title: Vitamin E supplementation and hepatic drug metabolism in humans.
abstract: Meta-analyses studies suggest that high-dose vitamin E may be associated with increased mortality in some populations. Vitamin E may increase the production of CYP3A4 in the liver, and this could lead to an increase in drug metabolism, potentially lowering the efficacy of therapeutic drugs. We hypothesized that upregulation of CYP3A4 by alpha-tocopherol (alpha-TOH) would decrease the plasma concentration of the CYP3A4 substrate midazolam. Baseline metabolism of midazolam (1 mg intravenously) was determined in 12 healthy subjects before randomization into 2 groups of 6 to receive either RRR-alpha-TOH (750 IU/d) or placebo for 3 weeks. At completion, subjects were given an additional 1 mg intravenous bolus of midazolam. Plasma midazolam, 1-hydroxy-midazolam, and urinary alpha-TOH metabolite excretion were measured using gas chromatography mass spectrometry. Serum alpha-TOH was measured using high performance liquid chromatography with electrochemical detection. Serum alpha-TOH increased by 100% (P = 0.002) and urinary alpha-TOH metabolite excretion increased 20-fold in the treatment group versus placebo (P = 0.001). There was no effect on the area under time curve of midazolam in subjects taking alpha-TOH compared with placebo. These findings do not support the hypothesis that alpha-TOH supplementation interferes with hepatic CYP3A4-mediated drug metabolism.
authors.affiliation: Department of Core Clinical Pathology and Biochemistry, PathWest Laboratory Medicine, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia. Michael.W.Clarke@health.wa.gov.au
authors.forename: Michael W
authors.initials: MW
authors.lastname: Clarke
authors.forename: John R
authors.initials: JR
authors.lastname: Burnett
authors.forename: Jason H Y
authors.initials: JH
authors.lastname: Wu
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Hodgson
authors.forename: Thomas
authors.initials: T
authors.lastname: Ledowski
authors.forename: Ian B
authors.initials: IB
authors.lastname: Puddey
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation / Q000187:drug effects; D002839:Chromans / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D019587:Dietary Supplements; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011422:Propionates / Q000652:urine; D014810:Vitamin E / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D024504:gamma-Tocopherol / Q000097:blood / Q000378:metabolism
chemical_list: D002839:Chromans; D004364:Pharmaceutical Preparations; D011422:Propionates; D014810:Vitamin E; C107690:2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman; C084852:2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman; D024504:gamma-Tocopherol; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D024502:alpha-Tocopherol; D008874:Midazolam