Disruption of multidrug and toxin extrusion MATE1 potentiates cisplatin-induced nephrotoxicity

Abstract

Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is expressed in the brush-border membrane of renal proximal tubules and mediates the efflux of cationic drugs. In the present study, the role of MATE1 in the nephrotoxicity of cisplatin was investigated in vivo and in vitro. Cisplatin (15 mg/kg) was administered intraperitoneally to wild-type (Mate1(+/+)) and Mate1 knockout (Mate1(−/−)) mice. Lifespan was significantly shorter in Mate1(−/−) mice than Mate1(+/+) mice. Three days after the administration of cisplatin, plasma creatinine and blood urea nitrogen (BUN) levels were increased in both Mate1(+/+) and Mate1(−/−) mice compared with vehicle-treated controls, and creatinine clearance was decreased. Moreover, a significant rise in creatinine and BUN levels was observed in cisplatin-treated Mate1(−/−) mice in comparison to Mate1(+/+) mice. A pharmacokinetic analysis revealed the plasma concentration and renal accumulation of cisplatin to be higher in Mate1(−/−) mice than Mate1(+/+) mice 1 h after a single intravenous administration of cisplatin (0.5 mg/kg). Furthermore, the combination of a selective MATE inhibitor, pyrimethamine, with cisplatin also elevated creatinine and BUN levels compared to cisplatin alone. In experiments in vitro, the cellular uptake of cisplatin was stimulated by the expression of mouse MATE1 as well as organic cation transporters OCT1 and OCT2. In conclusion, MATE1 mediates the efflux of cisplatin and is involved in cisplatin-induced nephrotoxicity.