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Originally published In Press as doi:10.1194/jlr.M800647-JLR200 on January 20, 2009 Originally published In Press as doi:10.1194/jlr.M800647-JLR200 on January 13, 2009

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Journal of Lipid Research, Vol. 50, 924-937, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Joo-Youn Cho*, Dong Wook Kang{dagger}, Xiaochao Ma*, Sung-Hoon Ahn*, Kristopher W. Krausz*, Hans Luecke{dagger}, Jeffrey R. Idle*,§ and Frank J. Gonzalez1,*

* Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institute of Diabetics and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
{dagger} Laboratory of Bioorganic Chemistry, National Institute of Diabetics and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892
§ Institute of Pharmacology, 1st Faculty of Medicine, Charles University, 12800 Praha 2, Czech Republic

Published, JLR Papers in Press, January 20, 2009.

1 To whom correspondence should be addressed. e-mail: fjgonz{at}helix.nih.gov

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 β-glucuronidase and β-glucosidase suggested that the novel urinary metabolite was {gamma}-CEHC β-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 β-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.

Supplementary key words pregnane X receptor • pregnenolone 16{alpha}-carbonitrile • carboxyethyl hydroxychroman • metabolomics • {gamma}-CEHC glucoside • sterol carrier protein 2 • peroxisomal beta-oxidation

Abbreviations: AUGlc, 3-Acetylumbelliferyl β-D-glucoside; BCFA, branched-chain fatty acids; CAR, constitutive androstane receptor; CEHC, carboxyethyl hydroxychroman; Fox, forkhead transcription factor; Glc, glucoside; Glu, glucuronide; hPXR, PXR-humanized; MS/MS, tandem mass spectrometry; OPLS, orthogonal partial least squares; PCA, principal components analysis; PCN, pregnenolone 16{alpha}-carbonitrile; PLS-DA, partial least-squares discriminant analysis; PPAR{alpha}, peroxisome proliferators activated receptor {alpha}; PPTGlu, phenolphthalein β-D-glucuronide; PXR, pregnane X receptor; qPCR, quantitative real-time polymerase chain reaction; RIF, rifampicin; SCP-x, sterol carrier protein-x; TOFMS, time-of-flight mass spectrometry; UGT, UDP-glucuronosyltransferase; UPLC, ultra-performance liquid chromatography


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J. Y. Cho, T. Matsubara, D. W. Kang, S. H. Ahn, K. W. Krausz, J. R. Idle, H. Luecke, and F. J. Gonzalez
Urinary metabolomics in Fxr-null mice reveals activated adaptive metabolic pathways upon bile acid challenge
J. Lipid Res., May 1, 2010; 51(5): 1063 - 1074.
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