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

TitleAlpha-tocopherol modulates genes involved in hepatic xenobiotic pathways in mice.
Publication TypeJournal Article
Year of Publication2009
AuthorsMustacich DJ, Gohil K, Bruno RS, Yan M, Leonard SW, Ho E, Cross CE, Traber MG
JournalThe Journal of nutritional biochemistry
Volume20
Issue6
Pagination469-76
Date Published2009 Jun
ISSN1873-4847
Keywordsalpha-Tocopherol, Animals, Antioxidants, Cytochrome P-450 Enzyme System, Female, Gene Expression Regulation, Liver, Mice, Mice, Inbred C57BL, Xenobiotics
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 alpha-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-alpha-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 alpha-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 alpha-tocopherol simultaneously coordinated Phase I, II and III gene expression. These data demonstrate that increased hepatic alpha-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.

Alternate JournalJ. Nutr. Biochem.