微囊藻毒素(MCLR),作为一种肝毒素,正在威胁着人类的公共卫生安全。在体内,肝脏是MCLR主要攻击的器官,然而具体代谢变化目前任然未知。近日,中国科学院水生生物研究所谢平等研究人员在与上海敏芯信息科技公司的合作下,通过对灌服MCLR的大鼠模型进行代谢组学的研究,向我们揭示了MCLR扰乱肝脏代谢的真面目,此研究已经刊登于国际杂志Journal of Proteome Research上。
该研究小组通过核磁共振(NMR)的实验平台完成了代谢组学研究,同时利用液质联用技术(LC-ESI-MS)对肝脏MCLR、谷胱苷肽与半胱氨酸轭合物进行定量。
代谢组学研究表明,MCLR作用于肝脏,导致酪氨酸合成与分解代谢明显受到抑制,三条胆碱相关代谢途径被截断,谷胱甘肽的消耗并且扰乱了核苷酸的合成。即使是低剂量给予MCLR(0.04mg/kg),虽在组织学上没有明显变化,但从代谢层面上说,已经能引起肝代谢的异常。
代谢组学的研究结果在功能水平上为MCLR肝毒机制研究提供了新的观点,同时也为以后关于微囊藻毒素威胁人类健康的评估及阐述打下了基础。(生物谷Bioon.com)
DOI: 10.1021/pr300685g
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Metabolic Response to Oral Microcystin-LR Exposure in the Rat by NMR-Based Metabonomic Study
Jun He †, Jun Chen *†, Laiyan Wu †‡, Guangyu Li †§, and Ping Xie *†
Microcystin-LR (MCLR), a potent hepatotoxin, is causing increased risks to public health. Although the liver is the main target organ of MCLR, the metabolic profiling of liver in response to MCLR in vivo remains unknown. Here, we comprehensively analyzed the metabolic change of liver and ileal flushes in rat orally gavaged with MCLR by 1H nuclear magnetic resonance (NMR). Quantification of hepatic MCLR and its glutathione and cysteine conjugates by liquid chromatography–electrospray ionization–mass spectrometry (LC-ESI-MS) was conducted. Metabonomics results revealed significant associations of MCLR-induced disruption of hepatic metabolisms with inhibition of nutrient absorption, as evidenced by a severe decrease of 12 amino acids in the liver and their corresponding elevation in ileal flushes. The hepatic metabolism signature of MCLR was characterized by significant inhibition of tyrosine anabolism and catabolism, three disrupted pathways of choline metabolism, glutathione exhaustion, and disturbed nucleotide synthesis. Notably, substantial alterations of hepatic metabolism were observable even at the low MCLR-treated group (0.04 mg/kg MCLR), although no apparent histological changes in liver were observed in the low- and medium-dosed groups. These observations offered novel insights into the microcystin hepatotoxic mechanism at a functional level, thereby facilitating further assessment and clarification of human health risk from MCs exposure.