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Translational Relevance of Animal Models for the Study of Organic Cation Transporter Function

  • Ivan SabolićEmail author
  • Davorka Breljak
  • Tvrtko Smital
Chapter

Abstract

In the mammalian organs, the members of SLC22 family of organic cation transporters (OCTs) mediate distribution, absorption, reabsorption, and secretion of various endogenous and xenobiotic organic cations. OCTs are also responsible for drug–drug interactions and drug-induced organ toxicity. In translational studies, various animal models have been used to study the OCTs-related pathogenesis of human diseases at molecular and cellular level, and to develop new therapeutic drugs and strategies. Particularly useful in this research proved to be mice with the inactivated genes (knockout mice) for specific OCTs. However, some findings in animal models have an uncertain significance for human conditions and diseases, because specific OCTs in their organs exhibit sex differences in protein and/or mRNA expression and species differences in cellular distribution, substrate selectivity and affinity, levels of mRNA and/or protein expression, sensitivity to inhibitors, and regulation. In comparison with animal models, in the human organs some OCTs are absent, others exhibit different localization in the cell membrane domains and different levels of expression, sensitivity to inhibitors, and rates and regulation of the transport of substrates, and none of the thus far tested exhibited the sex-dependent expression. The data from animal models initiated genetic studies in humans, which revealed that several wellknown conditions and diseases are associated with disfunctional OCTs due to gene polymorphism.

Keywords

Drosophila melanogaster Gene polymorphism Human diseases Humanized mice Knockout mice Organic cation transporters Caenorhabditis elegans Malpighian tubules SLC22 family of transporters Species differences Sex differences Translational research Zebrafish 

References

  1. 1.
    Aleksunes LM, Augustine LM, Scheffer GL, Cherrington NJ, Manautou JE. Renal xenobiotic transporters are differentially expressed in mice following cisplatin treatment. Toxicology. 2008;250:82–8.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Alnouti Y, Petrick JS, Klaassen CD. Tissue distribution and ontogeny of organic cation transporters in mice. Drug Metab Dispos. 2006;34:477–82.PubMedGoogle Scholar
  3. 3.
    Angelini S, Pantaleo MA, Ravegnini G, Zanesini C, Cavrini G, Nannini M, et al. Polymorphisms in OCTN1 and OCTN2 transporters genes are associated with prolonged time to progression in unresectable gastrointestinal stromal tumors treated with imatinib therapy. Pharmacol Res. 2013;68:1–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Bacq A, Balasse L, Biala G, Guiard B, Gardier AM, Schinkel A, et al. Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry. 2012;17:926–39.PubMedCrossRefGoogle Scholar
  5. 5.
    Cano MM, Calonge ML, Ilundain AA. Expression of OCTN2 and OCTN3 in the apical membrane of rat renal cortex and medulla. J Cell Physiol. 2010;223:451–9.PubMedGoogle Scholar
  6. 6.
    Cheah IK, Halliwell B. Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim Biophys Acta. 1822;2012:784–93.Google Scholar
  7. 7.
    Cheah IK, Ong RLS, Gruber J, Yew TSK, Ng LF, Chen CB, et al. Knockout of a putative ergothioneine transporter in Caenorhabditis elegans decreases lifespan and increases susceptibility to oxidative damage. Free Radic Res. 2013;47:1036–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen L, Hong C, Chen EC, Yee SW, Xu L, Almof EU, et al. Genetic and epigenetic regulation of the organic cation transporter 3, SLC22A3. Pharmacogenomics J. 2013;13:110–20.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Chen L, Shu Y, Liang X, Chen EC, Yee SW, Zur AA, et al. OCT1 is a high-capacity thiamine transporter that regulates hepatic steatosis and is a target of metformin. Proc Natl Acad Sci U S A. 2014;111:9983–8.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Chen Y-H, Liu H-P, Chen H-Y, Tsai F-J, Chang C-H, Lee Y-J, et al. Ethylene glycol induces calcium oxalate crystal deposition in Malpighian tubules: a Drosophila model for nephrolithiasis/urolithiasis. Kidney Int. 2011;80:369–77.PubMedCrossRefGoogle Scholar
  11. 11.
    Chu X, Bleasby K, Evers R. Species differences in drug transporters and implications for translating preclinical findings to humans. Expert Opin Drug Metab Toxicol. 2013;9:237–52.PubMedCrossRefGoogle Scholar
  12. 12.
    Ciarimboli G. Role of organic cation transporters in drug-induced toxicity. Expert Opin Drug Metab Toxicol. 2011;7:159–74.PubMedCrossRefGoogle Scholar
  13. 13.
    Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, et al. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol. 2010;176:1169–80.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Ciarimboli G, Lancaster CS, Schlatter E, Franke RM, Sprowl JA, Pavenstädt H, et al. Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin Cancer Res. 2012;18:1101–8.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Ciarimboli G, Schlatter E. Regulation of organic cation transport. Pflügers Arch Eur J Physiol. 2005;449: 423–41.CrossRefGoogle Scholar
  16. 16.
    Dai YJ, Jia YF, Chen N, Bian WP, Li QK, Ma YB, et al. Zebrafish as a model system to study toxicology. Environ Toxicol Chem. 2014;33:11–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Damme K, Nies AT, Schaeffeler E, Schwab M. Mammalian MATE (SLC47A) transport proteins: impact on efflux of endogenous substrates and xenobiotics. Drug Metab Rev. 2011;43:499–523.PubMedCrossRefGoogle Scholar
  18. 18.
    Degorter MK, Kim RB. Use of transgenic and knockout mouse models to assess solute carrier transporter function. Clin Pharmacol Ther. 2011;89:612–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Denk GU, Soroka CJ, Mennone A, Koepsell H, Beuers U, Boyer JL. Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis. Hepatology. 2004;39:1382–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Dow JA, Romero MF. Drosophila provides rapid modeling of renal development, function, and disease. Am J Physiol Renal Physiol. 2010;299:F1237–44.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Dresser MJ, Gray AT, Kathleen M, Giacomini KM. Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1). J Pharmacol Exp Ther. 2000;292:1146–52.PubMedGoogle Scholar
  22. 22.
    Duran JM, Peral MJ, Calonge ML, Ilundain AA. OCTN3: a Na+-independent L-carnitine transporter in enterocytes basolateral membrane. J Cell Physiol. 2005;202:929–35.PubMedCrossRefGoogle Scholar
  23. 23.
    Erman F, Tuzcu M, Orhan C, Sahin N, Sahin K. Effect of lycopene against cisplatin-induced acute renal injury in rats: organic anion and cation transporters evaluation. Biol Trace Elem Res. 2014;158:90–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Estudante M, Morais JG, Soveral G, Benet LZ. Intestinal drug transporters: an overview. Adv Drug Deliv Rev. 2013;65:1340–56.PubMedCrossRefGoogle Scholar
  25. 25.
    Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther. 2009;86:396–402.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Flanagan JL, Simmons PA, Vehige J, Willcox MDP, Garrett Q. Role of carnitine in disease. Nutr Metab. 2010;7:30.CrossRefGoogle Scholar
  27. 27.
    Gibert Y, Trengove MC, Ward AC. Zebrafish as a genetic model in pre-clinical drug testing and screening. Curr Med Chem. 2013;20:2458–66.PubMedCrossRefGoogle Scholar
  28. 28.
    Goldsmith JR, Jobin C. Think small: zebrafish as a model system of human pathology. J Biomed Biotechnol. 2012. doi: 10.1155/2012/87341.Google Scholar
  29. 29.
    Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, et al. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 1997;16:871–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Grover B, Buckley D, Buckley AR, Cacini W. Reduced expression of organic cation transporters rOCT1 and rOCT2 in experimental diabetes. J Pharmacol Exp Ther. 2004;308:949–56.PubMedCrossRefGoogle Scholar
  31. 31.
    Groves CE, Suhre WB, Cherrington NJ, Wright SH. 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. 2006;316:743–52.PubMedCrossRefGoogle Scholar
  32. 32.
    Gründemann D, Gorboulev V, Gambaryan S, Veyhl M, Koepsell H. Drug excretion mediated by a new prototype of polyspecific transporter. Nature. 1994;372:549–52.PubMedCrossRefGoogle Scholar
  33. 33.
    Gupta S, Burckhardt G, Hagos Y. SLC22 transporter family proteins as targets for cytostatic uptake into tumor cells. Biol Chem. 2011;392:117–24.PubMedGoogle Scholar
  34. 34.
    Gupta S, Wulf G, Henjakovic M, Koepsell H, Burckhardt G, Hagos Y. Human organic cation transporter 1 is expressed in lymphoma cells and increases susceptibility to irinotecan and paclitaxel. J Pharmacol Exp Ther. 2012;341:16–23.PubMedCrossRefGoogle Scholar
  35. 35.
    Heise M, Lautem A, Knapstein J, Schattenberg JM, Hoppe-Lotichius M, Foltys D, et al. Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance. BMC Cancer. 2012;12:109.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Hirata T, Cabrero P, Berkholz DS, Bondeson DP, Ritman EL, Thompson JR, et al. In vivo Drosophilia genetic model for calcium oxalate nephrolithiasis. Am J Physiol Renal Physiol. 2012;303:F1555–62.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Ho P, Bruce IN, Silman A, Symmons D, Newman B, Young H, et al. Evidence for common genetic control in pathways of inflammation for Chron’s disease and psoriatic arthritis. Arthritis Rheum. 2005;52:3506–602.Google Scholar
  38. 38.
    Ho RH, Kim RB. Transporters and drug therapy: implications for drug disposition and disease. Clin Pharmacol Ther. 2005;78:260–77.PubMedCrossRefGoogle Scholar
  39. 39.
    Holle SK, Ciarimboli G, Edemir B, Neugebauer U, Pavenstädt H, Schlatter E. Properties and regulation of organic cation transport in freshly isolated mouse proximal tubules analyzed with a fluorescence reader-based method. Pflügers Arch Eur J Physiol. 2011;462:359–69.CrossRefGoogle Scholar
  40. 40.
    Horton RE, Apple DM, Owens WA, Baganz NL, Cano S, Mitchell NC, et al. Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression. J Neurosci. 2013;33:10534–43.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Hu Q-H, Zhang X, Wang X, Jiao R-Q, Kong L-D. Quercetin rgulates organic ion transporter and uromodulin expression and improves renal function in hyperuricemic mice. Eur J Nutr. 2012;51:593–606.PubMedCrossRefGoogle Scholar
  42. 42.
    Hume WE, Shingaki T, Takashima T, Hashizume Y, Okauchi T, Katayama Y, et al. The synthesis and biodistribution of [(11)C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo. Bioorg Med Chem. 2013;21:7584–90.PubMedCrossRefGoogle Scholar
  43. 43.
    Januszewicz E, Pajak B, Gajkowska B, Samluk L, Djavadian RL, Hinton BT, et al. Organic cation/carnitine transporter OCTN3 is present in astrocytes and is up-regulated by peroxisome proliferators-activaror receptor agonist. Int J Biochem Cell Biol. 2009;41:2599–609.PubMedCrossRefGoogle Scholar
  44. 44.
    Ji L, Masuda S, Saito H, Inui K. Down-regulation of organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int. 2002;62:514–25.PubMedCrossRefGoogle Scholar
  45. 45.
    Jonker JW, Schinkel AH. Pharmacological and physiological functions of the polyspecific organic cation transporters: OCT1, 2, and 3 (SLC22A1-3). J Pharmacol Exp Ther. 2004;308:2–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Jonker JW, Wagenaar E, Mol CAAM, Buitelaar M, Koepsell H, Smit JW, et al. 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. 2001;21:5471–7.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Jonker JW, Wagenaar E, van Eijl S, Schinkel AH. Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol. 2003;23:7902–8.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Kalueff AV, Stewart AM, Gerlai R. Zebrafish as an emerging model for studying complex brain disorders. Trends Pharmacol Sci. 2014;35:63–75.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Kano T, Kato Y, Ito K, Ogihara T, Kubo Y, Tsuji A. Carnitine/organic cation transporter OCTN2 (Slc22a5) is responsible for renal secretion of cephaloridine in mice. Drug Metab Dispos. 2009;37:1009–16.PubMedCrossRefGoogle Scholar
  50. 50.
    Kari G, Rodeck U, Dicker AP. Zebrafish: an emerging model system for human disease and drug discovery. Clin Pharmacol Ther. 2007;82:70–80.PubMedCrossRefGoogle Scholar
  51. 51.
    Kato Y, Kubo Y, Iwata D, Kato S, Sudo T, Sugiura T, et al. Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1. Pharm Res. 2010;27:832–40.PubMedCrossRefGoogle Scholar
  52. 52.
    Kayouka M, Houze P, Baud FJ, Cisternino S, Debray M, Risede P, et al. Does modulation of organic cation transporters improve pralidoxime activity in an animal model of organophosphate poisoning? Crit Care Med. 2011;39:803–11.PubMedCrossRefGoogle Scholar
  53. 53.
    Kim HR, Park SW, Cho HJ, Chae KA, Sung JM, Kim JS, et al. Comparative gene expression profiles of intestinal transporters in mice, rats and humans. Pharmacol Res. 2007;56:224–36.PubMedCrossRefGoogle Scholar
  54. 54.
    Kimura N, Masuda S, Tanihara Y, Ueo H, Okuda M, Katsura T, et al. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005;20:379–86.PubMedCrossRefGoogle Scholar
  55. 55.
    Klaassen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol transporters: function and regulation. Pharmacol Rev. 2010;62:1–96.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Koepsell H. Polyspecific organic cation transporters and their biomedical relevance in kidney. Curr Opin Nephrol Hypertens. 2013;22:533–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Aspects Med. 2013;34:413–35.PubMedCrossRefGoogle Scholar
  58. 58.
    Koepsell H, Endou H. The SLC22 drug transporter family. Pflügers Arch Eur J Physiol. 2004;447:666–76.CrossRefGoogle Scholar
  59. 59.
    Koepsell H, Gorboulev V, Arndt P. Molecular pharmacology of organic cation transporters in kidney. J Membr Biol. 1999;167:103–17.PubMedCrossRefGoogle Scholar
  60. 60.
    Koepsell H, Schmitt BM, Gorboulev V. Organic cation transporters. Rev Physiol Biochem Pharmacol. 2003;150:1–35.Google Scholar
  61. 61.
    König J, Müller F, Fromm MM. Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol Rev. 2013;65:944–66.PubMedCrossRefGoogle Scholar
  62. 62.
    Kummer W, Wiegand S, Akinci S, Wessler I, Schinkel AH, Wess J, et al. Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse. Respir Res. 2006;7:65.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Lahjouji K, Mitchell GA, Qureshi IA. Carnitine transport by organic cation transporters and systemic carnitine deficiency. Mol Genet Metab. 2001;73:287–97.PubMedCrossRefGoogle Scholar
  64. 64.
    Lai Y, Sampson KE, Balogh LM, Brayman TG, Cox SR, Adams WJ, et al. Preclinical and clinical evidence for the collaborative transport and renal secretion of an oxazolidinone antibiotic by organic anion transporter 3 (OAT3/SLC22A8) and multidrug and toxin extrusion protein 1 (MATE1/SLC47A1). J Pharmacol Exp Ther. 2010;334:936–44.PubMedCrossRefGoogle Scholar
  65. 65.
    Lamhonwah A-M, Ackerley CA, Tilups A, Edwards VD, Wanders RJ, Tein I. OCTN3 is a mammalian peroxisomal membrane carnitine transporter. Biochem Biophys Res Commun. 2005;338:1966–72.PubMedCrossRefGoogle Scholar
  66. 66.
    Lamhonwah A-M, Skaug J, Stephen W, Scherer SW, Tein I. A third human carnitine/organic cation transporter (OCTN3) as a candidate for the 5q31 Crohn’s disease locus (IBD5). Biochem Biophys Res Commun. 2003;301:98–101.PubMedCrossRefGoogle Scholar
  67. 67.
    Lautem A, Heise M, Grasel A, Hoppe-Lotichius M, Weiler N, Foltys D, et al. Downregulation of organic cation transporter 1 (SLC22A1) is associated with tumor progression and reduced patient survival in human cholangiocellular carcinoma. Int J Oncol. 2013;42:1297–304.PubMedGoogle Scholar
  68. 68.
    Lazar A, Zimmermann T, Koch W, Grundemann D, Schomig A, Kastrati A, et al. Lower prevalence of the OCT2 Ser270 allele in patients with essential hypertension. Clin Exp Hypertens. 2006;28:645–53.PubMedCrossRefGoogle Scholar
  69. 69.
    Lee W, Kim RB. Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol. 2004;44:137–66.PubMedCrossRefGoogle Scholar
  70. 70.
    Lee W-K, Reichold R, Edemir B, Ciarimboli G, Warth R, Koepsell H, et al. Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule. Am J Physiol Renal Physiol. 2009;296:F1504–13.PubMedCrossRefGoogle Scholar
  71. 71.
    Li M, Anderson GD, Wang J. Drug-drug interactions involving membrane transporters in the human kidney. Expert Opin Drug Metab Toxicol. 2006;2:505–32.PubMedCrossRefGoogle Scholar
  72. 72.
    Li Q, Guo D, Dong Z, Zhang W, Zhang L, Huang SM, et al. Ondansetron can enhance cisplatin-induced nephrotoxicity via inhibition of multiple toxin and extrusion proteins (MATEs). Toxicol Appl Pharmacol. 2013;273:100–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Li Q, Peng X, Yang H, Wang H, Shu Y. Deficiency of multidrug and toxin extrusion 1 enhances renal accumulation of paraquat and deteriorates kidney injury in mice. Mol Pharmacol. 2011;8:2476–83.CrossRefGoogle Scholar
  74. 74.
    Li S, Chen Y, Zhang S, More SS, Huang X, Giacomini KM. Role of organic cation transporter 1, OCT1 in the pharmacokinetics and toxicity of cis-diammine(pyridine) chloroplatinum(II) and oxaliplatin in mice. Pharm Res. 2011;28:610–25.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Lickteig AJ, Cheng X, Augustine LM, Klaassen CD, Cherrington NJ. Tissue distribution, ontogeny and induction of the transporters multidrug and toxin extrusion (MATE) 1 and MATE2 mRNA expression levels in mice. Life Sci. 2008;83:59–64.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Lieschke GJ, Currie PD. Animal models of human disease: zebrafish swim into view. Nat Rev Genet. 2007;8:353–67.PubMedCrossRefGoogle Scholar
  77. 77.
    Lin JH. Applications and limitations of genetically modified mouse models in drug discovery and development. Curr Drug Metab. 2008;9:419–38.PubMedCrossRefGoogle Scholar
  78. 78.
    Lips KS, Luhrmann A, Tschernig T, Stoeger T, Alessandrini F, Grau V, et al. Down-regulation of the non-neuronal acetylcholine synthesis and release machinery in acute allergic airway inflammation of rat and mouse. Life Sci. 2007;80:2263–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Lozano E, Herraez E, Briz O, Robledo VS, Hernandez-Iglesias J, Gonzalez-Hernandez A, et al. Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. Biomed Res Int. 2013. doi: 10.1155/2013/692071. Google Scholar
  80. 80.
    Marincola FM. The trouble with translational medicine. J Intern Med. 2011;270:123–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Massmann V, Edemir B, Schlatter E, Al-Monajjed R, Harrach S, Klassen P, et al. The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. Pflügers Arch Eur J Physiol. 2013. doi: 10.1007/s00424-013-1335-8.Google Scholar
  82. 82.
    Masuda S, Terada T, Yonezawa A, Tanihara Y, Kishimoto K, Katsura T, et al. 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. 2006;17:2127–35.PubMedCrossRefGoogle Scholar
  83. 83.
    McGartland Rubio D, Schoenbaum EE, Lee LS, Schteingart DE, Marantz PR, Anderson KE, et al. Defining translational research: implications for training. Acad Med. 2010;85:470–5.CrossRefGoogle Scholar
  84. 84.
    Meetam P, Srimaroeng C, Soodvilai S, Chatsudthipong V. Regulatory role of testosterone in organic cation transport: in vivo and in vitro studies. Biol Pharm Bull. 2009;32:982–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Meetam P, Srimaroeng C, Soodvilai S, Chatsudthipong V. Role of estrogen in renal handling of organic cation tetraethylammonium: in vivo and in vitro studies. Biol Pharm Bull. 2009;32:1968–72.PubMedCrossRefGoogle Scholar
  86. 86.
    Miller J, Chi T, Kapahi P, Kahn AJ, Kim MS, Hirata T, et al. Drosophila melanogaster as an emerging translational model of human nephrolithiasis. J Urol. 2013;190:1648–56.PubMedCrossRefGoogle Scholar
  87. 87.
    More SS, Li S, Yee SW, Chen L, Xu Z, Jablons DM, Giacomini KM. Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third-generation platinum analogue. Mol Cancer Ther. 2010;9:1058–69.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Morisaki T, Matsuzaki T, Yokoo K, Kusumoto M, Iwata K, Hamada A, et al. Regulation of renal organic ion transporters in cisplatin-induced acute kidney injury and uremia in rats. Pharm Res. 2008;25:2526–33.PubMedCrossRefGoogle Scholar
  89. 89.
    Motohashi H, Inui K. Organic cation transporter OCTs (SLC22) and MATE (SLC47) in the human kidney. Am Assoc Pharmaceut Sci J. 2013;15:581–7.Google Scholar
  90. 90.
    Nakamichi N, Taguchi T, Hosotani H, Wakayama T, Shimizu T, Sugiura T, et al. Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: possible involvement in neuronal differentiation. Neurochem Int. 2012;61:1121–32.PubMedCrossRefGoogle Scholar
  91. 91.
    Nakamura T, Yonezawa A, Hashimoto S, Katsura T, Inui K. Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity. Biochem Pharmacol. 2010;80:1762–7.PubMedCrossRefGoogle Scholar
  92. 92.
    Nies AT, Damme K, Schaeffeler E, Schwab M. Multidrug and toxin extrusion proteins as transporters of antimicrobial drugs. Expert Opin Drug Metab Toxicol. 2012;8:1565–77.PubMedCrossRefGoogle Scholar
  93. 93.
    Nies AT, Koepsell H, Damme K, Schwab M. Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy. Handb Exp Pharmacol. 2011;201:105–67.PubMedCrossRefGoogle Scholar
  94. 94.
    Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, et al. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009;50:1227–40.PubMedCrossRefGoogle Scholar
  95. 95.
    Nishihara K, Masuda S, Ji L, Katsura T, Inui K. Pharmacokinetic significance of luminal multidrug and toxin extrusion 1 in chronic renal failure rats. Biochem Pharmacol. 2007;73:1482–90.PubMedCrossRefGoogle Scholar
  96. 96.
    O’Donnell MJ. Too much of a good thing: how insects cope with excess ions or toxins in the diet. J Exp Biol. 2009;212:363–72.PubMedCrossRefGoogle Scholar
  97. 97.
    Ogasawara M, Yamauchi K, Satoh Y, Yamaji R, Inui K, Jonker JW, et al. Recent advances in molecular pharmacology of the histamine systems: organic cation transporters as a histamine transporter and histamine metabolism. J Pharmacol Sci. 2006;101:24–30.PubMedCrossRefGoogle Scholar
  98. 98.
    Olson H, Betton G, Robinson D, Thomas K, Monro A, Kolaja G, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol. 2000;32:56–67.PubMedCrossRefGoogle Scholar
  99. 99.
    Omote H, Hiasa M, Matsumoto T, Otsuka M, Moriyama Y. The MATE proteins as fundamental transporters of metabolic and xenobiotic organic cations. Trends Pharmacol Sci. 2006;27:587–93.PubMedCrossRefGoogle Scholar
  100. 100.
    Otsuka M, Matsumoto T, Morimoto R, Arioka S, Omote H, Moriyama Y. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc Natl Acad Sci U S A. 2005;102:17923–8.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Pan XL, Wang L, Grundemann D, Sweet DH. Interaction of ethambutol with human organic cation transporters of the SLC22 family indicates potential for drug-drug interactions during antituberculosis therapy. Antimicrob Agents Chemother. 2013;57:5053–9.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Paulson DJ. Carnitine deficiency-induced cardiomyopathy. Mol Cell Biochem. 1998;180:33–41.PubMedCrossRefGoogle Scholar
  103. 103.
    Petermann I, Triggs CM, Huebner C, Han DY, Gearry RB, Barclay ML, et al. Mushroom intolerance: a novel diet-gene interaction in Crohn’s disease. Br J Nutr. 2009;102:506–8.PubMedCrossRefGoogle Scholar
  104. 104.
    Pickart MA, Klee EW. Zebrafish approaches enhance the translational research tackle box. Transl Res. 2014;163:65–78.PubMedCrossRefGoogle Scholar
  105. 105.
    Pochini L, Scalise M, Galluccio M, Indiveri C. OCTN cation transporters in health and disease: role as drug targets and assay development. J Biomol Screen. 2013;18:851–67.PubMedCrossRefGoogle Scholar
  106. 106.
    Reznichenko A, Sinkeler SJ, Snieder H, van den Born J, de Borst MH, Damman J, et al. SLC22A2 is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation. Physiol Genomics. 2013;45:201–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Rheault MR, O’Donnell MJ. Organic cation transport by Malpighian tubules of Drosophila melanogaster: application of two novel electrophysiological methods. J Exp Biol. 2004;207:2173–84.PubMedCrossRefGoogle Scholar
  108. 108.
    Ringseis R, Luci S, Spielmann J, Kluge H, Fischer M, Geissler S, et al. Clofibrate treatment up-regulates novel organic cation transporter (OCTN)-2 in tissues of pigs as a model of non-proliferating species. Eur J Pharmacol. 2008;583:11–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Ringseis R, Pösel S, Hirche F, Eder K. Treatment with pharmacological peroxisome proliferator-activated receptor α agonist clofibrate causes upregulation of organic cation transporter 2 in liver and small intestine of rats. Pharmacol Res. 2007;56:175–83.PubMedCrossRefGoogle Scholar
  110. 110.
    Ringseis R, Wege N, Wen G, Rauer C, Hirche F, Kluge H, et al. Carnitine synthesis and uptake into cells are stimulated by fasting in pigs as model of nonproliferating species. J Nutr Biochem. 2009;20:840–7.PubMedCrossRefGoogle Scholar
  111. 111.
    Sabolic I, Asif AR, Budach WE, Wanke C, Bahn A, Burckhardt G. Gender differences in kidney function. Pflügers Arch Eur J Physiol. 2007;455:397–429.CrossRefGoogle Scholar
  112. 112.
    Sabolic I, Breljak D, Ljubojevic M, Brzica H. Are mice, rats, and rabbits good models for physiological, pharmacological and toxicological studies in humans? Period Biol. 2009;113:7–16.Google Scholar
  113. 113.
    Sanger GJ, Holbrook JD, Andrews PL. The translational value of rodent gastrointestinal functions: a cautionary tale. Trends Pharmacol Sci. 2011;32:402–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Schildkraut JJ, Mooney JJ. Toward a rapidly acting antidepressant: the normetanephrine and extraneuronal monoamine transporter (uptake 2) hypothesis. Am J Psychiatry. 2004;161:909–11.PubMedCrossRefGoogle Scholar
  115. 115.
    Schlatter E, Klassen P, Massmann V, Holle SK, Guckel D, Edemir B, et al. Mouse organic cation transporter 1 determines properties and regulation of basolateral organic cation transport in renal proximal tubules. Pflügers Arch Eur J Physiol. 2014;466:1581–9.CrossRefGoogle Scholar
  116. 116.
    Schneider E, Machavoine F, Pléau J-M, Bertron A-F, Thurmond RL, Ohtsu H, et al. Organic cation transporter 3 modulates murine basophil functions by controlling intracellular histamine levels. J Exp Med. 2005;202:387–93.PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Seth A, Stemple DL, Barroso I. The emerging use of zebrafish to model metabolic disease. Dis Model Mech. 2013;6:1080–8.PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Shekhawat PS, Yang HS, Bennett MJ, Carter AL, Matern D, Tamai I, et al. Carnitine content and expression of mitochondrial beta-oxidation enzymes in placentas of wild-type (OCTN2(+/+)) and OCTN2 null (OCTN2(-/-)) mice. Pediatr Res. 2004;56:323–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Shi Y-W, Wang C-P, Wang X, Zhang Y-L, Liu L, Wang R-W, et al. Uricosuric and nephroprotective properties of Ramulus Mori ethanol extract in hyperuricemic mice. J Ethnopharmacol. 2012;143:896–904.PubMedCrossRefGoogle Scholar
  120. 120.
    Shitara Y, Nakamichi N, Norioka M, Shima H, Kato Y, Horie T. Role of organic cation/carnitine transporter 1 in uptake of phenformin and inhibitory effect on complex I respiration in mitochondria. Toxicol Sci. 2013;132:32–42.PubMedCrossRefGoogle Scholar
  121. 121.
    Shnitsar V, Eckardt R, Gupta S, Grottker J, Müller GA, Koepsell H, et al. Expression of human organic cation transporter 3 in kidney carcinoma cell lines increases chemosensitivity to melphalan, irinotecan, and vincristine. Cancer Res. 2009;69:1494–501.PubMedCrossRefGoogle Scholar
  122. 122.
    Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther. 2008;83:273–80.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest. 2007;117:1422–31.PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7:118–30.PubMedCrossRefGoogle Scholar
  125. 125.
    Slitt AL, Cherrington NJ, Hartley DP, Leazer TM, Klaassen CD. Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab Dispos. 2002;30:212–9.PubMedCrossRefGoogle Scholar
  126. 126.
    Spaniol M, Brooks H, Auer L, Zimmermann A, Solioz M, Stieger B, et al. Development and characterization of an animal model of carnitine deficiency. Eur J Biochem. 2001;268:1876–87.PubMedCrossRefGoogle Scholar
  127. 127.
    Sprowl JA, Ciarimboli G, Lancaster CS, Giovinazzo H, Gibson AA, Du G, et al. Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci U S A. 2013;110:11199–204.PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109:1–11.PubMedCrossRefGoogle Scholar
  129. 129.
    Tahara H, Kusuhara H, Chida M, Fuse E, Sugiyama Y. Is the monkey an appropriate animal model to examine drug-drug interactions involving renal clearance? Effect of probenecid on the renal elimination of H2 receptor antagonists. J Pharmacol Exp Ther. 2006;316:1187–94.PubMedCrossRefGoogle Scholar
  130. 130.
    Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I. Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics. 2008;9:415–22.PubMedCrossRefGoogle Scholar
  131. 131.
    Tamai I. Pharmacological and pathophysiological roles of carnitine/organic cation transporters (OCTNs: SLC22A4, SLC22A5 and Slc22a21). Biopharm Drug Dispos. 2013;34:29–44.PubMedCrossRefGoogle Scholar
  132. 132.
    Tamai I, Ohashi R, Nezu JI, Sai Y, Kobayashi D, Oku A, et al. Molecular and functional characterization of organic cation/carnitine transporter family in mice. J Biol Chem. 2000;275:40064–72.PubMedCrossRefGoogle Scholar
  133. 133.
    Tang NLS, Ganapathy V, Wu X, Hui J, Seth P, Yuen PMP, et al. Mutations of OCTN2, an organic cation/carnitine transporter, lead to deficient cellular carnitine uptake in primary carnitine deficiency. Hum Mol Genet. 1999;8:655–60.PubMedCrossRefGoogle Scholar
  134. 134.
    Tarasova L, Kalnina I, Geldnere K, Bumbure A, Ritenberga R, Nikitina-Zake L, et al. Association of genetic variation i the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenet Genomics. 2012;22:659–66.PubMedCrossRefGoogle Scholar
  135. 135.
    Tatsumi S, Matsuoka H, Hashimoto Y, Hatta K, Maeda K, Kamoshida S. Organic cation transporter 2 and tumor budding as independent prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy. Int J Clin Exp Pathol. 2014;7:204–12.PubMedCentralPubMedGoogle Scholar
  136. 136.
    Taylor CA, Stanley KN, Shirras AD. The Orct gene of Drosophila melanogaster codes for a putative organic cation transporter with six or 12 transmembrane domains. Gene. 1997;201:69–74.PubMedCrossRefGoogle Scholar
  137. 137.
    Tein I. Carnitine transport: pathophysiology and metabolism of known molecular defects. J Inherit Metab Dis. 2003;26:147–69.PubMedCrossRefGoogle Scholar
  138. 138.
    Terada T, Inui K. Physiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A). Biochem Pharmacol. 2008;75:1689–96.PubMedCrossRefGoogle Scholar
  139. 139.
    Terada T, Masuda S, Asaka J-I, Tsuda M, Katsura T, Inui K. Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006;23:1696–701.PubMedCrossRefGoogle Scholar
  140. 140.
    Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T, et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet. 2003;35:341–8.PubMedCrossRefGoogle Scholar
  141. 141.
    Toyama K, Yonezawa A, Masuda S, Osawa R, Hosokawa M, Fujimoto S, et al. Loss of multidrug and toxin extrusion 1 (MATE1) is associated with metformin-induced lactic acidosis. Br J Pharmacol. 2012;166:1183–91.PubMedCentralPubMedCrossRefGoogle Scholar
  142. 142.
    Tsuda M, Terada T, Mizuno T, Katsura T, Shimakura J, Inui K. Targeted disruption of the multidrug and toxin extrusion 1 (Mate1) gene in mice reduces renal secretion of metformin. Mol Pharmacol. 2009;75:1280–6.PubMedCrossRefGoogle Scholar
  143. 143.
    Tzvetkov MV, Saadatmand AR, Bokelmann K, Meineke I, Kaiser R, Brockmöller J. Effects of OCT1 polymorphisms on the cellular uptake, plasma concentrations and efficacy of the 5-HT3 antagonists tropisetron and ondansetron. Pharmacogenomics J. 2012;12:22–9.PubMedCrossRefGoogle Scholar
  144. 144.
    Tzvetkov MV, Vormfelde CV, Balen D, Meineke I, Schmidt T, Sehrt D, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther. 2009;86:299–306.PubMedCrossRefGoogle Scholar
  145. 145.
    Urakami Y, Nakamura N, Takahashi K, Saito H, Hashimoto Y, Inui K. Gender differences in expression of organic cation transporter OCT2 in rat kidney. FEBS Lett. 1999;461:339–42.PubMedCrossRefGoogle Scholar
  146. 146.
    Urakami Y, Okuda M, Saito H, Inui K. Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett. 2000;473:173–6.PubMedCrossRefGoogle Scholar
  147. 147.
    Urban TJ, Gallagher RC, Brown C, Castro RA, Lagpacan LL, Brett CM, et al. Functional genetic diversity in the high-affinity carnitine transporter OCTN2 (SLC22A5). Mol Pharmacol. 2006;70:1602–11.PubMedCrossRefGoogle Scholar
  148. 148.
    Vialou V, Amphoux A, Zwart R, Giros B, Gautron S. Organic cation transporter 3 (Slc22a3) is implicated in salt-intake regulation. J Neurosci. 2004;24:2846–51.PubMedCrossRefGoogle Scholar
  149. 149.
    Vialou V, Balasse L, Callebert J, Launay JM, Giros B, Gautron S. Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem. 2008;106:1471–82.PubMedGoogle Scholar
  150. 150.
    Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002;302:510–5.PubMedCrossRefGoogle Scholar
  151. 151.
    Wang DS, Kusuhara H, Kato Y, Jonker JW, Schinkel AH, Sugiyama Y. Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. Mol Pharmacol. 2003;63:844–8.PubMedCrossRefGoogle Scholar
  152. 152.
    Wang L, Giannoudis A, Lane S, Williamson P, Pirmohamed M, Clark RE. Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemia. Clin Pharmacol Ther. 2008;83:258–64.PubMedCrossRefGoogle Scholar
  153. 153.
    Wang Y, Yin JY, Li XP, Chen J, Qian CY, Zheng Y, et al. The association of transporter gene polymorphisms and lung cancer chemotherapy response. PLoS One. 2014;9:e91967.PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Watanabe S, Tsuda M, Terada T, Katsura T, Inui K. Reduced renal clearance of a zwitterionic substrate cephalexin in Mate1-deficient mice. J Pharmacol Exp Ther. 2010;334:651–6.PubMedCrossRefGoogle Scholar
  155. 155.
    Wright SH. Role of organic cation transporters in the renal handling of therapeutic agents and xenobiotics. Toxicol Appl Pharmacol. 2005;204:309–19.PubMedCrossRefGoogle Scholar
  156. 156.
    Wultsch T, Grimberg G, Schmitt A, Painsipp E, Wetzstein H, Breitenkamp AF, et al. Decreased anxiety in mice lacking the organic cation transporter 3. J Neural Transm. 2009;116:689–97.PubMedCrossRefGoogle Scholar
  157. 157.
    Zaja R, Popovic M, Loncar J, Mihaljevic I, Smital T. The role of organic cation transporters (Octs, slc22a) in zebrafish (Danio rerio). Comp Biochem Physiol A. 2012;163(Suppl):S26–7.CrossRefGoogle Scholar
  158. 158.
    Zhang L, Dresser MJ, Gray AT, Yost SC, Terashita S, Giacomini KM. Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol. 1997;51:913–21.PubMedGoogle Scholar
  159. 159.
    Zhang X, Cherrington NJ, Wright SH. Molecular identification and functional characterization of rabbit MATE1 and MATE2-K. Am J Physiol Renal Physiol. 2007;293:F360–70.PubMedCrossRefGoogle Scholar
  160. 160.
    Zhu P, Hata R, Ogasawara M, Cao F, Kameda K, Yamauchi K, et al. Targeted disruption of organic cation transporter 3 (Oct3) ameliorates ischemic brain damage through modulating histamine and regulatory T cells. J Cereb Blood Flow Metab. 2012;32:1897–908.PubMedCentralPubMedCrossRefGoogle Scholar
  161. 161.
    Zwart R, Verhaagh S, Buitelaar M, Popp-Snijders C, Barlow DP. Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol. 2001;21:4188–96.PubMedCentralPubMedCrossRefGoogle Scholar
  162. 162.
    Xuan C, Zhang BB, Yang T, Deng KF, Li M, Tian RJ. Association between OCTN1/2 gene polymorphisms (1672C-T, 207G-C) and susceptibility of Crohn’s disease: a meta-analysis. Int J Colorectal Dis. 2012;27:11–9.PubMedCrossRefGoogle Scholar
  163. 163.
    Yakushiji K, Kai S, Yamauchi Y, Kuwajima M, Osada Y, Toshimori K. Expression and distribution of OCTN2 in mouse epididymis and its association with obstructive azoospermia in juvenile visceral steatosis mice. Int J Urol. 2006;13:420–6.PubMedCrossRefGoogle Scholar
  164. 164.
    Yokogawa K, Higash YI, Tamai I, Nomura M, Hashimoto N, Nikaido H, et al. Decreased tissue distribution of L-carnitine in juvenile visceral steatosis mice. J Pharmacol Exp Ther. 1999;289:224–30.PubMedGoogle Scholar
  165. 165.
    Yokoo S, Yonezawa A, Masuda S, Fukatsu A, Katsura T, Inui K. Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity. Biochem Pharmacol. 2007;74:477–87.PubMedCrossRefGoogle Scholar
  166. 166.
    Yonezawa A, Inui K. Importance of the multidrug and toxin extrusion MATE/SLC47A family to pharmacokinetics, pharmacodynamics/toxicodynamics and pharmacogenomics. Br J Pharmacol. 2011;164:1817–25.PubMedCentralPubMedCrossRefGoogle Scholar
  167. 167.
    Yonezawa A, Inui K. Organic cation transporter OCT/SLC22A and H+/organic cation transporter MATE/SLC47A are key molecules for nephrotoxicity of platinum agents. Biochem Pharmacol. 2011;81:563–8.PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Molecular Toxicology UnitInstitute for Medical Research and Occupational HealthZagrebCroatia
  2. 2.Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental ResearchRudjer Bošković InstituteZagrebCroatia

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