N‐Acetylcysteine prevents ifosfamide‐induced nephrotoxicity in rats

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 À1 daily for 5 days), NAC (1.2 g kg À1 daily for 6 days) or ifosfamide þ 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 À1 ) as well as a reduced elevation of b 2 -microglobulin excretion (25.44±3.3 vs 8.83±1.3 nmol l À1 ) and magnesium excretion (19.5±1.5 vs 11.16±1.5 mmol l À1 ). 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.

Carboplatin-induced Fanconi-like syndrome in rats: Amelioration by pentoxifylline

“…Glucose is normally reabsorbed from the kidney and negligible amounts appear in the urine whereas proteins like albumin are macromolecules and hence are readily filtered at the glomeruli. In line with other reports (Chen et al, 2008;Sener et al, 2004), we found a significant excretion of glucose and total protein in the animals that were administered carboplatin. This suggested a loss of glomerular retention and reabsorptive capacity of the kidneys.…”

“…This is in relation to the profile of Fanconi-like syndrome in rats (Chen et al, 2008). Depletion of the antioxidant GSH allows lipid peroxidation to occur and this oxidative stress leads to the loss of functional integrity of the cell.…”

Increased Lipid Accumulation in Liver and White Adipose Tissue in Aging in the SAMP10 Mouse

“…TBARS is an oxidative stress marker that is dependent on aging and associated with senescence in SAM mice (32,33). It is also known that lipid peroxide hampers tissue function (34). Thus, the possibility that age-dependent oxidative stress impairs tissue function and changes lipid and carbohydrate metabolism related to lifestyle diseases is plausible.…”

The effects ofN-acetyl-l-cysteine on the female reproductive performance and nephrotoxicity in rats

“…The effects on renal tissue Nephrotoxicity induced by IFO may due to the oxidative stress and free radical generation such as NO, local depletion of GSH, reduction in the level of renal SOD 53 and increased in MDA levels indicating the enhancement lipid peroxidation as a result of impaired antioxidant defense mechanism 22,23 Membrane peroxidation can lead to changes in membrane fluidity and permeability and also to enhanced rates of protein degradation, with these eventually leading to cell lysis. 54 Mohrmann et al 55 have shown that exposure of LLC-PK1 cells to IFO metabolites acrolein or chloroacetaldehyde significantly impairs several sodium-dependent transport systems and the sodium/proton antiport system.…”