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Disruption of mouse cytochrome p450 4f14 (Cyp4f14 gene) causes severe perturbations in vitamin E metabolism.

Vitamin E is a family of naturally occurring and structurally related lipophilic antioxidants, one of which, α-tocopherol (α-TOH), selectively accumulates in vertebrate tissues. The ω-hydroxylase cytochrome P450-4F2 (CYP4F2) is the only human enzyme shown to metabolize vitamin E. Using cDNA cloning, cell culture expression, and activity assays, we identified Cyp4f14 as a functional murine ortholog of CYP4F2. We then investigated the effect of Cyp4f14 deletion on vitamin E metabolism and status in vivo. Cyp4f14-null mice exhibited substrate-specific reductions in liver microsomal vitamin E-ω-hydroxylase activity ranging from 93% (γ-TOH) to 48% (γ-tocotrienol). In vivo data obtained from metabolic cage studies showed whole-body reductions in metabolism of γ-TOH of 90% and of 68% for δ- and α-TOH. This metabolic deficit in Cyp4f14(-/-) mice was partially offset by increased fecal excretion of nonmetabolized tocopherols and of novel ω-1- and ω-2-hydroxytocopherols. 12'-OH-γ-TOH represented 41% of whole-body production of γ-TOH metabolites in Cyp4f14(-/-) mice fed a soybean oil diet. Despite these counterbalancing mechanisms, Cyp4f14-null mice fed this diet for 6 weeks hyper-accumulated γ-TOH (2-fold increase over wild-type littermates) in all tissues and appeared normal. We conclude that CYP4F14 is the major but not the only vitamin E-ω-hydroxylase in mice. Its disruption significantly impairs whole-body vitamin E metabolism and alters the widely conserved phenotype of preferential tissue deposition of α-TOH. This model animal and its derivatives will be valuable in determining the biological actions of specific tocopherols and tocotrienols in vivo.

Pubmed ID: 22665481


  • Bardowell SA
  • Duan F
  • Manor D
  • Swanson JE
  • Parker RS


The Journal of biological chemistry

Publication Data

July 27, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK007158
  • Agency: NIDDK NIH HHS, Id: DK067494
  • Agency: NINR NIH HHS, Id: T32 NR007091

Mesh Terms

  • Animals
  • Cytochrome P-450 Enzyme System
  • Feces
  • Female
  • Gene Expression
  • Gene Knockout Techniques
  • Homologous Recombination
  • Hydroxylation
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microsomes, Liver
  • Mixed Function Oxygenases
  • Tocopherols