Santos N A G, Bezerra C S Catão, Martins N M, Curti C, Bianchi M L P, Santos A C
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Av do Café s/n, 14040-903, Ribeirao Preto, SP, Brazil.
Cancer Chemother Pharmacol. 2008 Jan;61(1):145-55. doi: 10.1007/s00280-007-0459-y. Epub 2007 Mar 30.
Nephrotoxicity is the major dose-limiting factor of cisplatin chemotherapy. Reactive oxygen species generated in mitochondria are thought to be the main cause of cellular damage in such injury. The present study examined, in vivo, the protective potential of the hydroxyl radical scavenger dimethylthiourea (DMTU) against cisplatin-induced effects on renal mitochondrial bioenergetics, redox state and oxidative stress. Adult male Wistar rats (200 to 220 g) were divided into four groups of eight animals each. The control group was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml/100 g body weight). The second group was given only DMTU (500 mg/kg body weight, i.p, followed by 125 mg/Kg, i.p., twice a day until they were killed). The third group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The fourth group was given DMTU (500 mg/kg body weight, i.p.), just before the cisplatin injection (10 mg/kg body weight, i.p.), followed by injections of DMTU (125 mg/kg body weight, i.p.) twice a day until they were killed. Animals were killed 72 h after the treatment. Besides not presenting any direct effect on mitochondria, DMTU substantially inhibited cisplatin-induced mitochondrial injury and cellular death by apoptosis, suppressing the occurrence of acute renal failure. All the following cisplatin-induced effects were prevented by DMTU: (1) increased plasmatic levels of creatinine and blood urea nitrogen (BUN); (2) decreased ATP content, calcium uptake and electrochemical potential; (3) oxidation of lipids, including cardiolipin; and oxidation of proteins, including sulfhydryl, and aconitase enzyme, as well as accumulation of carbonyl proteins; (4) depletion of the antioxidant defense (NADPH and GSH) and (5) increased activity of the apoptosis executioner caspase-3. Our findings show the important role played by mitochondria and hydroxyl radicals in cisplatin-induced nephrotoxicity, as well as the effectiveness of DMTU in preventing the renal mitochondrial damage caused by cisplatin. These results strongly suggest that protection of mitochondria by hydroxyl radical scavengers may be an interesting approach to prevent the kidney tissue damage caused by cisplatin-chemotherapy.
肾毒性是顺铂化疗的主要剂量限制因素。线粒体中产生的活性氧被认为是此类损伤中细胞损伤的主要原因。本研究在体内检测了羟基自由基清除剂二甲基硫脲（DMTU）对顺铂诱导的肾线粒体生物能量学、氧化还原状态和氧化应激影响的保护潜力。成年雄性Wistar大鼠（200至220克）被分为四组，每组八只动物。对照组仅腹腔注射生理盐水（1毫升/100克体重）。第二组仅给予DMTU（500毫克/千克体重，腹腔注射，随后125毫克/千克，腹腔注射，每天两次，直至处死）。第三组单次注射顺铂（10毫克/千克体重，腹腔注射）。第四组在顺铂注射前（10毫克/千克体重，腹腔注射）给予DMTU（500毫克/千克体重，腹腔注射），随后每天两次注射DMTU（125毫克/千克体重，腹腔注射），直至处死。治疗72小时后处死动物。除了对线粒体没有任何直接影响外，DMTU还通过抑制凋亡显著抑制了顺铂诱导的线粒体损伤和细胞死亡，从而抑制了急性肾衰竭的发生。DMTU预防了以下所有顺铂诱导的影响：（1）血浆肌酐和血尿素氮（BUN）水平升高；（2）ATP含量、钙摄取和电化学电位降低；（3）脂质氧化，包括心磷脂；蛋白质氧化，包括巯基和乌头酸酶，以及羰基蛋白的积累；（4）抗氧化防御（NADPH和GSH）的消耗；（5）凋亡执行蛋白酶caspase-3的活性增加。我们的研究结果表明线粒体和羟基自由基在顺铂诱导的肾毒性中起重要作用，以及DMTU在预防顺铂引起的肾线粒体损伤方面的有效性。这些结果强烈表明，用羟基自由基清除剂保护线粒体可能是预防顺铂化疗引起的肾组织损伤的一种有效方法。
