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

Sachiko Yokoo, Atsushi Yonezawa, Satohiro Masuda, Atsushi Fukatsu, Toshiya Katsura, Ken Ichi Inui

Research output: Contribution to journalArticle

165 Citations (Scopus)

Abstract

The mechanism of severe nephrotoxicity caused by cisplatin, but not carboplatin, oxaliplatin, and nedaplatin, is not fully understood. The renal accumulation and subsequent nephrotoxicity of platinum agents were examined in rats. Among these four drugs, only cisplatin induced nephrotoxicity at 2 days after its intraperitoneal administration. The urinary activity of N-acetyl-β-d-glucosaminidase and expression of kidney injury molecule-1 mRNA and osteopontin were markedly enhanced in the cisplatin-treated rats. Although some markers were affected in the rats administered nedaplatin, only minor histological change was observed. The renal accumulation of cisplatin was much greater than that of the other drugs. In the in vitro study, the cellular accumulation of cisplatin and oxaliplatin was stimulated by the expression of rat (r) OCT2. Oxaliplatin was also transported by rOCT3. A luminal H+/organic cation antiporter, rMATE1 (multidrug and toxin extrusion) as well as human (h) MATE1 and hMATE2-K, stimulated the H+-gradient-dependent antiport of oxaliplatin, but not of cisplatin. Carboplatin and nedaplatin were not transported by these transporters. In conclusion, the nephrotoxicity of platinum agents was closely associated with their renal accumulation, which is determined by the substrate specificity of the OCT and MATE families.

Original languageEnglish
Pages (from-to)477-487
Number of pages11
JournalBiochemical Pharmacology
Volume74
Issue number3
DOIs
Publication statusPublished - Aug 1 2007

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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