title: Cytochrome P450 regulation by α-tocopherol in Pxr-null and PXR-humanized mice.
abstract: The pregnane X receptor (PXR) has been postulated to play a role in the metabolism of α-tocopherol owing to the up-regulation of hepatic cytochrome P450 (P450) 3A in human cell lines and murine models after α-tocopherol treatment. However, in vivo studies confirming the role of PXR in α-tocopherol metabolism in humans presents significant difficulties and has not been performed. PXR-humanized (hPXR), wild-type, and Pxr-null mouse models were used to determine whether α-tocopherol metabolism is influenced by species-specific differences in PXR function in vivo. No significant difference in the concentration of the major α-tocopherol metabolites was observed among the hPXR, wild-type, and Pxr-null mice through mass spectrometry-based metabolomics. Gene expression analysis revealed significantly increased expression of Cyp3a11 as well as several other P450s only in wild-type mice, suggesting species-specificity for α-tocopherol activation of PXR. Luciferase reporter assay confirmed activation of mouse PXR by α-tocopherol. Analysis of the Cyp2c family of genes revealed increased expression of Cyp2c29, Cyp2c37, and Cyp2c55 in wild-type, hPXR, and Pxr-null mice, which suggests PXR-independent induction of Cyp2c gene expression. This study revealed that α-tocopherol is a partial agonist of PXR and that PXR is necessary for Cyp3a induction by α-tocopherol. The implications of a novel role for α-tocopherol in Cyp2c gene regulation are also discussed.
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Johnson
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Bonzo
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Kang
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; D015415:Biomarkers / Q000652:urine; D001711:Biotransformation; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D054333:Drug Partial Agonism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D056945:Hep G2 Cells; D006801:Humans; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000172:deficiency / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013997:Time Factors; D014162:Transfection; D024502:alpha-Tocopherol / Q000494:pharmacology* / Q000652:urine
chemical_list: D015415:Biomarkers; D007527:Isoenzymes; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; D024502:alpha-Tocopherol