Disruption of Mouse Cytochrome P450 4f14 (Cyp4f14 Gene) Causes Severe Perturbations in Vitamin E Metabolism
| Autor: | Sabrina A. Bardowell, Joy E. Swanson, Faping Duan, Robert S. Parker, Danny Manor |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Vitamin medicine.medical_treatment Gene Expression Tocopherols Hydroxylation Biochemistry Mixed Function Oxygenases Feces Gene Knockout Techniques Mice chemistry.chemical_compound Cytochrome P-450 Enzyme System In vivo medicine Animals Cytochrome P450 Family 4 Tocopherol Homologous Recombination Molecular Biology Mice Knockout chemistry.chemical_classification biology Vitamin E Cytochrome P450 Cell Biology Metabolism Molecular biology Mice Inbred C57BL Enzyme Liver chemistry Microsomes Liver biology.protein Female |
| Zdroj: | Journal of Biological Chemistry. 287:26077-26086 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.373597 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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