Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity.
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-beta-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.
Yokoo
Sachiko
S
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto 606-8507, Japan.
Yonezawa
Atsushi
A
Masuda
Satohiro
S
Fukatsu
Atsushi
A
Katsura
Toshiya
T
Inui
Ken-Ichi
K
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017920:Antiporters / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D017931:DNA Primers; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D027701:Organic Cation Transport Proteins / Q000502:physiology*; D000075102:Organic Cation Transporter 2; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D017920:Antiporters; D017931:DNA Primers; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C100590:Slc22a2 protein, rat; C515734:Slc47a1 protein, rat; D002945:Cisplatin