Oxidative stress contributes to methotrexate-induced small intestinal toxicity in rats
Oxidative stress contributes to methotrexate-induced small intestinal toxicity in rats
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DOI：
10.1080/00365520410003605
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发表时间：
2004-11-01
影响因子：
1.9
通讯作者：
Horie, T
中科院分区：
文献类型：
--
作者：
Miyazono, Y;Gao, F;Horie, T
背景：胃肠道毒性是甲氨蝶呤（MTX）治疗中最严重的副作用之一。但其毒性机制尚未完全阐明，这可能是进行对症治疗的原因。另一方面，已知氧化应激在各种疾病和药物诱导的副作用中起重要作用。本研究从氧化应激角度探讨MTX对小肠组织的损伤，尤其是中性粒细胞浸润的机制。方法：MTX（20 mg/kg体重）静脉注射给药。从小肠制备粘液匀浆并用于测定生化参数，通过其评估氧化应激和中性粒细胞浸润的诱导。N-乙酰半胱氨酸（NAC; 80 mg/kg体重）、抗氧化剂或钨酸钠（钨; 0.7 g/kg体重）、黄嘌呤脱氢酶（XD）/黄嘌呤氧化酶（XO）的抑制剂（已知为活性氧（ROS）的重要来源）给予MTX大鼠，以研究ROS对中性粒细胞浸润的贡献。结果：MTX治疗大鼠可引起小肠氧化应激。在髓过氧化物酶活性增加之前观察到ROS产生，这表明中性粒细胞浸润。NAC和钨的治疗都防止了MTX诱导的ROS产生和中性粒细胞浸润。结论：这些结果表明，氧化应激在甲氨蝶呤诱导的小肠损伤中发挥重要作用，尤其是中性粒细胞浸润。因此，氧化应激的调节将有助于减少MTX治疗中的肠损伤。
Background: Gastrointestinal toxicity is one of the most serious side effects in the methotrexate (MTX) treatment. However, the mechanism of the toxicity has not been completely clarified, which may be the reason why symptomatic therapy is carried out. On the other hand, the oxidative stress is known to play an important role in various diseases and drug-induced side effects. In this study the focus was on the oxidative stress in order to clarify the mechanism of MTX-induced small intestinal damage, especially neutrophil infiltration. Methods: MTX ( 20 mg/kg body wt) was administered to rats intravenously. Mucosal homogenates were prepared from the small intestine and used for assay of biochemical parameters, by which induction of oxidative stress and neutrophil infiltration were evaluated. N-acetylcysteine (NAC; 80 mg/kg body wt), an antioxidant or sodium tungstate ( tungsten; 0.7 g/kg body wt), an inhibitor of xanthine dehydrogenase (XD)/xanthine oxidase (XO) known as an important source of reactive oxygen species (ROS) was given to rats with MTX to investigate the contribution of ROS to neutrophil infiltration. Results: The MTX treatment of rats induced the oxidative stress in the small intestine. The ROS production was seen preceding an increase of myeloperoxidase activity, which suggested neutrophil infiltration. Both treatments of NAC and tungsten prevented the MTX-induced ROS production and neutrophil infiltration. Conclusions: These results suggest that oxidative stress plays an important role in the MTX-induced small intestinal damage, especially neutrophil infiltration. Thus, the modulation of oxidative stress would be useful in reducing intestinal damage in MTX treatment.