Cisplatin, rather than oxaliplatin, increases paracellular permeability of LLC-PK1 cells via activating protein kinase C

• Zhang, Yunpeng

  Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital･Graduate School and Faculty of Pharmaceutical Science, Kyoto University

• Yonezawa, Atsushi

  Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital･Graduate School and Faculty of Pharmaceutical Science, Kyoto University

• Nakagawa, Shunsaku

  Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital

• Imai, Satoshi

  Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital

• Denda, Masaya

  Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital･Graduate School and Faculty of Pharmaceutical Science, Kyoto University

• Omura, Tomohiro

  Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital

• Nakagawa, Takayuki

  Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital

• Matsubara, Kazuo

  Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital

Abstract

The clinical use of cisplatin is limited by its adverse events, particularly serious nephrotoxicity. It was clarified that cisplatin is transported by a kidney-specific organic cation transporter (OCT2). OCT2 also mediates the uptake of oxaliplatin into renal proximal tubular cells; however, this agent does not lead nephrotoxicity. In the present study, we carried out comparative experiments with cisplatin and oxaliplatin using porcine kidney LLC-PK1 cell monolayers. In the fluorescein-labeled isothiocyanate-dextran flux assay, the basolateral application of cisplatin, but not oxaliplatin, resulted in an increase in the paracellular permeability of cell monolayers. Even though the cellular accumulation of platinum at 50 μM oxaliplatin could reach the same level at 30 μM cisplatin, oxaliplatin did not induce hyper-permeability in cell monolayers. Cisplatin, but not oxaliplatin, significantly activated PKC. In addition, the combination of PKC inhibitors recovered the increase in paracellular permeability. In conclusion, pharmacodynamic mechanisms via PKC could explain the difference in nephrotoxicity between cisplatin and oxaliplatin.

Journal

• Drug Metabolism and Pharmacokinetics

  Drug Metabolism and Pharmacokinetics 35 (1), 2019-09

  Elsevier BV

Keywords

• Cisplatin
• Oxaliplatin
• Nephrotoxicity
• Protein kinase C
• Paracellular permeability

Details

• CRID: 1050846638327494528
• NII Article ID: 120006796498
• NII Book ID: AA1162652X
• ISSN: 13474367
• ISSN: 18800920
• HANDLE: 2433/245791
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles