N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats
N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats
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DOI：
10.1038/bjp.2008.15
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发表时间：
2008-04-01
影响因子：
7.3
通讯作者：
Koren, G.
中科院分区：
文献类型：
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作者：
Chen, N.;Aleksa, K.;Koren, G.
背景和目的：异环磷酰胺肾毒性是接受癌症化疗的儿童的严重不良反应。我们最近的体外研究表明，抗氧化剂N-乙酰半胱氨酸（NAC）广泛用作儿童对乙酰氨基酚（对乙酰氨基酚）中毒的解毒剂，可在临床相关浓度下保护肾小管细胞免受异环磷酰胺诱导的毒性。为了进一步验证这一观察结果，使用异环磷酰胺诱导的肾毒性的动物模型来确定NAC.Experimental approach的保护作用：雄性Wistar白化病大鼠腹腔内注射生理盐水、异环磷酰胺（50或80 mg/kg，每日一次，持续5天）、NAC（1.2 g/kg，每日一次，持续6天）或异环磷酰胺+NAC（持续6天）。最后一次注射后24小时，处死大鼠，收集血清和尿液进行生化分析。获得肾脏组织用于谷胱甘肽、谷胱甘肽S-转移酶和脂质过氧化物水平的分析以及组织学分析。关键结果：NAC可显著降低异环磷酰胺诱导的肾功能不全的严重程度，并显著降低血清肌酐升高（57.8 +/- 2.3 vs 45.25 +/- 2.1 mmol l（-1））以及β（2）-微球蛋白排泄升高降低（25.44 +/- 3.3 vs 8.83 +/- 1.3 nmol l（-1））和镁排泄（19.5 +/- 1.5 vs 11.16 +/- 1.5 mmol l（-1））。此外，NAC显着改善异环磷酰胺诱导的谷胱甘肽耗竭和谷胱甘肽S-转移酶活性的降低，降低脂质过氧化物的升高，并防止典型的形态学损害在肾小管和glomeruli.Conclusions和影响：我们的研究结果表明，NAC在儿科患者在预防异环磷酰胺肾毒性的潜在治疗作用。
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.