Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity
Introduction
Cis-diamminedichloroplatinum II (cisplatin) is widely used against solid tumors of the prostate gland, bladder, colon, lung, testis, and brain. Despite the effectiveness of cisplatin, severe nephrotoxicity limits its clinical application. Other platinum agents, cis-diammine(1,1-cyclobutanedicarboxylato)platinum II (carboplatin), trans-l-1,2-diaminocyclohexaneoxalatoplatinum II (oxaliplatin) and cis-diammineglycolatoplatinum (nedaplatin), are less nephrotoxic than cisplatin [1]. However, there was no report that the influence of these four agents on renal function was simultaneously examined in vivo, and it is not clear why only cisplatin is nephrotoxic. The chemical structure of each of these agents is shown in Fig. 1.
The mechanisms of cellular uptake and efflux of platinum agents are not fully understood, although the cellular uptake of cisplatin was suggested to be mediated by specific transporter(s) in the renal epithelial cells [2]. We reported that rat organic cation transporter 2 (rOCT2/Slc22a2) transported cisplatin, and was responsible for cisplatin-induced nephrotoxicity [3]. Human (h)OCT2 was also found to transport cisplatin [4]. Recently, we have found that some platinum agents were transported by human organic cation transporters such as the OCT (SLC22A) family and MATE (multidrug and toxin extrusion) family [5]. These reports raise the possibility that substrate specificity of organic cation transporters determines the renal handling of platinum agents and the frequency/degree of nephrotoxicity.
The organic cation transporters transport drugs, toxins, and endogenous metabolites [6], [7]. In the rat, rOCT1 (Slc22a1) is expressed in the liver and kidney [8], rOCT2 (Slc22a2) is expressed preferentially in the kidney [9], and rOCT3 (Slc22a3) is expressed predominantly in the placenta and weakly in the intestine, heart, brain, and kidney [10]. rOCT1 and rOCT2 are expressed in the basolateral membranes of proximal tubules and mediate the accumulation of various cationic drugs in proximal tubular epithelial cells from the circulation [6], [7], [11]. The membrane localization and physiological role of rOCT3 are not clearly understood. Rat multidrug and toxin extrusion 1 (rMATE1) was recently cloned and characterized in our laboratory [12]. It is considered to be expressed in the brush-border membrane of proximal tubules and to mediate tubular secretion of cationic drugs with an oppositely H+-gradient as a driving force. These transporters are thought to play an important role in the renal handling of cationic drugs.
Based on these findings, we hypothesized that these tubular organic cation transporters were determinants of the extent to which platinum agents cause nephropathy. In this study, we compared the renal function and renal accumulation of platinum after the administration of platinum agents in rats. In addition, the substrate specificity of rOCT1-3, rMATE1, hMATE1, and hMATE2-K for platinum agents was also examined in the in vitro expression system.
Section snippets
Animals
Male Wistar/ST rats (8 weeks) were purchased from SLC Animal Research Laboratories (Shizuoka, Japan). The rats were fed normal pellet food ad libitum, and given water freely. They were administered intraperitoneally with 2 mg/kg or 10 mg/kg of cisplatin (Randa®; Nippon Kayaku Co., Ltd., Tokyo, Japan), carboplatin (Paraplatin®; Bristol-Myers Squibb Co., Tokyo, Japan), oxaliplatin (Elplat®; Yakult Co., Ltd., Tokyo, Japan), or nedaplatin (Aqupla®; Shionogi & Co., Ltd., Osaka, Japan). These drug
Biochemical parameters
Biochemical parameters 2 days after the intraperitoneal administration of cisplatin, carboplatin, oxaliplatin, and nedaplatin at a dose of 2 mg/kg or 10 mg/kg are shown in Table 2, Table 3, respectively. Administration of 2 mg/kg of cisplatin tended to increase the urinary albumin level. In rats administered 10 mg/kg of cisplatin, the plasma creatinine level and urinary albumin level were significantly increased, and body weight and creatinine clearance were significantly decreased. There was not
Discussion
Until now, no investigation has simultaneously compared the extent to which four platinum agents cause nephropathy in vivo. In this report, the nephropathy caused by platinum agents, and the relationship between the nephrotoxicity and platinum accumulation in the kidney in vivo was examined. Based on the various biochemical parameters, carboplatin, oxaliplatin, and nedaplatin were shown to have lower nephrotoxicity than cisplatin, and as expected, the nephrotoxicity of the platinum agent was
Acknowledgments
This work was supported in part by a grant-in-aid for Research on Advanced Medical Technology from the Ministry of Health, Labor and Welfare of Japan, by the Japan Health Science Foundation “Research on Health Sciences Focusing on Drug Innovation”, by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Culture and Sports of Japan, and by the 21st Century COE program “Knowledge Information Infrastructure for Genome Science”. A. Yonezawa was supported as a Research
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