Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation

Cho, Joo-Youn; Kang, Dong Wook; Ma, Xiaochao; Ahn, Sung-Hoon; Krausz, Kristopher W; Luecke, Hans; Idle, Jeffrey R; Gonzalez, Frank J (2009). Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation. Journal of lipid research, 50(5), pp. 924-37. Bethesda, Md.: American Society for Biochemistry and Molecular Biology ASBMB 10.1194/jlr.M800647-JLR200

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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 16alpha-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. Activation of PXR results in attenuated levels of the two vitamin E conjugates that may be useful as biomarkers of PXR activation.

Item Type:

Journal Article (Original Article)

ISSN:

0022-2275

Publisher:

American Society for Biochemistry and Molecular Biology ASBMB

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:10

Last Modified:

04 May 2014 23:22

Publisher DOI:

10.1194/jlr.M800647-JLR200

PubMed ID:

19141872

Web of Science ID:

000264969300017

URI:

https://boris.unibe.ch/id/eprint/30848 (FactScience: 195183)

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