Section of Molecular Carcinogenesis and Chemoprevention, Department of Medical Elementology and Toxicology, Faculty of Science, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi, 110062, India.
Mol Cell Biochem. 2014 Jan;385(1-2):215-23. doi: 10.1007/s11010-013-1830-4. Epub 2013 Oct 24.
Methotrexate (MTX), a folic acid antagonist, an effective chemotherapeutic agent is used in the treatment of a wide range of tumors and autoimmune diseases. Moreover, hepatotoxicity limits its clinical use. Several studies have already confirmed that the oxidative stress plays a major role in the pathogenesis of MTX-induced damage in the various organs especially in liver. The aim of this study was to determine the protective effect of Chrysin against MTX-induced hepatic oxidative stress and apoptosis in rats. In the present study, efficacy of Chrysin was investigated against hepatotoxicity caused by MTX in terms of biochemical investigations of antioxidant enzymes, apoptosis, and histopathological alteration in rat liver. In the MTX-treated group there was a significant increase in alanine transaminase, aspartate aminotransferase, lactate dehydrogenase activity and malondialdehyde content as well as decreased glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase activities and reduced glutathione content were also observed compared to the control group as a marker of oxidative stress. Histopathological alterations and apoptosis through the immunopositive staining of p53, cleaved caspases-3 and Bcl-2-associated X protein in rat liver were observed. Pretreatment of Chrysin at both doses prevents the hepatotoxicity by ameliorating oxidative stress, histopathological alterations, and apoptosis and thus our results suggest that Chrysin has a protective effect against hepatotoxicity induced by MTX and it may, therefore, improve the therapeutic index of MTX if co-administration is done.
甲氨蝶呤（MTX）是一种叶酸拮抗剂，作为一种有效的化疗药物，被广泛用于治疗多种肿瘤和自身免疫性疾病。然而，其肝毒性限制了其临床应用。已有多项研究证实，氧化应激在 MTX 诱导的各种器官（尤其是肝脏）损伤的发病机制中起着重要作用。本研究旨在确定白杨素对 MTX 诱导的大鼠肝氧化应激和细胞凋亡的保护作用。本研究从抗氧化酶、细胞凋亡和肝组织病理学改变等方面，对白杨素治疗 MTX 诱导的肝毒性的疗效进行了研究。与对照组相比，MTX 治疗组丙氨酸转氨酶、天冬氨酸转氨酶、乳酸脱氢酶活性和丙二醛含量显著升高，而谷胱甘肽过氧化物酶、谷胱甘肽还原酶、超氧化物歧化酶、过氧化氢酶活性和还原型谷胱甘肽含量降低，表明氧化应激标志物增加。通过免疫组化检测大鼠肝 p53、裂解型半胱天冬酶-3 和 Bcl-2 相关 X 蛋白的表达，观察到组织病理学改变和细胞凋亡。白杨素的两种剂量预处理均可通过改善氧化应激、组织病理学改变和细胞凋亡来预防肝毒性，因此我们的结果表明，白杨素有预防 MTX 诱导的肝毒性的作用，如果联合使用，可能会提高 MTX 的治疗指数。
