Despite the extensive use of cisplatin (CP) as a chemotherapeutic agent, its clinical use is often restricted by undesirable side effects, such as toxicity to normal tissues. The aim of this study was to probe the effect of a combinatorial treatment of low multiple doses of antioxidants on CP‐induced toxicity and the mitochondrial apoptotic pathway in hepatocytes. Animals received a single toxic dose of CP (7.5 mg/kg body weight) with or without combined multiple doses of epigallocatechin gallate (EGCG) and coenzyme Q10 (CoQ10) (15 and 5 mg/kg body weight, respectively). CP‐treated animals showed altered biochemical parameters, denoting hepatotoxicity, which was markedly improved by the multidose treatment with EGCG + CoQ10. The increased levels of oxidants found in the cytosolic and mitochondrial fractions isolated from the liver of CP‐administered rats were significantly attenuated by the combinatorial doses of antioxidants. EGCG + CoQ10 ameliorated the CP‐induced compromised antioxidant defenses, oxidative modification of macromolecules, decreased activities of respiratory chain enzymes, altered membrane depolarization, and swelling of liver mitochondria. Furthermore, EGCG + CoQ10 treatment inhibited CP‐induced apoptosis by suppressing the activation and mitochondrial accumulation of proapoptotic proteins and preventing the inhibition of antiapoptotic protein expression, cytochrome c efflux, caspase‐3 activation, and DNA fragmentation. Histological findings further confirmed the protective effects of EGCG + CoQ10 against CP‐induced cellular injury. Our findings revealed that the combination of EGCG and CoQ10, owing to their individual antioxidant properties, can be an effective remedy, which by maintaining redox hemostasis attenuate the mitochondrial stress‐mediated molecular and cellular processes involved in CP‐induced liver toxicity and cell death.

中文翻译：

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表没食子儿茶素没食子酸酯和辅酶Q10通过靶向线粒体应激和凋亡来减轻顺铂对大鼠的肝毒性

尽管广泛使用顺铂（CP）作为化学治疗剂，但其临床应用通常受到不良副作用（例如对正常组织的毒性）的限制。这项研究的目的是探讨低剂量多剂量抗氧化剂的联合治疗对肝细胞内CP诱导的毒性和线粒体凋亡途径的影响。动物接受单次有毒剂量的CP（7.5 mg / kg体重），有或没有联合使用多剂量的表没食子儿茶素没食子酸酯（EGCG）和辅酶Q10（CoQ10）（分别为15和5 mg / kg体重）。经CP处理的动物表现出改变的生化参数，表示肝毒性，通过EGCG + CoQ10的多剂量治疗明显改善了肝毒性。联合剂量的抗氧化剂可显着减弱从CP给药大鼠肝脏中分离出的胞质和线粒体组分中发现的氧化剂水平的升高。EGCG + CoQ10改善了CP诱导的抗氧化防御功能受损，大分子的氧化修饰，呼吸链酶活性降低，膜去极化改变和肝线粒体肿胀。此外，EGCG + CoQ10处理可通过抑制促凋亡蛋白的活化和线粒体蓄积并阻止对抗凋亡蛋白表达的抑制来抑制CP诱导的细胞凋亡。大分子的氧化修饰，呼吸链酶活性降低，膜去极化改变和肝线粒体肿胀。此外，EGCG + CoQ10处理可通过抑制促凋亡蛋白的活化和线粒体蓄积并阻止对抗凋亡蛋白表达的抑制来抑制CP诱导的细胞凋亡。大分子的氧化修饰，呼吸链酶活性降低，膜去极化改变和肝线粒体肿胀。此外，EGCG + CoQ10处理可通过抑制促凋亡蛋白的活化和线粒体蓄积并防止对抗凋亡蛋白表达的抑制来抑制CP诱导的细胞凋亡。c外排，caspase-3激活和DNA片段化。组织学结果进一步证实了EGCG + CoQ10对CP诱导的细胞损伤的保护作用。我们的研究结果表明，EGCG和CoQ10的结合由于其各自的抗氧化剂特性而成为一种有效的治疗方法，通过维持氧化还原止血作用，可以减轻与CP诱导的肝毒性和细胞死亡有关的线粒体应激介导的分子和细胞过程。