Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption
Differential metabolomics reveals ophthalmic acid as an oxidative stress biomarker indicating hepatic glutathione consumption
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DOI：
10.1074/jbc.m601876200
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发表时间：
2006-06-16
影响因子：
4.8
通讯作者：
Tomita, Masaru
中科院分区：
文献类型：
--
作者：
Soga, Tomoyoshi;Baran, Richard;Tomita, Masaru
代谢组学是一种新兴的工具，可用于深入了解细胞和生理反应。在这里，我们提出了一种基于毛细管电泳飞行时间质谱的代谢组差异显示方法来分析对乙酰氨基酚诱导的肝毒性后的肝脏代谢物。我们在小鼠肝脏提取物中检测到1，859个峰，并强调了代谢物水平的多种变化，包括邻苯二甲酸酯生物合成途径的激活。我们证实了邻苯二甲酸酯是由2-氨基丁酸通过与γ-谷氨酰半胱氨酸和谷胱甘肽合成酶的连续反应合成的。小鼠血清和肝脏提取物中酞酸盐水平的变化密切相关，酞酸盐水平与谷胱甘肽消耗量显著相关。总的来说，我们的结果提供了对乙酰氨基酚治疗后肝脏代谢物变化的广泛情况。此外，我们特别发现血清酞酸盐是肝脏GSH耗竭的敏感指标，可能是氧化应激的新生物标志物。因此，我们的方法可以精确定位特定的代谢物变化，并提供大规模的代谢途径扰动的见解，并作为一个强大的新工具，发现低分子量生物标志物。
Metabolomics is an emerging tool that can be used to gain insights into cellular and physiological responses. Here we present a metabolome differential display method based on capillary electrophoresis time-of-flight mass spectrometry to profile liver metabolites following acetaminophen-induced hepatotoxicity. We globally detected 1,859 peaks in mouse liver extracts and highlighted multiple changes in metabolite levels, including an activation of the ophthalmate biosynthesis pathway. We confirmed that ophthalmate was synthesized from 2-aminobutyrate through consecutive reactions with gamma-glutamylcysteine and glutathione synthetase. Changes in ophthalmate level in mouse serum and liver extracts were closely correlated and ophthalmate levels increased significantly in conjunction with glutathione consumption. Overall, our results provide a broad picture of hepatic metabolite changes following acetaminophen treatment. In addition, we specifically found that serum ophthalmate is a sensitive indicator of hepatic GSH depletion, and may be a new biomarker for oxidative stress. Our method can thus pinpoint specific metabolite changes and provide insights into the perturbation of metabolic pathways on a large scale and serve as a powerful new tool for discovering low molecular weight biomarkers.