N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats

Background and purpose: Ifosfamide nephrotoxicity is a serious adverse effect for children undergoing cancer chemotherapy. Our recent in vitro studies have shown that the antioxidant N-acetylcysteine (NAC), which is used extensively as an antidote for paracetamol ( acetaminophen) poisoning in children, protects renal tubular cells from ifosfamide-induced toxicity at a clinically relevant concentration. To further validate this observation, an animal model of ifosfamide-induced nephrotoxicity was used to determine the protective effect of NAC. Experimental approach: Male Wistar albino rats were injected intraperitoneally with saline, ifosfamide ( 50 or 80 mg kg(-1) daily for 5 days), NAC ( 1.2 g kg(-1) daily for 6 days) or ifosfamide+NAC ( for 6 days). Twenty-four hours after the last injection, rats were killed and serum and urine were collected for biochemical analysis. Kidney tissues were obtained for analysis of glutathione, glutathione S-transferase and lipid peroxide levels as well as histology analysis. Key results: NAC markedly reduces the severity of renal dysfunction induced by ifosfamide with a significant decrease in elevations of serum creatinine ( 57.8 +/- 2.3 vs 45.25 +/- 2.1 mmol l(-1)) as well as a reduced elevation of beta(2)-microglobulin excretion ( 25.44 +/- 3.3 vs 8.83 +/- 1.3 nmol l(-1)) and magnesium excretion ( 19.5 +/- 1.5 vs 11.16 +/- 1.5 mmol l(-1)). Moreover, NAC significantly improved the ifosfamide-induced glutathione depletion and the decrease of glutathione S-transferase activity, lowered the elevation of lipid peroxides and prevented typical morphological damages in renal tubules and glomeruli. Conclusions and implications: Our results suggest a potential therapeutic role for NAC in paediatric patients in preventing ifosfamide nephrotoxicity.