Alpha-tocopherol modulates genes involved in hepatic xenobiotic pathways in mice

Debbie J. Mustacich, Kishorchandra Gohil, Richard S. Bruno, Michelle Yan, Scott W. Leonard, Emily Ho, Carroll E Cross, Maret G. Traber

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Hepatic proteins involved in xenobiotic pathways (Phases I, II and III) are responsible for the metabolism and disposition of endogenous and exogenous compounds including dietary phytochemicals. To test the hypothesis that elevated α-tocopherol intakes alter gene expression of hepatic xenobiotic pathways, mice were fed diets supplemented with either 1000 IU (+E) or 35 IU (E) all-rac-α-tocopheryl acetate for 4 months; liver RNA was isolated, and gene expression was determined using both whole genome microarray and real-time quantitative polymerase chain reaction analyses. Hepatic α-tocopherol (173±18 vs. 21±1 nmol/g, mean±S.E.) and its metabolite (2,5,7,8-tetramethyl-2-(2′-carboxyethyl)-6-hydroxychroman, 0.232±0.046 vs. 0.031±0.019 nmol/g) concentrations were approximately eightfold higher following the +E dietary treatment. In +E relative to E mice, gene expression of Phase I enzymes, P450 oxidoreductase and cytochrome P450 3a11 increased 1.6- and 4.0-fold, respectively; two Phase II genes, sulfotransferase 2a and glutathione S-transferase mu 3, increased 10.8- and 1.9-fold respectively, and a Phase III biliary transporter, Abcb1a, doubled. Thus, consumption of high-level dietary α-tocopherol simultaneously coordinated Phase I, II and III gene expression. These data demonstrate that increased hepatic α-tocopherol modulates its own concentrations through increasing xenobiotic metabolism, a process that may alter metabolism of other foreign compounds, such as therapeutic drugs and phytochemicals, in humans.

Original languageEnglish (US)
Pages (from-to)469-476
Number of pages8
JournalJournal of Nutritional Biochemistry
Volume20
Issue number6
DOIs
StatePublished - Jun 2009

Keywords

  • α-tocopherol
  • Cytochrome P450
  • Glutathione S-transferase
  • MDR1
  • Sulfotransferase
  • Xenobiotic metabolism

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

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