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      Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity.

      Clinical Pharmacology and Therapeutics

      Animals, Antineoplastic Agents, blood, toxicity, urine, Cisplatin, Humans, Kidney Diseases, chemically induced, pathology, Male, Mice, Mice, Knockout, Organic Cation Transport Proteins, genetics, metabolism, Organic Cation Transporter 1, Polymerase Chain Reaction, Polymorphism, Single Nucleotide

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          Abstract

          Cisplatin is one of the most widely used anticancer agents for the treatment of solid tumors. The clinical use of cisplatin is associated with dose-limiting nephrotoxicity, which occurs in one-third of patients despite intensive prophylactic measures. Organic cation transporter 2 (OCT2) has been implicated in the cellular uptake of cisplatin, but its role in cisplatin-induced nephrotoxicity remains unknown. In mice, deletion of Oct1 and Oct2 resulted in significantly impaired urinary excretion of cisplatin without an apparent influence on plasma levels. Furthermore, the Oct1/Oct2-deficient mice were protected from severe cisplatin-induced renal tubular damage. Subsequently, we found that a nonsynonymous single-nucleotide polymorphism (SNP) in the OCT2 gene SLC22A2 (rs316019) was associated with reduced cisplatin-induced nephrotoxicity in patients. Collectively, these results indicate the critical importance of OCT2 in the renal handling and related renal toxicity of cisplatin and provide a rationale for the development of new targeted approaches to mitigate this debilitating side effect.

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          Author and article information

          Journal
          19625999
          2746866
          10.1038/clpt.2009.139

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