Prevention of nephrotoxicity of cisplatin by repeated oral administration of ebselen in rats.
The ability of ebselen, which exhibits glutathione peroxidase (GSH-Px)-like activity, to prevent cisplatin (CDDP)-induced nephrotoxicity was examined in rats. CDDP (6 mg/kg [20 micromol/kg] body weight) was injected intraperitoneally. In subgroups, daily ebselen doses of 2.75 (10 micromol), 5.5 (20 micromol), or 11.0 mg (40 micromol)/kg body weight were administrated orally 1 hour prior to CDDP treatment. Treatment with CDDP alone resulted in significantly increased plasma creatinine (Cr) and blood urea nitrogen (BUN) levels. Repeated administration of 5.5 and 11.0 mg/kg ebselen prevented the CDDP-induced elevation of plasma Cr and BUN levels and protected against kidney damage. Relative to controls, rat that received CDDP treatment displayed a decreased ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG), an indicator directly related to oxidative stress, and elevated malondialdehyde (MDA) levels in the kidney. In comparison with controls, activity of GSH-Px activity, which antioxidant enzyme, was also reduced in the kidney of rats treated with CDDP. Repeated administration of 5.5 or 11.0 mg/kg ebselen prevented CDDP-induced alteration of GSH/GSSG ratios, MDA levels, and GSH-Px activity; however, no protection against CDDP was observed with administration of 2.75 mg/kg ebselen. Effective protection of CDDP-induced nephrotoxicity with ebselen was observed only when the molar amount of each daily ebselen treatment equaled or exceeded
Yoshida
M
M
Department of Chemistry, St. Marianna University School of Medicine, Kawasaki, Japan. m2yosida@marianna-u.ac.jp
Iizuka
K
K
Terada
A
A
Hara
M
M
Nishijima
H
H
Akinori
Shimada
Nakada
K
K
Satoh
Y
Y
Akama
Y
Y
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000975:Antioxidants / Q000008:administration & dosage*; D001393:Azoles / Q000008:administration & dosage*; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D054833:Isoindoles; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D016566:Organoselenium Compounds / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D008315:Malondialdehyde; D003404:Creatinine; D005979:Glutathione Peroxidase; D005978:Glutathione; D002945:Cisplatin; D019803:Glutathione Disulfide