title: Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation.
abstract: 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.
authors.affiliation: 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, USA.
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Hans
authors.initials: H
authors.lastname: Luecke
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D002839:Chromans / Q000737:chemistry / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010084:Oxidation-Reduction; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000737:chemistry / Q000378:metabolism; D011422:Propionates / Q000737:chemistry / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D014556:Urine / Q000737:chemistry; D014810:Vitamin E / Q000378:metabolism*; D014815:Vitamins / Q000378:metabolism*
chemical_list: D002839:Chromans; D000077297:Pregnane X Receptor; D011422:Propionates; D011987:Receptors, Steroid; D014815:Vitamins; C483420:carboxyethyl-hydroxychroman; D014810:Vitamin E; D011285:Pregnenolone Carbonitrile; C107690:2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman