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

ABSTRACT: Vitamin E is a family of naturally occurring and structurally related lipophilic antioxidants, one of which, ?-tocopherol (?-TOH), selectively accumulates in vertebrate tissues. The ?-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-?-hydroxylase activity ranging from 93% (?-TOH) to 48% (?-tocotrienol). In vivo data obtained from metabolic cage studies showed whole-body reductions in metabolism of ?-TOH of 90% and of 68% for ?- and ?-TOH. This metabolic deficit in Cyp4f14(-/-) mice was partially offset by increased fecal excretion of nonmetabolized tocopherols and of novel ?-1- and ?-2-hydroxytocopherols. 12'-OH-?-TOH represented 41% of whole-body production of ?-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 ?-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-?-hydroxylase in mice. Its disruption significantly impairs whole-body vitamin E metabolism and alters the widely conserved phenotype of preferential tissue deposition of ?-TOH. This model animal and its derivatives will be valuable in determining the biological actions of specific tocopherols and tocotrienols in vivo.

SUBMITTER: Bardowell SA 

PROVIDER: S-EPMC3406691 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature