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Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity

Sachiko Yokoo1, Atsushi Yonezawa, Satohiro Masuda

  • 1Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto 606-8507, Japan.

Biochemical Pharmacology
|June 22, 2007
PubMed

Insights

Cisplatin causes severe kidney damage due to higher renal accumulation, unlike other platinum drugs. This nephrotoxicity is linked to specific transporter interactions, explaining differences in platinum-based chemotherapy side effects.

Area of Science:

  • Pharmacology
  • Nephrology
  • Toxicology

Background:

  • Severe nephrotoxicity is a significant side effect of platinum-based chemotherapy agents.
  • The precise mechanisms underlying differential nephrotoxicity among platinum drugs like cisplatin, carboplatin, oxaliplatin, and nedaplatin remain unclear.

Purpose of the Study:

  • To investigate the renal accumulation and nephrotoxicity of four platinum agents in a rat model.
  • To elucidate the role of organic cation transporters (OCTs) and multidrug and toxin extrusion (MATE) transporters in platinum-induced nephrotoxicity.

Main Methods:

  • Rats were administered cisplatin, carboplatin, oxaliplatin, or nedaplatin intraperitoneally.
  • Renal accumulation and markers of kidney injury (NAG, KIM-1, osteopontin) were assessed.
  • In vitro studies using cell lines expressing rat and human OCT and MATE transporters were performed to evaluate drug transport.

Main Results:

  • Cisplatin induced significant nephrotoxicity and higher renal accumulation compared to other platinum agents.
  • Urinary NAG activity and kidney injury markers were elevated in cisplatin-treated rats.
  • In vitro, cisplatin and oxaliplatin cellular uptake was mediated by OCT2, while oxaliplatin was also transported by OCT3, MATE1, MATE2-K, but cisplatin was not transported by MATEs.

Conclusions:

  • Platinum agent nephrotoxicity is closely correlated with their renal accumulation.
  • The substrate specificity of OCT and MATE transporter families significantly influences platinum drug accumulation and subsequent nephrotoxicity.

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