Systems level metabolic phenotype of methotrexate administration in the context of non-alcoholic steatohepatitis in the rat.
Systems level metabolic phenotype of methotrexate administration in the context of non-alcoholic steatohepatitis in the rat.
复制标题
DOI：
10.1093/toxsci/kfu160
复制
发表时间：
2014-11
期刊：
影响因子：
--
通讯作者：
Coen M
中科院分区：
文献类型：
--
作者：
Kyriakides M;Hardwick RN;Jin Z;Goedken MJ;Holmes E;Cherrington NJ;Coen M
药物不良反应 (ADR) 是患者发病率和死亡率方面的重大临床挑战。我们研究了甲氨蝶呤（MTX）在常见肝病背景下的肝毒性和系统水平代谢表型；非酒精性脂肪性肝炎（NASH）。采用基于核磁共振波谱的代谢组学方法来分析 MTX（0、10、40 和 100 mg/kg）在健康大鼠（对照饮食）的尿液和肝脏以及 NASH（蛋氨酸胆碱缺乏饮食）模型中的代谢后果。组织病理学分析证实了 NASH 模型中的基线（0 mg/kg）肝坏死、肝脏炎症和脂质积累。给予MTX（40和100 mg/kg）会导致对照组出现肝坏死，而NASH组也出现胆道增生和肝纤维化（100 mg/kg），这为MTX和NASH的协同作用提供了证据。 NASH 模型的互补肝脏和尿液代谢表型在基线时揭示了与氧化和能量应激以及叶酸稳态相关的多种代谢物的扰动。在两个饮食队列中施用 MTX 均显示出剂量依赖性代谢后果，影响肠道微生物、能量、核碱基、核苷和叶酸代谢。此外，还确定了反映 MTX 和 NASH 协同作用的一组独特的代谢变化，包括肝苯丙氨酸、尿刊酸盐、乙酸盐以及尿和肝甲亚氨基谷氨酸的升高。这种对 NASH 背景下 MTX 肝毒性的系统级代谢组学分析为进一步了解肝脏病理学作为 ADR 危险因素的作用提供了潜在更广泛临床相关性的新机制见解。
Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs.
登录
查看更多内容
影响因子：
15.9
作者：
Leclercq, IA;Farrell, GC;Robertson, GR
通讯作者：
Robertson, GR
影响因子：
19.6
作者：
Fowler, B
通讯作者：
Fowler, B
影响因子：
1.8
作者：
Nicholson, JK;Lindon, JC;Holmes, E
通讯作者：
Holmes, E
影响因子：
3.9
作者：
Fisher, Craig D.;Lickteig, Andrew J.;Cherrington, Nathan J.
通讯作者：
Cherrington, Nathan J.
DOI：
10.1002/mpo.2950170404
发表时间：
1989-01-01
期刊：
MEDICAL AND PEDIATRIC ONCOLOGY
影响因子：
--
作者：
HILTON, MA;BERTOLONE, S;PATEL, CC
通讯作者：
PATEL, CC