Effects of genetic variants in SLC22A2 organic cation transporter 2 and SLC47A1 multidrug and toxin extrusion 1 transporter on cisplatin-induced adverse events

Abstract

Susceptibility to cisplatin (CDDP) nephrotoxicity is known to vary between individuals, but the basis of this variation has not been fully elucidated. In the kidney, CDDP is taken up into the renal proximal tubular cells mainly via SLC22A2 organic cation transporter 2 (OCT2) and secreted into lumen via other transporters including SLC47A1 multidrug and toxin extrusion 1 (MATE1). Here, we explore the effect of single-nucleotide polymorphisms (SNPs) at 808G>T in OCT2 and at rs2289669 G>A in MATE1 on CDDP-induced adverse events. Fifty-three patients who had been treated with CDDP were enrolled. The plasma concentration of CDDP was measured on days 4 and 7 after treatment. The grade of hematology and nephrotoxicity was evaluated by Common Terminology Criteria for Adverse Events. In the first treatment cycle, serum creatinine (SCr) levels in the patients with OCT2 808GG and 808GT were increased by 1.43- and 1.19-fold, respectively. In the total treatment cycles, 12 patients (27%) with 808GG experienced over grade 2 SCr elevation, whereas those with 808GT did not show any apparent nephrotoxicity. The hematological toxicity and plasma concentrations of CDDP showed no difference between patients in both groups. The rs2289669 G>A SNP in MATE1 was not associated with adverse effects and disposition of CDDP. The 808G>T SNP in OCT2 ameliorated CDDP-induced nephrotoxicity without alteration of disposition, whereas the rs2289669 G>A SNP in MATE1 had no effect on CDDP toxicity.