Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity
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.
|Persistent URL||dx.doi.org/10.1038/clpt.2009.139, hdl.handle.net/1765/24547|
|Journal||Clinical Pharmacology and Therapeutics|
Filipski, K.K, Mathijssen, A.H.J, Mikkelsen, T.S, Schinkel, A.H, & Sparreboom, A. (2009). Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clinical Pharmacology and Therapeutics, 86(4), 396–402. doi:10.1038/clpt.2009.139