School of Environmental Science and Engineering, 74618Shaanxi University of Science and Technology, Xian, China.
Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, 68779Mansoura University, Dakahlia, Egypt.
Hum Exp Toxicol. 2021 Jul;40(7):1194-1207. doi: 10.1177/0960327121991905. Epub 2021 Feb 3.
Methotrexate (MTX) is frequently used drug in treatment of cancer and autoimmune diseases. Unfortunately, MTX has many side effects including the hepato-renal toxicity. In this study, we hypothesized that Luteolin (Lut) exhibits protective effect against the MTX-induced hepato-renal toxicity. In order to investigate our hypothesis, the experiment was designed to examine the effect of exposure of male rats to MTX (20 mg/kg, i.p., at day 9) alone or together with Lut (50 mg/kg, oral for 14 days) compared to the control rats (received saline). The findings demonstrated that MTX treatment induced significant increases in the liver and kidney functions markers in serum samples including Aspartate transaminase (AST), Alanine transaminase (ALT), creatinine, urea and uric acid. MTX also mediated an oxidative stress expressed by elevated malondialdehyde (MDA) level and decreased level of reduced glutathione (GSH), antioxidant enzyme activities, and downregulation of the Nrf2 gene expression as an antioxidant trigger. Moreover, the inflammatory markers (NF-κB, TNF-α, and IL-1β) were significantly elevated upon MTX treatment. In addition, MTX showed an apoptotic response mediated by elevating the pro-apoptotic (Bax) and lowering the anti-apoptotic (Bcl-2) proteins. All of these changes were confirmed by the observed alterations in the histopathological examination of the hepatic and renal tissues. Lut exposure significantly reversed all the MTX-induced changes in the measured parameters suggesting its potential protective role against the MTX-induced toxicity. Finally, our findings concluded the antioxidative, anti-inflammatory and anti-apoptotic effects of Lut as a mechanism of its protective role against the MTX-induced hepato-renal toxicity in rats.
甲氨蝶呤（MTX）是治疗癌症和自身免疫性疾病的常用药物。不幸的是，MTX 有许多副作用，包括肝肾功能毒性。在这项研究中，我们假设木樨草素（Lut）对 MTX 诱导的肝肾功能毒性具有保护作用。为了验证我们的假设，该实验设计为研究雄性大鼠单独或与 Lut（50mg/kg，口服 14 天）一起暴露于 MTX（20mg/kg，腹腔注射，第 9 天）对肝肾功能的影响与对照组（生理盐水）大鼠。研究结果表明，MTX 治疗可导致血清样本中肝肾功能标志物显著升高，包括天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、肌酐、尿素和尿酸。MTX 还介导氧化应激，表现为丙二醛（MDA）水平升高和还原型谷胱甘肽（GSH）水平降低、抗氧化酶活性降低以及作为抗氧化剂触发因子的 Nrf2 基因表达下调。此外，MTX 治疗后炎症标志物（NF-κB、TNF-α 和 IL-1β）显著升高。此外，MTX 通过升高促凋亡（Bax）和降低抗凋亡（Bcl-2）蛋白来介导细胞凋亡反应。所有这些变化都通过肝肾功能组织学检查中观察到的改变得到证实。Lut 暴露可显著逆转 MTX 诱导的所有测量参数的变化，表明其对 MTX 诱导的毒性具有潜在的保护作用。最后，我们的研究结果得出结论，Lut 的抗氧化、抗炎和抗凋亡作用是其对 MTX 诱导的大鼠肝肾功能毒性的保护作用的机制。
