Sehirli Ozer, Sakarcan Abdullah, Velioğlu-Oğünç Ayliz, Cetinel Sule, Gedik Nursal, Yeğen Berrak C, Sener Göksel
Marmara University, School of Pharmacy, Department of Pharmacology, Tibbiye Cad. 34668 Istanbul, Turkey.
Toxicol Appl Pharmacol. 2007 Jul 1;222(1):33-41. doi: 10.1016/j.taap.2007.03.025. Epub 2007 Mar 31.
Regarding the mechanisms of ifosfamide (IFO)-induced urinary toxicity, several hypotheses have been put forward, among which oxidative stress and depletion of glutathione are suggested. This investigation elucidates the role of free radicals in IFO-induced toxicity and the protection by resveratrol, a natural phytoalexin. Wistar albino rats were injected intraperioneally with saline (0.9% NaCl; control), saline+resveratrol (RVT; 10 mg/kg/day), ifosfamide (IFO; 50 mg/kg/day) or IFO+RVT for 5 days. Urine was collected for 24 h during the 5th day, and at the 120th h after the first injections, animals were killed by decapitation and trunk blood was collected. Lactate dehydrogenase (LDH) activity, total antioxidant capacity (AOC) and pro-inflammatory cytokines TNF-alpha, IL-beta and IL-6 were assayed in plasma samples. Kidney and bladder tissues were obtained for biochemical and histological analysis. Formation of reactive oxygen species in the tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. The results demonstrated that IFO induced a Fanconi syndrome characterized by increased urinary sodium, phosphate, glucose and protein, along with increased serum creatinine and urea levels. On the other hand, RVT markedly ameliorated the severity of renal dysfunction induced by IFO. Furthermore IFO caused a significant decrease in plasma AOC, which was accompanied with significant increases in the levels of the pro-inflammatory mediators and LDH activity, while RVT treatment reversed all these biochemical indices. In the saline-treated IFO group, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity and collagen content were increased in both tissues, which were in parallel with the increases in CL values. In the RVT-treated IFO group, all of these oxidant responses were prevented significantly. Our results suggest that IFO causes oxidative damage in the renal and bladder tissues and resveratrol, via its antioxidant effects, protects these tissues. Therefore, its therapeutic role in preventing the development of chemotherapeutic drug-induced major toxicity in the urinary system requires further elucidation.
关于异环磷酰胺（IFO）诱导的泌尿系统毒性机制，已经提出了几种假说，其中氧化应激和谷胱甘肽耗竭被认为是可能的原因。本研究阐明了自由基在IFO诱导的毒性中的作用以及白藜芦醇（一种天然植保素）的保护作用。将Wistar白化大鼠腹腔注射生理盐水（0.9% NaCl；对照组）、生理盐水+白藜芦醇（RVT；10 mg/kg/天）、异环磷酰胺（IFO；50 mg/kg/天）或IFO+RVT，持续5天。在第5天收集24小时尿液，在首次注射后第120小时，通过断头处死动物并收集躯干血液。检测血浆样本中的乳酸脱氢酶（LDH）活性、总抗氧化能力（AOC）以及促炎细胞因子TNF-α、IL-β和IL-6。获取肾脏和膀胱组织进行生化和组织学分析。使用鲁米诺和光泽精探针通过化学发光（CL）技术监测组织样本中活性氧的形成。结果表明，IFO诱导了范科尼综合征，其特征为尿钠、磷酸盐、葡萄糖和蛋白质增加，同时血清肌酐和尿素水平升高。另一方面，RVT显著改善了IFO诱导的肾功能障碍的严重程度。此外，IFO导致血浆AOC显著降低，同时促炎介质水平和LDH活性显著增加，而RVT治疗逆转了所有这些生化指标。在生理盐水处理的IFO组中，谷胱甘肽水平显著降低，而两种组织中的丙二醛水平、髓过氧化物酶活性和胶原蛋白含量均增加，这与CL值的增加平行。在RVT处理的IFO组中，所有这些氧化应激反应均得到显著预防。我们的结果表明，IFO会导致肾脏和膀胱组织的氧化损伤，而白藜芦醇通过其抗氧化作用保护这些组织。因此，其在预防化疗药物诱导的泌尿系统主要毒性发展中的治疗作用需要进一步阐明。
