Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2

Am J Pathol. 2005 Dec;167(6):1477-84. doi: 10.1016/S0002-9440(10)61234-5.


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 micromol/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 micromol/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A5 / metabolism
  • Apoptosis
  • Cell Line
  • Cisplatin / toxicity*
  • Humans
  • Kidney / drug effects
  • Kidney / pathology*
  • Kinetics
  • Octamer Transcription Factor-1 / drug effects
  • Octamer Transcription Factor-1 / metabolism*
  • Octamer Transcription Factor-2 / drug effects
  • Octamer Transcription Factor-2 / metabolism*


  • Annexin A5
  • Octamer Transcription Factor-1
  • Octamer Transcription Factor-2
  • POU2F1 protein, human
  • Cisplatin