Toxicological Research

  • 제23권1호
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  • Pages.1-9
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  • 2007
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  • 1976-8257(pISSN)
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  • 2234-2753(eISSN)
한국독성학회 (Korean Society of Toxicology & Korea Environmental Mutagen Society)
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Toxicological Relevance of Transporters

  • 발행 : 2007.03.31
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초록

Transporters are membrane proteins that mediate the transfer of substrate across the cellular membrane. In this overview, the characteristics and the toxicological relevance were discussed for various types of transporters. For drug transporters, the overview focused on ATP-binding cassette transporters and solute carrier family 21A/22A member transporters. Except for OCTN transporters and OATP transporters, drug transporters tend to have broad substrate specificity, suggesting drug-drug interaction at the level of transport processes (e.g., interaction between methotrexate and non-steroidal anti-inflammatory agents) is likely. For metal transporters, transporters for zinc, copper and multiple metals were discussed in this overview. These metal transporters have comparatively narrow substrate specificity, except for multiple metal transporters, suggesting that inter-substrate interaction at the level of transport is less likely. In contrast, the expressions of the transporters are often regulated by their substrates, suggesting cellular adaptation mechanism exists for these transporters. The drug-drug interactions in drug transporters and the cellular adaptation mechanisms for metal transporters are likely to lead to alterations in pharmacokinetics and cellular metal homeostasis, which may be linked to the development of toxicity. Therefore, the transporter-mediated alterations may have toxicological relevance.

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참고문헌

  1. Aherne, G.W., Piall, E., Marks, V., Mould, G. and White, W.F. (1978). Prolongation and enhancement of serum methotrexate concentrations by probenicid. Br. Med. J., 1, 1097- 1099 https://doi.org/10.1136/bmj.1.6120.1097
  2. Beringer, P.M. and Slaughter, R.L. (2005). Transporters and their impact on drug disposition. Ann. Pharmacother., 39, 1097-1108 https://doi.org/10.1345/aph.1E614
  3. Canonne-Hergaux, F., Gruenheid, S., Ponka, P. and Gros, P. (1999). Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood, 93, 4406-4417
  4. Cole, T.B., Robbins, C.A., Wenzel, H.J., Schwartzkroin, P.A. and Palmiter, R.D. (2000). Seizures and neuronal damage in mice lacking vesicular zinc. Epilepsy Res., 39, 153-169 https://doi.org/10.1016/S0920-1211(99)00121-7
  5. Conrad, M.D., Umbreit, J.N., Moore, E.G., Mainsworth, L.N., Porubcin, M., Simovich, M.J., Nakada, M.T., Dolan, K. and Garrick, M.D. (2000). Separate pathways for cellular uptake of ferric and ferrous iron. Am. J. Physiol., 279, 767-774
  6. Dameron, C.T. and Harrison, M.D. (1998). Mechanisms for protection against copper toxicity. Am. J. Clin. Nutr., 67(suppl), 1091-1097 https://doi.org/10.1093/ajcn/67.5.1091S
  7. Dressor, G.K., Kim, R.B. and Bailey, D.G. (2005). Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides. Clin. Pharmacol. Ther., 77, 170-177 https://doi.org/10.1016/j.clpt.2004.10.005
  8. Eisses, J.F. and Kaplan, J.H. (2002). Molecular characterization of hCTR1, the human copper uptake protein. J. Biol. Chem., 277, 29162-29171 https://doi.org/10.1074/jbc.M203652200
  9. El-Tanani, M.K. and Green, C.D. (1997). Interaction between estradiol and growthfactors in the regulation of specific gene expression in MCF-7 human breast cancer cells. J. Steroid Biochem. Mol. Biol., 60, 269-276 https://doi.org/10.1016/S0960-0760(96)00226-9
  10. Gaither, L.A. and Eide, D.J. (2000). Functional expression of the human hZIP2 zinc transporter. J. Biol. Chem., 275, 5560-5564 https://doi.org/10.1074/jbc.275.8.5560
  11. Garrick, M.D., Dolan, K.G., Horbinski, C., Ghio, A.J., Higgins, D., Porubcin, M., Moore, E.G., Hainsworth, L.N., Umbreit, J.N., Conrad, M.E., Feng, L., Lis, A., Roth, J.A., Singleton, S. and Garrick, L.M. (2003). DMT1: A mammalian transporter for multiple metals. BioMetals, 16, 41-54 https://doi.org/10.1023/A:1020702213099
  12. Gitan, R.S. and Eide, D.J. (2000). Zinc-regulated ubiquitin conjugation signals endocytosis of the yeast ZRT1 zinc transporter. Biochem. J., 346, 329-336 https://doi.org/10.1042/0264-6021:3460329
  13. Gunshin, H., Mackenzie, B., Berger, U.V., Gunshin, Y., Romero, M.F., Boron, W.F., Nussberger, S., Gollan, J.L. and Hediger, M.A. (1997). Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature, 388, 482-488 https://doi.org/10.1038/41343
  14. Huang, L., Kirschke, C.P. and Gitschier, J. (2002). Functional characterization of a novel mammalian zinc transporter, ZnT6. J. Biol. Chem., 277, 26389-26395 https://doi.org/10.1074/jbc.M200462200
  15. Hubert, N. and Hentze, M.W. (2001). Regulation of the iron transporter DMT in Caco2 cells. BioIron, 146
  16. Kambe, T., Yamaguchi-Iwai, Y., Sasaki, R. and Nagao, M. (2004). Overview of mammalian zinc transporters. Cell. Mol. Life Sci., 61, 49-68 https://doi.org/10.1007/s00018-003-3148-y
  17. Kim, R.B. (2004). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) and genetic variability (single nucleotide polymorphism) in a hepatic drug uptake transporter: what's it all about? Clin. Pharmacol. Ther., 75, 381-385 https://doi.org/10.1016/j.clpt.2004.01.004
  18. Kusuhara, H. and Sugiyama, Y. (2004). Efflux transport systems for organic anions and cations at the blood-CSF barrier. Advanced Drug Delivery Reviews, 56, 1741-1763 https://doi.org/10.1016/j.addr.2004.07.007
  19. Lee, J., Pena, M.M., Nose, Y. and Thiele, D.J. (2002). Biochemical characterization of the human copper transporter Ctr1. J. Biol. Chem., 277, 4380-4387 https://doi.org/10.1074/jbc.M104728200
  20. Leslie, E.M., Deeley, R.G. and Cole, S.P. (2001). Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters. Toxicology, 167, 3-23 https://doi.org/10.1016/S0300-483X(01)00454-1
  21. Loe, D.W., Stewart, R.K., Massey, T.E., Deeley, R.G. and Cole, S.P.C. (1997). ATP-dependent transport of aflatoxin B1 and its glutathione conjugates by the product of the MRP gene. Mol. Pharmacol., 51, 1034-1041 https://doi.org/10.1124/mol.51.6.1034
  22. McMahon, R.J. and Cousins, R.J. (1998). Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc. Natl. Acad. Sci. USA, 95, 4841-4846
  23. Miyazaki, H., Sekine, T. and Endou, H. (2004). The multispecific organic anion transporter family: properties and pharmacological significance. Trends Pharmacol. Sci., 25, 654-662 https://doi.org/10.1016/j.tips.2004.10.006
  24. Moe, S.M. and Sprague, S.M. (1994). Uremic encephalopathy. Clin. Nephrol., 42, 251-256
  25. Nishizato, Y., Ieiri, I., Suzuki, H., Kimura, M., Kawabata, K., Hirota, T., Takane, H., Irie, S., Kusuhara, H., Urasaki, Y., Urae, A., Higuchi, S., Otsubo, K. and Sugiyama, Y. (2003). Polymorphism of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin. Pharmacol. Ther., 73, 554-565 https://doi.org/10.1016/S0009-9236(03)00060-2
  26. Petris, M.J. (2004). The SLC31 (Ctr) copper transporter family. Eur. J. Physiol., 447, 752-755 https://doi.org/10.1007/s00424-003-1092-1
  27. Roth, J.A., Feng, L., Dolan, K.G., Lis, A. and Garrick, M.D. (2002). Effect of the iron chelator, desferrioximine, on manganese-induced toxicity of rat pheochromocytoma (PC12) cells. J. Neurosci. Res., 68, 76-83 https://doi.org/10.1002/jnr.10207
  28. Sadeque, A.J., Wandel, C., He, H., Shah, S. and Wood, A.J. (2000). Increased drug delivery to the brain by P-glycoprotein inhibition. Clin. Pharmacol. Ther., 68, 231-237 https://doi.org/10.1067/mcp.2000.109156
  29. Song, I.S., Lee, Y.M., Chung, S.J. and Shim, C.K. (2003): Multiple alterations of canalicular membrane transport activities in rats with $CCl_{4}$-induced hepatic injury. Drug Met. Disp., 31, 482-490 https://doi.org/10.1124/dmd.31.4.482
  30. Sung, J.H., Yu, K.H., Park, J.S., Tsuruo, T., Kim, D.D., Shim, C.K. and Chung, S.J. (2005). Saturable distribution of tacrine into the striatal extracellular fluid of the rat: evidence of involvement of multiple organic cation transporters in the transport. Drug Met. Dispos., 33, 440-448
  31. Sweet, D.H. (2005). Organic anion transporters (Slc22a) family members as mediators of toxicity. Toxicol. Appl. Pharmacol., 204,198-215 https://doi.org/10.1016/j.taap.2004.10.016
  32. Vallee, B.L. and Auld, D.S. (1990). Zinc coordination, function and structure of zinc enzymes and other proteins. Biochem., 29, 5647-5659 https://doi.org/10.1021/bi00476a001
  33. Vallee, B.L. and Falchuk, K.H. (1993). The biochemical basis of zinc physiology. Physiol. Rev., 73, 79-118 https://doi.org/10.1152/physrev.1993.73.1.79
  34. Van Wouwe, J.P. (1989). Clinical and laboratory diagnosis of acrodermatitis enteropathica. Eur. J. Pediatr., 149, 2-8 https://doi.org/10.1007/BF02024322
  35. Wang, K., Zhou, B., Kuo, Y.M., Zemansky, J. and Gitschier, J. (2002). A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Am. J. Hum. Genet., 71, 66-73 https://doi.org/10.1086/341125
  36. Wang, X., Ghio, A.J., Yang, F., Dolan, K.G., Garrick, M.D. and Piantadosi, C.A. (2002). Iron uptake and Nramp2/DMT1/ DCT1 in human bronchial epithelial cells. Am. J. Physiol., 282, 987-995
  37. Zhou, B. and Gitschier, J. (1997). hCTR1: a human gene for copper uptake identified by complementation in yeast. Proc. Natl. Acad. Sci. USA, 94, 7481-7486