Kuloğlu Nurhan, Karabulut Derya, Kaymak Emin, Akin Ali Tuğrul, Ceylan Tayfun, Yıldırım Ayşegül Burçin, Yakan Birkan
Healthcare Services Department, Niğde Ömer Halisdemir University, Nigde, Turkey.
Histology-Embryology Department, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
Iran J Basic Med Sci. 2024;27(6):733-739. doi: 10.22038/IJBMS.2024.74161.16120.
Methotrexate (MTX) is a drug with anti-inflammatory and immunosuppressive effects and is also a folic acid antagonist. Our aim in this study is to determine the molecular mechanisms of cardiotoxicity caused by MTX, a chemotherapeutic drug, and to evaluate the protective effects of vitamin B12 on this toxicity.
A total of 32 rats were used in our study and 4 groups were formed. Control group, Vit B12 group (3 μg/kg B12 for 15 days, IP), MTX group (20 mg/kg MTX single dose on day 8 of the experiment, IP), MTX +Vit B12 group (3 μg/kg, IP ), Vit B12 throughout the 15 days, and a single dose of 20 mg/kg MTX (IP) on day 8 of the experiment. Immunohistochemically, expressions of hypoxia-inducible factor 1α (HIF1-α), vascular endothelial growth factor receptor-2 (VEGFR-2), erythropoietin (EPO), and interleukin-6 (IL-6) were evaluated in the heart tissue. Total catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were measured in the heart tissue. At the same time, ANP and NT-proBNP levels were measured in the blood serum.
In the study, the expression of HIF1-α and VEGFR-2 increased significantly in the MTX group, while IL-6 and EPO significantly decreased. At the same time, CAT and SOD levels were significantly decreased and MDA levels increased significantly in the MTX group. While vitamin B12 significantly corrected all these values, it also greatly reduced the increases in ANP and NT-proBNP levels caused by MTX.
It is important to use Vit B12 before and after MTX administration to replace the folate that MTX has reduced.
甲氨蝶呤（MTX）是一种具有抗炎和免疫抑制作用的药物，也是一种叶酸拮抗剂。本研究的目的是确定化疗药物MTX引起心脏毒性的分子机制，并评估维生素B12对这种毒性的保护作用。
本研究共使用32只大鼠，分为4组。对照组、维生素B12组（15天内每天腹腔注射3μg/kg B12）、MTX组（实验第8天腹腔注射20mg/kg MTX单剂量）、MTX +维生素B12组（15天内每天腹腔注射3μg/kg维生素B12，并在实验第8天腹腔注射20mg/kg MTX单剂量）。采用免疫组织化学方法评估心脏组织中缺氧诱导因子1α（HIF1-α）、血管内皮生长因子受体-2（VEGFR-2）、促红细胞生成素（EPO）和白细胞介素-6（IL-6）的表达。检测心脏组织中总过氧化氢酶（CAT）、超氧化物歧化酶（SOD）和丙二醛（MDA）水平。同时，检测血清中ANP和NT-proBNP水平。
研究中，MTX组HIF1-α和VEGFR-2表达显著增加，而IL-6和EPO显著降低。同时，MTX组CAT和SOD水平显著降低，MDA水平显著升高。维生素B12可显著纠正所有这些值，还可大大降低MTX引起的ANP和NT-proBNP水平升高。
在MTX给药前后使用维生素B12以补充MTX所降低的叶酸很重要。
