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Research ArticleArticle

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

Caroline H. Johnson, Jessica A. Bonzo, Jie Cheng, Kristopher W. Krausz, Dong Wook Kang, Hans Luecke, Jeffrey R. Idle and Frank J. Gonzalez
Drug Metabolism and Disposition February 2013, 41 (2) 406-413; DOI: https://doi.org/10.1124/dmd.112.048009
Caroline H. Johnson
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.H.J., J.A.B., J.C., K.W.K., F.J.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.W.K., H.L.); and Hepatology Research Group, Department of Clinical Research, University of Bern, Bern, Switzerland (J.R.I.)
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Jessica A. Bonzo
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.H.J., J.A.B., J.C., K.W.K., F.J.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.W.K., H.L.); and Hepatology Research Group, Department of Clinical Research, University of Bern, Bern, Switzerland (J.R.I.)
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Jie Cheng
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.H.J., J.A.B., J.C., K.W.K., F.J.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.W.K., H.L.); and Hepatology Research Group, Department of Clinical Research, University of Bern, Bern, Switzerland (J.R.I.)
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Kristopher W. Krausz
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.H.J., J.A.B., J.C., K.W.K., F.J.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.W.K., H.L.); and Hepatology Research Group, Department of Clinical Research, University of Bern, Bern, Switzerland (J.R.I.)
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Dong Wook Kang
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.H.J., J.A.B., J.C., K.W.K., F.J.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.W.K., H.L.); and Hepatology Research Group, Department of Clinical Research, University of Bern, Bern, Switzerland (J.R.I.)
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Hans Luecke
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.H.J., J.A.B., J.C., K.W.K., F.J.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.W.K., H.L.); and Hepatology Research Group, Department of Clinical Research, University of Bern, Bern, Switzerland (J.R.I.)
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Jeffrey R. Idle
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.H.J., J.A.B., J.C., K.W.K., F.J.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.W.K., H.L.); and Hepatology Research Group, Department of Clinical Research, University of Bern, Bern, Switzerland (J.R.I.)
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Frank J. Gonzalez
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (C.H.J., J.A.B., J.C., K.W.K., F.J.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.W.K., H.L.); and Hepatology Research Group, Department of Clinical Research, University of Bern, Bern, Switzerland (J.R.I.)
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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.

Footnotes

  • This work was supported by the Intramural Research Program of the National Institutes of Health National Cancer Institute [Grant 1ZIABC005562-24]; and an intramural award from the National Institutes of Health Office of Dietary Supplements (C.H.J.).

  • dx.doi.org/10.1124/dmd.112.048009.

  • Received July 20, 2012.
  • Accepted November 15, 2012.
  • U.S. Government work not protected by U.S. copyright
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleArticle

The Regulation of P450 Gene Expression by α-Tocopherol

Caroline H. Johnson, Jessica A. Bonzo, Jie Cheng, Kristopher W. Krausz, Dong Wook Kang, Hans Luecke, Jeffrey R. Idle and Frank J. Gonzalez
Drug Metabolism and Disposition February 1, 2013, 41 (2) 406-413; DOI: https://doi.org/10.1124/dmd.112.048009

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Research ArticleArticle

The Regulation of P450 Gene Expression by α-Tocopherol

Caroline H. Johnson, Jessica A. Bonzo, Jie Cheng, Kristopher W. Krausz, Dong Wook Kang, Hans Luecke, Jeffrey R. Idle and Frank J. Gonzalez
Drug Metabolism and Disposition February 1, 2013, 41 (2) 406-413; DOI: https://doi.org/10.1124/dmd.112.048009
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