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.
Filipski
K K
KK
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
Mathijssen
R H
RH
Mikkelsen
T S
TS
Schinkel
A H
AH
Sparreboom
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000633:toxicity* / Q000652:urine; D002945:Cisplatin / Q000097:blood / Q000633:toxicity* / Q000652:urine; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; D002945:Cisplatin