Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation
Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation
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DOI：
10.1194/jlr.m800647-jlr200
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发表时间：
2009-05-01
影响因子：
6.5
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
--
作者：
Cho, Joo-Youn;Kang, Dong Wook;Gonzalez, Frank J.
孕烷X受体（Pregnane X receptor，PXR）是一种重要的核受体异种感受器，参与外源性物质和内源性物质代谢的代谢酶和转运蛋白的表达调控。在这项研究中，超高效液相色谱法（UPLC）与电喷雾飞行时间质谱法（TOFMS）相结合，揭示了用小鼠PXR激活剂双烯醇酮16 α-甲腈（PCN）治疗的PXR无效和野生型小鼠的尿代谢组的改变。多变量数据分析显示，PCN显著减弱了野生型但非Pxr基因敲除小鼠的尿维生素E代谢产物α-羧乙基羟基苯并二氢吡喃（CEHC）葡萄糖醛酸苷以及一种新型代谢产物。β-葡萄糖醛酸酶和β-葡萄糖苷酶的解结合实验表明，新的尿液代谢产物为γ-CEHC β-D-葡萄糖苷（Glc）。通过化学合成和比较尿代谢产物与真实标准品的串联质量裂解，确认γ-CEHC Glc的同一性。较低的尿CEHC可能是由于PXR介导的参与支链脂肪酸（BCFA）过氧化物酶体β氧化的肝固醇载体蛋白2的抑制。使用代谢组学分析和转基因小鼠模型的组合，该研究揭示了PXR的激活导致两种维生素E缀合物的水平降低，并鉴定了一种新型维生素E代谢物γ-CEHC Glc。jlr PXR的激活导致两种维生素E缀合物的水平减弱，这可能可用作PXR激活的生物标志物。- Cho，J-Y.，D. W.康，X.妈S-H Ahn，K. W. Krausz，H. Luecke，J. R. Idle和F. J·冈萨雷斯代谢组学揭示了一种新的维生素E代谢物和减弱的维生素E代谢后PXR激活。J. Lipid Res. 2009. 50：924-937。
Pregnane X receptor (PXR) is an important nuclear receptor xenosensor that regulates the expression of metabolic enzymes and transporters involved in the metabolism of xenobiotics and endobiotics. In this study, ultra-performance liquid chromatography (UPLC) coupled with electrospray time-of-flight mass spectrometry (TOFMS), revealed altered urinary metabolomes in both Pxr-null and wild-type mice treated with the mouse PXR activator pregnenolone 16 alpha-carbonitrile (PCN). Multivariate data analysis revealed that PCN significantly attenuated the urinary vitamin E metabolite alpha-carboxyethyl hydroxychroman (CEHC) glucuronide together with a novel metabolite in wild-type but not Pxr-null mice. Deconjugation experiments with beta-glucuronidase and beta-glucosidase suggested that the novel urinary metabolite was gamma-CEHC beta-D-glucoside (Glc). The identity of gamma-CEHC Glc was confirmed by chemical synthesis and by comparing tandem mass fragmentation of the urinary metabolite with the authentic standard. The lower urinary CEHC was likely due to PXR-mediated repression of hepatic sterol carrier protein 2 involved in peroxisomal beta-oxidation of branched-chain fatty acids (BCFA). Using a combination of metabolomic analysis and a genetically modified mouse model, this study revealed that activation of PXR results in attenuated levels of the two vitamin E conjugates, and identification of a novel vitamin E metabolite, gamma-CEHC Glc. jlr Activation of PXR results in attenuated levels of the two vitamin E conjugates that may be useful as biomarkers of PXR activation.-Cho, J-Y., D. W. Kang, X. Ma, S-H. Ahn, K. W. Krausz, H. Luecke, J. R. Idle, and F. J. Gonzalez. Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation. J. Lipid Res. 2009. 50: 924-937.