El-Sisi Alaa El-Din E, El-Syaad Magda E, El-Desoky Karima I, Moussa Ethar A
Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tanta, Tanta, Egypt.
Department of Pathology, Faculty of Medicine, University of Tanta, Tanta, Egypt.
Toxicol Ind Health. 2015 Feb;31(2):97-107. doi: 10.1177/0748233712469649. Epub 2013 Jan 8.
Ifosfamide (IFO) is a highly effective chemotherapeutic agent for treating a variety of pediatric solid tumors. However, its use is limited due to its serious side effect on kidneys. The side-chain oxidation of IFO in renal tubular cells produces a reactive toxic metabolite that is believed to be responsible for its nephrotoxic effect. Therefore, this study was carried out to investigate the possible underlying mechanisms that may be involved in IFO-induced nephrotoxicity, including free radical generation and the possible role of alpha lipoic acid (ALA) versus N-acetylcysteine (NAC) in protection against this toxicity. Male albino rats were injected intraperitoneally with saline, IFO (50 mg/kg daily for 5 days), IFO + ALA (100 mg/kg daily for 8 days) and IFO + NAC (200 mg/kg daily for 8 days). Kidney malondialdehyde, nitric oxide and glutathione contents and serum biochemical parameters and histopathological analysis were determined. Both ALA and NAC markedly reduced the severity of renal dysfunction induced by IFO. NAC was more nephroprotective than ALA. This study suggests that oxidative stress is possibly involved in the IFO-induced nephrotoxicity in rats. The study also suggests the potential therapeutic role for ALA and NAC against IFO-induced nephrotoxicity.
异环磷酰胺（IFO）是一种治疗多种小儿实体瘤的高效化疗药物。然而，由于其对肾脏有严重副作用，其应用受到限制。IFO在肾小管细胞中的侧链氧化会产生一种具有反应活性的毒性代谢产物，据信该产物是其肾毒性作用的原因。因此，本研究旨在探究可能参与IFO诱导肾毒性的潜在机制，包括自由基生成以及α硫辛酸（ALA）与N-乙酰半胱氨酸（NAC）在预防这种毒性方面可能发挥的作用。雄性白化病大鼠腹腔注射生理盐水、IFO（每日50mg/kg，共5天）、IFO + ALA（每日100mg/kg，共8天）以及IFO + NAC（每日200mg/kg，共8天）。测定肾脏丙二醛、一氧化氮和谷胱甘肽含量以及血清生化参数，并进行组织病理学分析。ALA和NAC均显著降低了IFO诱导的肾功能障碍的严重程度。NAC的肾保护作用比ALA更强。本研究表明氧化应激可能参与了大鼠中IFO诱导的肾毒性。该研究还表明ALA和NAC对IFO诱导的肾毒性具有潜在的治疗作用。
