title: Cytochrome P450-dependent metabolism of vitamin E isoforms is a critical determinant of their tissue concentrations in rats.
abstract: The aim of this study was to clarify the contribution of cytochrome P450 (CYP)-dependent metabolism of vitamin E isoforms to their tissue concentrations. We studied the effect of ketoconazole, a potent inhibitor of CYP-dependent vitamin E metabolism in cultured cells, on vitamin E concentration in rats. Vitamin E-deficient rats fed a vitamin E-free diet for 4 weeks were administered by oral gavage a vitamin E-free emulsion, an emulsion containing alpha-tocopherol, gamma-tocopherol or a tocotrienol mixture with or without ketoconazole. Alpha-tocopherol was detected in the serum and various tissues of the vitamin E-deficient rats, but gamma-tocopherol, alpha- and gamma-tocotrienol were not detected. Ketoconazole decreased urinary excretion of 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman after alpha-tocopherol or a tocotrienol mixture administration, and that of 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC) after gamma-tocopherol or a tocotrienol mixture administration. The gamma-tocopherol, alpha- and gamma-tocotrienol concentrations in the serum and various tissues at 24 h after their administration were elevated by ketoconazole, while the alpha-tocopherol concentration was not affected. The gamma-tocopherol or gamma-tocotrienol concentration in the jejunum at 3 h after each administration was also elevated by ketoconazole. In addition, significant amount of gamma-CEHC was in the jejunum at 3 h after gamma-tocopherol or gamma-tocotrienol administration, and ketoconazole inhibited gamma-tocopherol metabolism to gamma-CEHC in the jejunum. These results showed that CYP-dependent metabolism of gamma-tocopherol and tocotrienol is a critical determinant of their concentrations in the serum and tissues. The data also suggest that some amount of dietary vitamin E isoform is metabolized by a CYP-mediated pathway in the intestine during absorption.
authors.affiliation: Department of Nutritional Sciences, Nagoya University of Arts and Sciences, 57 Takenoyama, Iwasaki, Nissin 470-0196, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Abe
authors.forename: Tomono
authors.initials: T
authors.lastname: Uchida
authors.forename: Moeka
authors.initials: M
authors.lastname: Ohta
authors.forename: Tomio
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Kanae
authors.initials: K
authors.lastname: Yamashita
authors.forename: Saiko
authors.initials: S
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D024505:Tocopherols / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D014811:Vitamin E Deficiency / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C017763:alpha-tocopherol transfer protein; D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; D024505:Tocopherols; D007654:Ketoconazole