Knockout of CYP4f14 causes severe perturbations in vitamin E metabolism and results in tissue accumulation of vitamin E in the mouse

Vitamin E is a family of eight naturally‐occurring lipophilic antioxidants, of which one, α‐tocopherol (TOH), selectively accumulates in vertebrate tissues. Cytochrome P450‐4F2 (CYP4F2), an ω‐hydroxylase, is the only enzyme shown to metabolize vitamin E in humans. We identified CYP4f14 as a functional murine ortholog of CYP4F2, via cloning, cell culture expression and activity assays. We then investigated the effect of its deletion on vitamin E metabolism and status in vivo. Cyp4f14‐null mice exhibited substrate‐specific reductions in microsomal vitamin E‐ω‐hydroxylase capacity 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 by 90% and 68% for δ‐ and α‐TOH. While fecal excretion of TOHs increased in null mice, partially compensating for the metabolic deficit, Cyp4f14‐null mice fed a soybean oil diet for 6 weeks hyper‐accumulated γ‐TOH in tissues but were otherwise apparently 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 selective tissue deposition of α‐TOH. This model and its derivatives should prove valuable in determining the in vivo biological potential of specific TOHs and tocotrienols. Funded by NIH DK067494. Grant Funding Source : NIH DK067494