黄独素B致小鼠急性肝损伤的代谢组学研究
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篇名: 黄独素B致小鼠急性肝损伤的代谢组学研究
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摘要: 目的:从代谢层面探索黄独素B致小鼠急性肝损伤的潜在生物标志物,研究其肝毒性作用机制。方法:将24只小鼠随机分成正常组(0.5%羧甲基纤维素钠溶液)和黄独素B组(200 mg/kg),每组12只。一次性灌胃给予相应药物24 h后,检测小鼠血清中丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)水平和肝组织中丙二醛(MDA)、超氧化物歧化酶(SOD)水平;采用苏木精-伊红染色法观察肝组织病理学变化;采用核磁共振氢谱(1H-NMR)检测尿液和肝组织中的代谢产物水平,并采用正交偏最小二乘法-判别分析(OPLS-DA)筛选黄独素B肝毒性的潜在生物标志物。结果:与正常组比较,黄独素B组小鼠血清中ALT、AST水平均显著上升,肝组织中MDA水平显著上升、SOD水平显著下降(P<0.05);肝组织细胞受损,出现明显病理性改变;尿液和肝组织中代谢产物水平发生显著改变,各筛选得到3种和6种与肝损伤相关的潜在生物标志物(P<0.05),分别为α-酮戊二酸、二甲胺、氧化三甲胺(尿液)和谷胱甘肽、牛磺酸、肌苷、酪氨酸、苯丙氨酸、组氨酸(肝组织)。结论:黄独素B主要是通过自由基氧化作用损伤肝细胞,其对机体三羧酸循环、氨基酸代谢、肠道菌群产生影响可能是其肝毒性的作用机制。
ABSTRACT: OBJECTIVE: To explore potential biomarkers of acute hepatic injury induced by diosbulbin B and study its hepatotoxicity mechanism from metabolic aspect. METHODS: Totally 24 mice were randomly divided into normal group (0.5% sodium carboxymethylcellulose solution) and diosbulbin B group (200 mg/kg), with 12 mice in each group. They were given relevant medicine intragastrically; 24 h later, the levels of ALT, AST in serum and MDA, SOD in liver tissue were determined. HE staining was used to observe the histopathological changes of liver tissue. The levels of metabolism products in urine and liver tissue were determined by 1H-NMR. The potential biomarkers of diosbulbin B hepatotoxicity were screened by OPLS-DA. RESULTS: Compared with normal group, the levels of ALT and AST in serum, the level of MDA in liver tissue were increased significantly in diosbulbin B group, while the level of SOD in liver tissue was decreased (P<0.05). The liver cells were damaged,with marked pathological changes. The levels of metabolic products were significantly changed in urine and liver tissue. Three and six potential biomarkers related to acute hepatic injury were obtained (P<0.05), i.e. α-ketopglutaric acid, dimethylamine, trimethylamine oxide (urine) and glutathione, taurine, inosine, tyrosine, phenylalanine,  histidine (liver tissue). CONCLUSIONS: The hepatic injury induced by diosbulbin B are caused by free radical oxidation. The mechanism of hepatotoxicity may be the effect of diosbulbin B on tricarboxylic acid cycle, amino acid metabolism and intestinal flora.
期刊: 2018年第29卷第22期
作者: 巫圣乾,张璐,龚梦鹃,王淑美,梁生旺,邹忠杰
AUTHORS: WU Shengqian,ZHANG Lu,GONG Mengjuan,WANG Shumei,LIANG Shengwang,ZOU Zhongjie
关键字: 黄独素B;急性肝损伤;肝毒性;代谢组学;核磁共振氢谱;小鼠
KEYWORDS: Diosbulbin B;Acute hepatic injury;Hepatotoxicity; Metabonomics; 1H-NMR; Mice
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