dos Santos Neife Aparecida Guinaim, Martins Nádia Maria, Curti Carlos, Pires Bianchi Maria de Lourdes, dos Santos Antonio Cardozo
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Avenida do Café s/n, 14040-903 Ribeirão Preto, SP, Brazil.
Chem Biol Interact. 2007 Dec 15;170(3):177-86. doi: 10.1016/j.cbi.2007.07.014. Epub 2007 Aug 6.
Cisplatin is one of the most effective chemotherapeutic agents. However, at higher doses liver injury may occur. The purpose of this study was to explore whether the hydroxyl radical scavenger dimethylthiourea (DMTU) protects against cisplatin-induced oxidative damage in vivo and to define the mitochondrial pathways involved in cytoprotection. Adult male Wistar rats (200-220 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 DMTU group was given only DMTU (500 mg/kg body weight, i.p), followed by 125 mg/kg body weight, i.p. (twice a day) until sacrifice. The cisplatin group was given a single injection of cisplatin (10 mg/kg body weight, i.p.). The DMTU+cisplatin 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 sacrifice (72 h after the treatment). DMTU did not present any direct effect on mitochondria and substantially inhibited cisplatin-induced mitochondrial damage in liver, therefore preventing elevation of AST and ALT serum levels. DMTU protected against (a) decreased hepatic ATP levels; (b) lipid peroxidation; (c) cardiolipin oxidation; (d) sulfhydryl protein oxidation; (e) mitochondrial membrane rigidification; (f) GSH oxidation; (g) NADPH oxidation; (h) apoptosis. Results suggest that antioxidants, particularly hydroxyl radical scavengers, protect liver mitochondria against cisplatin-induced oxidative damage. Several mitochondrial changes were delineated and proposed as interesting targets for cytoprotective strategy.
顺铂是最有效的化疗药物之一。然而，高剂量使用时可能会发生肝损伤。本研究的目的是探讨羟基自由基清除剂二甲基硫脲（DMTU）是否能在体内保护肝脏免受顺铂诱导的氧化损伤，并确定细胞保护作用所涉及的线粒体途径。成年雄性Wistar大鼠（200 - 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）。DMTU组仅给予DMTU（500毫克/千克体重，腹腔注射），随后给予125毫克/千克体重，腹腔注射（每天两次）直至处死。顺铂组单次腹腔注射顺铂（10毫克/千克体重）。DMTU + 顺铂组在顺铂注射前（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（治疗后72小时）。DMTU对线粒体没有任何直接影响，并且能显著抑制顺铂诱导的肝脏线粒体损伤，从而防止血清AST和ALT水平升高。DMTU可防止（a）肝脏ATP水平降低；（b）脂质过氧化；（c）心磷脂氧化；（d）巯基蛋白氧化；（e）线粒体膜硬化；（f）谷胱甘肽氧化；（g）NADPH氧化；（h）细胞凋亡。结果表明，抗氧化剂，尤其是羟基自由基清除剂，可保护肝脏线粒体免受顺铂诱导的氧化损伤。描述了几种线粒体变化，并将其作为细胞保护策略的有趣靶点。
