TY - JOUR
T1 - Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity
AU - Yokoo, Sachiko
AU - Yonezawa, Atsushi
AU - Masuda, Satohiro
AU - Fukatsu, Atsushi
AU - Katsura, Toshiya
AU - Inui, Ken Ichi
N1 - Funding Information:
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 Assistant by the 21st Century COE program “Knowledge Information Infrastructure for Genome Science”.
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2007/8/1
Y1 - 2007/8/1
N2 - The mechanism of severe nephrotoxicity caused by cisplatin, but not carboplatin, oxaliplatin, and nedaplatin, is not fully understood. The renal accumulation and subsequent nephrotoxicity of platinum agents were examined in rats. Among these four drugs, only cisplatin induced nephrotoxicity at 2 days after its intraperitoneal administration. The urinary activity of N-acetyl-β-d-glucosaminidase and expression of kidney injury molecule-1 mRNA and osteopontin were markedly enhanced in the cisplatin-treated rats. Although some markers were affected in the rats administered nedaplatin, only minor histological change was observed. The renal accumulation of cisplatin was much greater than that of the other drugs. In the in vitro study, the cellular accumulation of cisplatin and oxaliplatin was stimulated by the expression of rat (r) OCT2. Oxaliplatin was also transported by rOCT3. A luminal H+/organic cation antiporter, rMATE1 (multidrug and toxin extrusion) as well as human (h) MATE1 and hMATE2-K, stimulated the H+-gradient-dependent antiport of oxaliplatin, but not of cisplatin. Carboplatin and nedaplatin were not transported by these transporters. In conclusion, the nephrotoxicity of platinum agents was closely associated with their renal accumulation, which is determined by the substrate specificity of the OCT and MATE families.
AB - The mechanism of severe nephrotoxicity caused by cisplatin, but not carboplatin, oxaliplatin, and nedaplatin, is not fully understood. The renal accumulation and subsequent nephrotoxicity of platinum agents were examined in rats. Among these four drugs, only cisplatin induced nephrotoxicity at 2 days after its intraperitoneal administration. The urinary activity of N-acetyl-β-d-glucosaminidase and expression of kidney injury molecule-1 mRNA and osteopontin were markedly enhanced in the cisplatin-treated rats. Although some markers were affected in the rats administered nedaplatin, only minor histological change was observed. The renal accumulation of cisplatin was much greater than that of the other drugs. In the in vitro study, the cellular accumulation of cisplatin and oxaliplatin was stimulated by the expression of rat (r) OCT2. Oxaliplatin was also transported by rOCT3. A luminal H+/organic cation antiporter, rMATE1 (multidrug and toxin extrusion) as well as human (h) MATE1 and hMATE2-K, stimulated the H+-gradient-dependent antiport of oxaliplatin, but not of cisplatin. Carboplatin and nedaplatin were not transported by these transporters. In conclusion, the nephrotoxicity of platinum agents was closely associated with their renal accumulation, which is determined by the substrate specificity of the OCT and MATE families.
UR - http://www.scopus.com/inward/record.url?scp=34250764918&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250764918&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2007.03.004
DO - 10.1016/j.bcp.2007.03.004
M3 - Article
C2 - 17582384
AN - SCOPUS:34250764918
VL - 74
SP - 477
EP - 487
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 3
ER -