Kolli V K, Natarajan K, Isaac B, Selvakumar D, Abraham P
Department of Biochemistry, Christian Medial College, Bagayam, Vellore, Tamil Nadu, India.
Department of Anatomy, Christian Medial College, Bagayam, Vellore, Tamil Nadu, India.
Hum Exp Toxicol. 2014 Oct;33(10):1051-65. doi: 10.1177/0960327113515503. Epub 2013 Dec 17.
The efficacy of methotrexate (MTX), a widely used chemotherapeutic drug, is limited by its gastrointestinal toxicity and the mechanism of which is not clear. The present study investigates the possible role of mitochondrial damage in MTX-induced enteritis. Small intestinal injury was induced in Wistar rats by the administration of 7 mg kg(-1) body wt. MTX intraperitoneally for 3 consecutive days. MTX administration resulted in severe small intestinal injury and extensive damage to enterocyte mitochondria. Respiratory control ratio, the single most useful and reliable test of mitochondrial function, and 3-(4,5-dimethylthiazol-2-yll)-2,5-diphenyltetrazolium bromide reduction, a measure of cell viability were significantly reduced in all the fractions of MTX-treated rat enterocytes. A massive decrease (nearly 70%) in the activities of complexes II and IV was also observed. The results of the present study suggest that MTX-induced damage to enterocyte mitochondria may play a critical role in enteritis. MTX-induced alteration in mitochondrial structure may cause its dysfunction and decreases the activities of the electron chain complexes. MTX-induced mitochondrial damage can result in reduced adenosine triphosphate synthesis, thereby interfering with nutrient absorption and enterocyte renewal. This derangement may contribute to malabsorption of nutrients, diarrhea, and weight loss seen in patients on MTX chemotherapy.
甲氨蝶呤（MTX）是一种广泛使用的化疗药物，其疗效受到胃肠道毒性的限制，且其机制尚不清楚。本研究调查了线粒体损伤在MTX诱导的肠炎中可能发挥的作用。通过腹腔注射7 mg kg(-1)体重的MTX连续3天，诱导Wistar大鼠出现小肠损伤。MTX给药导致严重的小肠损伤和肠上皮细胞线粒体的广泛损伤。呼吸控制率是线粒体功能最有用和可靠的单一检测指标，而3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐还原法（一种细胞活力的测量方法）在MTX处理的大鼠肠上皮细胞的所有组分中均显著降低。还观察到复合物II和IV的活性大幅下降（近70%）。本研究结果表明，MTX诱导的肠上皮细胞线粒体损伤可能在肠炎中起关键作用。MTX诱导的线粒体结构改变可能导致其功能障碍，并降低电子链复合物的活性。MTX诱导的线粒体损伤可导致三磷酸腺苷合成减少，从而干扰营养物质吸收和肠上皮细胞更新。这种紊乱可能导致接受MTX化疗的患者出现营养物质吸收不良、腹泻和体重减轻。
