| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Medizinische Klinik und Poliklinik D,* Experimentelle Nephrologie, the Institut für Physiologie II, the Klinik und Poliklinik für Urologie und Poliklinik für Allgemeine Chirurgie,¶ Universitätsklinikum Münster, Münster; the Institut für Anatomie und Zellbiologie, Universität Würzburg, Würzburg; and the Pharmazeutisches Institut,|| Klinische Pharmazie, Universität Bonn, Bonn, Germany
Cis-platin is an effective anti-neoplastic agent, but it is also highly nephrotoxic. Here, we clearly identify the human organic cation transporter 2 (hOCT2) as the critical transporter for cis-platin nephrotoxicity in isolated human proximal tubules and offer a potential mechanism for reducing nephrotoxicity in clinical practice. Interaction of cis-platin with hOCT2 in kidney or hOCT1 in liver was investigated with the fluorescent cation 4-[4-(dimethyl-amino)styril]-methylpyridinium in stably transfected HEK293 cells and for the first time in tissues physiologically expressing these transporters, human proximal tubules, and human hepatocyte couplets. Cis-platin (100 µmol/L) inhibited transport via hOCT2-HEK293 but not hOCT1-HEK293. In human proximal tubules cis-platin competed with basolateral organic cation transport, whereas it had no effect in tubules from a diabetic kidney or in hepatocytes. In hOCT2-HEK293 cells treated for 15 hours, incubation with cis-platin induced apoptosis, which was completely suppressed by contemporaneous incubation with the hOCT2 substrate cimetidine (100 µmol/L). These findings demonstrate that uptake of cis-platin is mediated by hOCT2 in renal proximal tubules, explaining its organ-specific toxicity. A combination of cis-platin with other substrates that compete for hOCT2 offers an effective option to decrease nephrotoxicity in the clinical setting.
This article has been cited by other articles:
 |
|
 |
|
  M. Aoki, T. Terada, M. Kajiwara, K. Ogasawara, I. Ikai, O. Ogawa, T. Katsura, and K.-i. Inui Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation Am J Physiol Renal Physiol, July 1, 2008; 295(1): F165 - F170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Soodvilai, A. Chatsudthipong, and V. Chatsudthipong Role of MAPK and PKA in regulation of rbOCT2-mediated renal organic cation transport Am J Physiol Renal Physiol, July 1, 2007; 293(1): F21 - F27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-i. Asaka, T. Terada, K. Ogasawara, T. Katsura, and K.-i. Inui Characterization of the Basal Promoter Element of Human Organic Cation Transporter 2 Gene J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 684 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Cristofori, E. Zanetti, D. Fregona, A. Piaia, and A. Trevisan Renal Proximal Tubule Segment-Specific Nephrotoxicity: An Overview on Biomarkers and Histopathology Toxicol Pathol, February 1, 2007; 35(2): 270 - 275. [Abstract] [PDF]
|
|
|
|
|
|
A. Yonezawa, S. Masuda, S. Yokoo, T. Katsura, and K.-i. Inui Cisplatin and Oxaliplatin, but Not Carboplatin and Nedaplatin, Are Substrates for Human Organic Cation Transporters (SLC22A1-3 and Multidrug and Toxin Extrusion Family) J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 879 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Zhang, K. S. Lovejoy, J. E. Shima, L. L. Lagpacan, Y. Shu, A. Lapuk, Y. Chen, T. Komori, J. W. Gray, X. Chen, et al. Organic Cation Transporters Are Determinants of Oxaliplatin Cytotoxicity. Cancer Res., September 1, 2006; 66(17): 8847 - 8857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Biermann, D. Lang, V. Gorboulev, H. Koepsell, A. Sindic, R. Schroter, A. Zvirbliene, H. Pavenstadt, E. Schlatter, and G. Ciarimboli Characterization of regulatory mechanisms and states of human organic cation transporter 2 Am J Physiol Cell Physiol, June 1, 2006; 290(6): C1521 - C1531. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
