Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver
Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver
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DOI：
10.1002/jat.1284
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发表时间：
2008-04-01
影响因子：
3.3
通讯作者：
Santos, A. C.
中科院分区：
文献类型：
--
作者：
Martins, N. M.;Santos, N. A. G.;Santos, A. C.
顺铂是一种有效且广泛使用的化疗剂。这种药物引起的肾毒性已得到充分证明。然而，关于顺铂诱导的肝毒性的信息很少，其潜在机制仍不清楚。已知高剂量顺铂会产生肝毒性。此外，表达升高的E2E1已与增强顺铂诱导的肝毒性。几项研究表明，顺铂毒性是通过线粒体中活性氧（ROS）的产生增加而发生的。因此，本研究在体内研究了顺铂诱导的对肝线粒体结构和功能的影响以及通过细胞凋亡导致肝细胞死亡的发生。将成年雄性Wistar大鼠（200 - 220 g）分为两组（n = 8），处理如下：（1）对照组（生理盐水，1 ml 100 g（-1）体重，i.p.）顺铂组（10 mg/kg体重，腹腔注射）。给药后72 h处死动物。肝毒性在顺铂组中表现为丙氨酸（ALT）和天冬氨酸（AST）转氨酶的血清水平升高。顺铂诱导的肝毒性机制涉及膜硬化; GSH/GSSG比值、ATP、GSH和NADPH水平降低;脂质过氧化;心磷脂和蛋白巯基的氧化损伤。此外，细胞凋亡导致的细胞死亡也得到了证实，这些发现强烈表明线粒体信号通路参与了这一过程。因此，结果显示了线粒体在顺铂诱导的肝毒性中的关键作用，并描绘了未来细胞保护治疗方法中可能靶向的几个线粒体过程。版权所有（C）2007约翰威利父子有限公司
Cisplatin is a potent and widely used chemotherapeutic agent. Nephrotoxicity induced by this drug has been well documented. However, very little information is available on cisplatin-induced hepatotoxicity and its underlying mechanism remains unclear. High doses of cisplatin have been known to produce hepatotoxicity. Additionally, elevated expression of CYP 2E1 has been associated with enhanced cisplatin-induced hepatotoxicity. Several studies suggest that cisplatin toxicity occurs by the increased generation of reactive oxygen species (ROS) in mitochondria. Therefore, the present study examined, in vivo, the cisplatin-induced effects on hepatic mitochondrial structure and function as well as the occurrence of hepatocellular death by apoptosis. Adult male Wistar rats (200-220 g) were divided into two groups (n = 8) treated as follows: (1) control group (saline solution, 1 ml 100 g(-1) body weight, i.p.) and (2) cisplatin group (10 mg kg(-1) body weight, i.p.). The animals were killed 72 h after the treatment. Hepatotoxicity was evidenced in the cisplatin group by the increased serum levels of alanine (ALT) and aspartate (AST) aminotransferases. The mechanism of cisplatin-induced hepatotoxicity was found to involve membrane rigidification; decreased GSH/GSSG ratio, ATP, GSH and NADPH levels; lipid peroxidation; oxidative damage of cardiolipin and protein sulfhydryl groups. Moreover, cell death by apoptosis was also demonstrated and the findings strongly suggest the participation of the mitochondrial signaling pathway in this process. Therefore, the results show the key role of mitochondria in the hepatotoxicity induced by cisplatin and delineate several mitochondrial processes that could be targeted in future cytoprotective therapy approaches. Copyright (C) 2007 John Wiley & Sons, Ltd.