N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats.
OBJECTIVE
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.


METHODS
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.


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
Our results suggest a potential therapeutic role for NAC in paediatric patients in preventing ifosfamide nephrotoxicity.
Chen
N
N
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
Aleksa
K
K
Woodland
C
C
Rieder
M
M
Koren
G
G
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D007069:Ifosfamide / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control; D008054:Lipid Peroxides / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D001613:beta 2-Microglobulin / Q000187:drug effects / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D016166:Free Radical Scavengers; D008054:Lipid Peroxides; D001613:beta 2-Microglobulin; D003404:Creatinine; D005982:Glutathione Transferase; D005978:Glutathione; D008274:Magnesium; D007069:Ifosfamide; D000111:Acetylcysteine