Inhibition of cisplatin-induced nephrotoxicity in rats by buthionine sulfoximine, a glutathione synthesis inhibitor.
DL-Buthionine-(S,R)-sulfoximine (BSO), a glutathione-depleting agent, was found to diminish the nephrotoxic effect of cisplatin (cis-diamminedichloroplatinum). Pretreatment of rats with BSO (4 mmol/kg s.c.) 2 h prior to cisplatin, either as a single dose of 5 mg/kg or at a daily dose of 2.5 mg/kg for 3 consecutive days, resulted in diminished elevations of plasma BUN concentration and decreased cisplatin-induced inhibition of renal gamma-glutamylcysteine synthetase and gamma-glutamyl transpeptidase activity measured 6 days following treatment. Administration of BSO prior to cisplatin at 7.5 mg/kg did not significantly alter the effect of cisplatin on either BUN concentration or enzyme activity. The influence of BSO pretreatment on the antitumor activity of cisplatin was studied using implantation of a murine bladder cancer (MBT-2) in C3H mice. Pretreatment of mice with BSO (5 mmol/kg) did not influence cisplatin antitumor efficacy.
D000818:Animals; D019328:Buthionine Sulfoximine; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D005721:Glutamate-Cysteine Ligase / Q000032:analysis; D005978:Glutathione / Q000032:analysis / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy; D005723:gamma-Glutamyltransferase / Q000032:analysis
D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005723:gamma-Glutamyltransferase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D002945:Cisplatin