Metabolomics reveals a novel vitamin E metabolite and attenuated vitamin E metabolism upon PXR activation.
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.
Cho
Joo-Youn
JY
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.
Kang
Dong Wook
DW
Ma
Xiaochao
X
Ahn
Sung-Hoon
SH
Krausz
Kristopher W
KW
Luecke
Hans
H
Idle
Jeffrey R
JR
Gonzalez
Frank J
FJ
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*
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