Cisplatin Induces Acute Renal Failure by Impairing Antioxidant System in Guinea Pigs: Effects of Antioxidant Supplementation on the Cisplatin Nephrotoxicity

Abstract

This study aims to investigate the role of oxidants in cisplatin-induced nephrotoxicity. Cisplatin was administered intraperitoneally (i.p.) in a single dose (5 mg/kg) and guinea pigs were killed either after 24 h or 7 days. The same experiment was performed using animals treated with vitamins C and E combination and a natural antioxidant extract (SARMEX). The kidneys were then removed to be used in the analyses. Blood samples were also obtained from the animals to be used in routine biochemical assays. Twenty-four hours after treatment there was a significant decrease in the renal activities of total superoxide scavenger activity (TSSA), superoxide dismutase (SOD) and catalase (CAT) accompanied by a rise in malondialdehyde (MDA) levels. After 7 days, the fall in kidney enzymatic activities was far greater, while the increase in blood urea (BUN) and creatinine (CRE) was marked. Treatment with antioxidants causes significant increases in renal TSSA (7 day), non-enzymatic superoxide scavenger activity (NSSA) (24 h and 7 day) and SOD (7 day) activities, does not change glutathione peroxidase (GSH-Px) activity and decreases renal MDA (24 h and 7 day), blood BUN (7 day) and CRE (7 day) levels. Our results suggest that cisplatin treatment impairs both enzymatic and non-enzymatic antioxidant systems and causes peroxidation in the renal tissue, which leads to kidney failure. Antioxidant supplementation strengthens the renal antioxidant system, eliminates oxidation reactions, and prevents cisplatin-induced kidney failure.

Protective Effects of Vitamin C on Cisplatin-Induced Renal Damage: A Light and Electron Microscopic Study

“…The administration of antioxidants such as vitamin E, vitamin C, lycopene, and melatonin, before or after treatment with cisplatin, has been used to protect or ameliorate against nephrotoxicity in human and animals. [5,6,20,[39][40][41] Much attention has been given to the possible role that dietary antioxidants play in protecting against cisplatin-induced nephrotoxicity. [6,42] Vitamin C is a watersoluble dietary antioxidant that plays an important role in controlling the oxidative stress.…”

“…[5,28] The major side effect limiting its clinical use is dose-related nephrotoxicity. [4,5,28,29] The current package circular issued by its manufacturer warns that renal toxicity may occur in 28-36% of patients receiving a single dose of cisplatin of 50 mg/m 2 . [2] Cisplatin is mainly excreted from the kidney, and the kidney tissue content of this agent is higher than the concentrations in other organs.…”

“…[6,7] Thus, the effect of cisplatin has been studied in animals with the aim of understanding mechanisms of toxicity. [5,8,9] The mechanism by which cisplatin induces renal injury is not well understood. It may involve direct interference with tubular or mitochondrial transport processes, [10] the covalent modification of cellular constituents, [11] or the generation of free radicals.…”

“…[12] Cisplatin-induced nephrotoxicity is closely associated with an increase in lipid peroxidation in the kidney tissues. [1,5,[13][14][15][16] This agent was able to generate reactive oxygen species (ROS), such as superoxide anions and hydroxyl radicals, [3,4,17,18] and inhibit the activity of antioxidant enzymes in renal tissues. [4,5,12] Cisplatin chemotherapy induces a fall in plasma antioxidant levels, which may reflect a failure of the antioxidant defense mechanism against oxidative damage induced by commonly used antitumor drugs.…”

“…[1,2] High doses of cisplatin produce hepatoxicity, but the impairment of kidney function by cisplatin is recognized as the main side-effect and the most important dose-limiting factor. [3][4][5] Cisplatin-induced renal damage is associated with increased renal vascular resistance and histologic damage to proximal tubular cells. [1] The exact cellular mechanism of cisplatin-induced nephrotoxicity is insufficiently known.…”