title: Alpha-tocopherol modulates Cyp3a expression, increases gamma-CEHC production, and limits tissue gamma-tocopherol accumulation in mice fed high gamma-tocopherol diets.
abstract: Although all forms of vitamin E are absorbed, the liver preferentially secretes alpha-, but not gamma-tocopherol, into plasma. Liver alpha-tocopherol secretion is under the control of the alpha-tocopherol transfer protein (TTP). Therefore, to assess gamma-tocopherol bioactivities Ttpa-/-, +/- and +/+ mice were fed for 5 weeks diets containing gamma-tocopherol 550 (gamma-T550), gamma-tocopherol 60 (gamma-T60) mg/kg that also contained trace amounts of alpha-tocopherol, a vitamin E-deficient diet, or a control diet. Plasma and tissues from mice fed gamma-T550 diets were found to contain similar gamma- and alpha-tocopherol concentrations despite the high dietary gamma-tocopherol content; nervous tissues contained almost no gamma-tocopherol. Liver vitamin E metabolites (carboxyethyl hydroxychromans, CEHCs) were also measured. In mice with widely ranging liver alpha- (from 0.7 to 16 nmol/g) and gamma-tocopherol concentrations (0 to 13 nmol/g), hepatic alpha-CEHC was undetectable, but gamma-CEHC concentrations (0.1 to 0.8 nmol/g) were correlated with both alpha- and gamma-tocopherol concentrations (P < 0.004). Hepatic cytochrome P450s (CYPs) involved in vitamin E metabolism, Cyp4f and Cyp3a, were also measured. There were no variations in Cyp4f protein expression as related to diet or mouse genotype. However, Cyp3a was correlated (P < 0.0001) with liver alpha-, but not gamma-tocopherol concentrations. These data support the hypothesis that alpha-tocopherol modulates xenobiotic metabolism by increasing Cyp3a expression, gamma-CEHC formation, and the excretion of both gamma-tocopherol and gamma-CEHC.
authors.affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512, USA.
authors.forename: Maret G
authors.initials: MG
authors.lastname: Traber
authors.forename: Lisbeth K
authors.initials: LK
authors.lastname: Siddens
authors.forename: Scott W
authors.initials: SW
authors.lastname: Leonard
authors.forename: Bettina
authors.initials: B
authors.lastname: Schock
authors.forename: Kishorchandra
authors.initials: K
authors.lastname: Gohil
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Krueger
authors.forename: Carroll E
authors.initials: CE
authors.lastname: Cross
authors.forename: David E
authors.initials: DE
authors.lastname: Williams
mesh_terms: D000821:Animal Feed; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002839:Chromans / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D010100:Oxygen / Q000378:metabolism; D011422:Propionates / Q000378:metabolism*; D013997:Time Factors; D014810:Vitamin E / Q000378:metabolism; D015262:Xenobiotics; D024502:alpha-Tocopherol / Q000378:metabolism / Q000494:pharmacology*; D024504:gamma-Tocopherol / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D002839:Chromans; D011422:Propionates; D015262:Xenobiotics; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; C107690:2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman; D024504:gamma-Tocopherol; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D024502:alpha-Tocopherol; D010100:Oxygen