Dadoun C, Raguenez-Viotte G
INSERM U295, U.E.R. Medecine-Pharmacie de Rouen, Saint-Etienne-du-Rouvray, France.
Cancer Chemother Pharmacol. 1990;27(3):178-86. doi: 10.1007/BF00685710.
The antitumor drug celiptium, or N2-methyl-9-hydroxyellipticinium (NMHE), is an ellipticine derivative used in the treatment of breast cancer. Celiptium-induced dose-dependent renal toxicity in rats is characterized by tubular necrosis, tubulo-interstitial lesions and lipid overload in proximal tubular cells. Since biooxidative activation of celiptium occurs in kidney via highly electrophilic intermediates, we studied the effects of celiptium on rat renal cortex lipids in the context of lipid peroxidation damage. Female Wistar rats were injected with a single i.v. dose of 20 mg/kg celiptium and were killed on day 2, 4 or 8. Histochemical analysis of kidney sections detected Oil Red O (ORO)-positive deposits, whereas the same sections studied using Holczinger's copper rubeanic acid method showed free fatty acid (FFA) granules in renal tubular cells of celiptium-treated rats. Electron microscopy revealed large fatty droplets in proximal tubular cells. As creatinine clearance decreased on days 4 and 8, celiptium induced a significant increase in renal cortex FFA levels (6-fold increase over pretreatment values on day 8), whereas total glycerides increased 1.5 times. A 15% decrease in total phospholipids (PL) and a 50% decline in the mass of phosphatidylethanolamine (PE) were detected by lipid phosphorus assay. A 1.2-fold decrease in the unsaturation index of total PL was noted, with a significant decline in arachidonic acid (20:4). A 15% decrease in arachidonic content was observed in the fatty acid composition of PE. Analysis of the fatty acid composition of neutral lipids showed changes only in the FFA class. A great proportion of oleic (18:1) and linoleic (18:2) acids was found. Iodometric titration and thiobarbituric acid (TBA) reactivity detected respectively significant amounts of lipid hydroperoxides and TBA-reactive material in renal cortex lipid extracts on days 2, 4 and 8. The lipid-peroxidation process appeared to be involved in the pathogenesis of celiptium nephrotoxicity.
抗肿瘤药物塞利铂，即N2 - 甲基 - 9 - 羟基玫瑰树碱（NMHE），是一种用于治疗乳腺癌的玫瑰树碱衍生物。塞利铂在大鼠中诱导的剂量依赖性肾毒性表现为肾小管坏死、肾小管间质损伤以及近端肾小管细胞中的脂质过载。由于塞利铂通过高亲电子中间体在肾脏中发生生物氧化活化，我们在脂质过氧化损伤的背景下研究了塞利铂对大鼠肾皮质脂质的影响。给雌性Wistar大鼠静脉注射单次剂量20 mg/kg的塞利铂，并在第2、4或8天处死。肾脏切片的组织化学分析检测到油红O（ORO）阳性沉积物，而使用霍尔钦格铜红氨酸法研究的相同切片显示，在接受塞利铂治疗的大鼠肾小管细胞中有游离脂肪酸（FFA）颗粒。电子显微镜显示近端肾小管细胞中有大的脂肪滴。随着第4天和第8天肌酐清除率下降，塞利铂导致肾皮质FFA水平显著升高（第8天比预处理值增加6倍），而总甘油酯增加1.5倍。通过脂质磷测定法检测到总磷脂（PL）减少15%，磷脂酰乙醇胺（PE）质量下降50%。总PL的不饱和指数下降了1.2倍，花生四烯酸（20:4）显著减少。在PE的脂肪酸组成中观察到花生四烯酸含量下降15%。中性脂质脂肪酸组成分析仅在FFA类别中显示出变化。发现油酸（18:1）和亚油酸（18:2）的比例很大。在第2、4和8天，碘量滴定法和硫代巴比妥酸（TBA）反应性分别在肾皮质脂质提取物中检测到大量脂质氢过氧化物和TBA反应性物质。脂质过氧化过程似乎参与了塞利铂肾毒性的发病机制。
