Role of oxidative stress in cisplatin - induced nephrotoxicity in rats

ABSTRACT

Cisplatin [cis diammine dichloroplatinum] is a potent antitumor drug. Expansion of the clinical utility of cisplatin has been limited by its toxicity where acute and chronic forms of renal injury have been described due to apoptosis. The mechanism by which it activates the myriad of apoptotic pathways remains unclear. Several studies have now documented the importance of reactive oxygen metabolites [ROM] in cisplatin-induced renal cell apoptosis. To further clarify this point the present study was conducted to evaluate the oxidative stress induced by cisplatin. Rats were treated either by high single intraperiotoneal dose [7mg/kg] or by repeated small doses [4mg/kg] twice weekly for one month. Rats were sacrificed by decapitation after 48 hours of high dose intake or 24 hours after intake repeated small doses. Kidney tissues were removed for histopathological examination, after homogenization these tissues were removed for determination of glutathione [GSH]. Blood samples were taken from rats for determination of serum level of creatinine, blood urea nitrogen [BUN] and nitric oxide [NO]. Histopathological examination of kidney tissue revealed degenerative changes with tubular change, especially in the proximal convoluted tubules. Significant elevation in serum creatinine [2.24 +/- 0.18 vs 2.12 +/- 0.18] and BUN [146 +/- 10.6 vs132 +/- 11.2] levels were observed. Administration of cisplatin in large dose or small repeated doses causes significant elevation in serum [NO] level [10.4 +/- 0.8 micro mol/l and 9 +/- 0.53 micro mol/l respectively] as well as depletion in renal [GSH] tissue levels [1.02 +/- 0.09 micro mol/l w.wt wet, weight] and 1.12 +/- 0.08 micro mol/g w.wt, respectively]. From these results, it can be concluded that single high dose or small repeated doses of cisplatin-induced nephrotoxicity was associated with induction of oxidative stress. Use of antioxidants in conjunction with cisplatin could be a value in minimizing its toxicity