Immunotoxicology Laboratory, Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110062, India.
Food Chem Toxicol. 2010 Jul;48(7):1973-9. doi: 10.1016/j.fct.2010.04.047. Epub 2010 May 6.
Methotrexate (MTX) is a folic acid antagonist widely used as a cytotoxic chemotherapeutic agent for leukemia and other malignancies. The purpose of this study was to investigate the damage caused by MTX on liver mitochondria and its protection by using antioxidant properties of lipoic acid. MTX substantially affects mitochondrial function by reducing glutathione levels leading to disturbances in antioxidant enzyme defense system. Lipoic acid occurs naturally in mitochondria as a coenzyme. In various studies lipoic acid has been convincingly shown to exhibit an antioxidant role when supplemented exogenously. We studied the effect of lipoic acid pre-treatment on the toxicity of MTX in mouse liver mitochondria focusing specifically on the oxidative stress. MTX caused a significant rise in the mitochondrial lipid peroxidation (LPO), protein carbonyl (PC) content and superoxide radical generation. It also affected the mitochondrial thiol profile. Pre-treatment of mice with lipoic acid (35 mg/kg) markedly lowered mitochondrial LPO, PC content and superoxide radical generation. It also restored decreased enzymatic and non-enzymatic antioxidants of mitochondria. It is suggested that lipoic acid has a potential role in suppressing MTX-induced mitochondrial toxicity, and it affords protection either by reversing the decline of antioxidants or by the directly scavenging the free radicals.
甲氨蝶呤（MTX）是一种广泛用于白血病和其他恶性肿瘤的细胞毒性化疗药物的叶酸拮抗剂。本研究的目的是通过使用硫辛酸的抗氧化特性来研究 MTX 对肝线粒体的损伤及其保护作用。MTX 通过降低谷胱甘肽水平，显著影响线粒体功能，导致抗氧化酶防御系统紊乱。硫辛酸作为辅酶在线粒体中自然存在。在各种研究中，已经令人信服地表明，外源性补充硫辛酸具有抗氧化作用。我们研究了硫辛酸预处理对 MTX 在小鼠肝线粒体中毒性的影响，特别是对氧化应激的影响。MTX 导致线粒体脂质过氧化（LPO）、蛋白质羰基（PC）含量和超氧自由基生成显著增加。它还影响线粒体巯基谱。用硫辛酸（35mg/kg）预处理小鼠可显著降低线粒体 LPO、PC 含量和超氧自由基生成。它还恢复了降低的线粒体酶和非酶抗氧化剂。研究表明，硫辛酸在抑制 MTX 诱导的线粒体毒性方面具有潜在作用，它通过逆转抗氧化剂的下降或直接清除自由基来提供保护。
