2006).PubMedCrossRefGoogle Scholar
  207. 207.
    S. Hsing, Z. Gatmaitan, and I. M. Arias. The function of Gp170, the multidrug-restistance gene product, in the brush border of rat intestinal mucosa. Gastroenterology 102:879–885 (1992).PubMedGoogle Scholar
  208. 208.
    F. Thiebaut, T. Tsuruo, H. Hamada, M. M. Gottesman, I. Pastan, and M. C. Willingham. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl. Acad. Sci. U.S.A. 84:7735–7738 (1987).PubMedCrossRefGoogle Scholar
  209. 209.
    J. E. Van Montfoort, M. Müller, G. M. M. Groothuis, D. K. F. Meijer, H. Koepsell, and P. J. Meier. Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J. Pharmacol. Exp. Ther. 298:110–115 (2001).PubMedGoogle Scholar
  210. 210.
    M. Acara and B. Rennick. Regulation of plasma choline by the renal tubule: bidirectional transport of choline. Am. J. Physiol. 225:1123–1128 (1973).PubMedGoogle Scholar
  211. 211.
    K. Besseghir, L. B. Pearce, and B. Rennick. Renal tubular transport and metabolism of organic cations by the rabbit. Am. J. Physiol. 241:F308–F314 (1981).PubMedGoogle Scholar
  212. 212.
    F. Roch-Ramel, K. Besseghir, and H. Murer. Renal excretion and tubular transport of organic anions and cations. In E. E. Windhager (ed.), Handbook of Physiology, Oxford University Press, New York Oxford, 1992, pp. 2189–2262.Google Scholar
  213. 213.
    K. J. Ullrich. Specificity of transporters for ‘organic anions’ and ‘organic cations’ in the kidney. Biochim. Biophys. Acta 1197:45–62 (1994).PubMedGoogle Scholar
  214. 214.
    L. T. Y. Wong, M. R. Escobar, D. D. Smyth, and D. S. Sitar. Gender-associated differences in rat renal tubular amantadine transport and absence of stereoselective transport inhibition by quinine and quinidine in distal tubules. J. Pharmacol. Exp. Ther. 267:1440–1444 (1993).PubMedGoogle Scholar
  215. 215.
    M. R. Escobar and D. S. Sitar. Site-selective effect of bicarbonate on amantadine renal transport: quinine-sensitive in proximal vs quinidine-sensitive sites in distal tubules. J. Pharmacol. Exp. Ther. 273:72–79 (1995).PubMedGoogle Scholar
  216. 216.
    H. Koepsell, V. Gorboulev, and P. Arndt. Molecular pharmacology of organic cation transporters in kidney. J. Membr. Biol. 167:103–117 (1999).PubMedCrossRefGoogle Scholar
  217. 217.
    W. M. Barendt and S. H. Wright. The human organic cation transporter (hOCT2) recognizes the degree of substrate ionization. J. Biol. Chem. 277:22491–22496 (2002).PubMedCrossRefGoogle Scholar
  218. 218.
    S. H. Cha, T. Sekine, J.-I. Fukushima, Y. Kanai, Y. Kobayashi, T. Goya, and H. Endou. Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol. Pharmacol. 59:1277–1286 (2001).PubMedGoogle Scholar
  219. 219.
    S. Gluck and R. Nelson. The role of the V-ATPase in renal epithelial H+ transport. J. Exp. Biol. 172:205–218 (1992).PubMedGoogle Scholar
  220. 220.
    A. Somogyi, A. McLean, and B. Heinzow. Cimetidine-procainamide pharmacokinetic interaction in man: evidence of competition for tubular secretion of basic drugs. Eur. J. Clin. Pharmacol. 25:339–345 (1983).PubMedCrossRefGoogle Scholar
  221. 221.
    A. Somogyi and B. Heinzow. Cimetidine reduces procainamide elimination. N. Engl. J. Med. 307:1080 (1982).PubMedGoogle Scholar
  222. 222.
    M. B. Davidson and A. L. Peters. An overview of metformin in the treatment of type 2 diabetes mellitus. Am. J. Med. 102:99–110 (1997).PubMedCrossRefGoogle Scholar
  223. 223.
    J. E. Nestler. Metformin and the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 86:1430 (2001).PubMedCrossRefGoogle Scholar
  224. 224.
    E. M. Velazquez, S. Mendoza, T. Hamer, F. Sosa, and C. J. Glueck. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism 43:647–654 (1994).PubMedCrossRefGoogle Scholar
  225. 225.
    G. Horvath, N. Schmid, M. A. Fragoso, A. Schmid, G. E. Conner, M. Salathe, and A. Wanner. Epithelial organic cation transporters ensure pH dependent drug absorption in the airway. Am. J. Respir. Cell Mol. Biol. PMID: 16917073 (2006).Google Scholar
  226. 226.
    K. S. Lips, A. Lührmann, T. Tschernig, T. Stoeger, F. Alessandrini, V. Grau, R. V. Haberberger, H. Koepsell, R. Pabst, and W. Kummer. Down-regulation of the non-neuronal cholinergic system in acute allergic airway inflammation of rat and mouse, Life Sci., DOI  10.1016/j.lfs.2007.01.026
  227. 227.
    K. Kitaichi, M. Fukuda, H. Nakayama, N. Aoyama, Y. Ito, Y. Fujimoto, K. Takagi, K. Takagi, and T. Hasegawa. Behavioral changes following antisense oligonucleotide-induced reduction of organic cation transporter-3 in mice. Neurosci. Lett. 382:195–200 (2005).PubMedCrossRefGoogle Scholar
  228. 228.
    N. Feng, B. Mo, P. L. Johnson, M. Orchinik, C. A. Lowry, and K. J. Renner. Local inhibition of organic cation transporters increases extracellular serotonin in the medial hypothalamus. Brain Res. 1063:69–76 (2005).PubMedCrossRefGoogle Scholar
  229. 229.
    F. H. Falcone, H. Haas, and B. F. Gibbs. The human basophil: a new appreciation of its role in immune responses. Blood 96:4028–4038 (2000).PubMedGoogle Scholar
  230. 230.
    S. Corbel, E. Schneider, F. M. Lemoine, and M. Dy. Murine hematopoietic progenitors are capable of both histamine synthesis and uptake. Blood 86:531–539 (1995).PubMedGoogle Scholar
  231. 231.
    M. Ogasawara, K. Yamauchi, Y.-i. Satoh, R. Yamaji, K. Inui, J. W. Jonker, A. H. Schinkel, and K. Maeyama. Recent advances in molecular pharmacology of the histamine systems: organic cation transporters as a histamine transporter and histamine metabolism. J. Pharmacol. Sci. 101:24–30 (2006).PubMedCrossRefGoogle Scholar
  232. 232.
    A. Yonezawa, S. Masuda, K. Nishihara, I. Yano, T. Katsura, and K.-i. Inui. Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat. Biochem. Pharmacol. 70:1823–1831 (2005).PubMedCrossRefGoogle Scholar
  233. 233.
    A. Yonezawa, S. Masuda, S. Yokoo, T. Katsura, and K.-i. Inui. Cisplatin and oxaliplatin, but not nedaplatin, are substrates of human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family. J. Pharmacol. Ex. Ther. 319:879–886 (2006).CrossRefGoogle Scholar
  234. 234.
    O. Briz, M. A. Serrano, N. Rebollo, B. Hagenbuch, P. J. Meier, H. Koepsell, and J. J. G. Marin. Carriers involved in targeting the cytostatic bile acid-cisplatin derivatives cis-diammine-chloro-cholylglycinate-platinum(II) and cis-diammine-bisursodeoxycholate-platinum(II) toward liver cells. Mol. Pharmacol. 61:853–860 (2002).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Hermann Koepsell
    • 1
  • Katrin Lips
    • 2
  • Christopher Volk
    • 1
  1. 1.Institute of Anatomy and Cell BiologyJulius-Maximilians-UniversityWürzburgGermany
  2. 2.Institute of Anatomy and Cell BiologyJustus-Liebig-UniversityGiessenGermany

Personalised recommendations