Cytochrome P450 Regulation by -Tocopherol in Pxr-Null and PXR-Humanized Mice

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.

The Good Society. A Comparative Study of Denmark and Switzerland

Denmark and Switzerland are small and successful countries with exceptionally content populations. However, they have very different political institutions and economic models. They have followed the general tendency in the West toward economic convergence, but both countries have managed to stay on top. They both have a strong liberal tradition, but otherwise their economic strategies are a welfare state model for Denmark and a safe haven model for Switzerland. The Danish welfare state is tax-based, while the expenditures for social welfare are insurance-based in Switzerland. The political institutions are a multiparty unicameral system in Denmark, and a permanent coalition system with many referenda and strong local government in Switzerland. Both approaches have managed to ensure smoothly working political power-sharing and economic systems that allocate resources in a fairly efficient way. To date, they have also managed to adapt the economies to changes in the external environment with a combination of stability and flexibility.