Association between tubular toxicity of cisplatin and expression of organic cation transporter rOCT2 (Slc22a2) in the rat.
Cisplatin is an effective anticancer drug, but has its severe adverse effects, especially nephrotoxicity. The molecular mechanism of cisplatin-induced nephrotoxicity is still not clear. In the present study, we examined the role of rat (r)OCT2, an organic cation transporter predominantly expressed in the kidney, in the tubular toxicity of cisplatin. Using HEK293 cells stably expressing rOCT2 (HEK-rOCT2), we evaluated the cisplatin-induced release of lactate dehydrogenase and the uptake of cisplatin. The release of lactate dehydrogenase and the accumulation of platinum were greater in HEK-rOCT2 cells treated with cisplatin than in mock-transfected cells. Moreover, cimetidine and corticosterone, OCT2 inhibitors, inhibited the cytotoxicity and the transport of cisplatin in HEK-rOCT2 cells. Pharmacokinetics of cisplatin was investigated in male and female rats because the renal expression level of rOCT2 was higher in male than female rats. The renal uptake clearance of cisplatin was greater in male than female rats, while the hepatic uptake clearance was similar between the sexes. In addition, glomerular filtration rate and liver function were unchanged, but N-acetyl-beta-D-glucosaminidase activity in the bladder urine and the urine volume were markedly increased 2 days after the administration of 2 mg/kg of cisplatin in male rats. Moreover, cisplatin did not induce the elevation of urinary N-acetyl-beta-D-glucosaminidase activity in the castrated male rats whose renal rOCT2 level was lower than that of the sham-operated rats. In conclusion, the present results indicated that renal rOCT2 expression was the major determinant of cisplatin-induced tubular toxicity.
Yonezawa
Atsushi
A
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Sakyo-ku, Kyoto 606-507, Japan.
Masuda
Satohiro
S
Nishihara
Kumiko
K
Yano
Ikuko
I
Katsura
Toshiya
T
Inui
Ken-ichi
K
D000818:Animals; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D002945:Cisplatin / Q000633:toxicity*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000502:physiology*; D000075102:Organic Cation Transporter 2; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D013757:Tetraethylammonium Compounds / Q000493:pharmacokinetics
D050482:Catecholamine Plasma Membrane Transport Proteins; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; C493212:Slc22a1 protein, rat; C100590:Slc22a2 protein, rat; D013757:Tetraethylammonium Compounds; D002945:Cisplatin