TY - JOUR T1 - Cytochrome P450 Regulation by <em>α</em>-Tocopherol in <em>Pxr</em>-Null and <em>PXR</em>-Humanized Mice JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 406 LP - 413 DO - 10.1124/dmd.112.048009 VL - 41 IS - 2 AU - Caroline H. Johnson AU - Jessica A. Bonzo AU - Jie Cheng AU - Kristopher W. Krausz AU - Dong Wook Kang AU - Hans Luecke AU - Jeffrey R. Idle AU - Frank J. Gonzalez Y1 - 2013/02/01 UR - http://dmd.aspetjournals.org/content/41/2/406.abstract N2 - 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. ER -