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Br J Pharmacol. 2008 Apr;153(7):1364-72. doi: 10.1038/bjp.2008.15. Epub 2008 Feb 18.

N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats.

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  • 1Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.

Abstract

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 micromol l(-1)) as well as a reduced elevation of beta2-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.

PMID:
18278066
[PubMed - indexed for MEDLINE]
PMCID:
PMC2437918
Free PMC Article

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