Two common variants in the human CYP4F2 gene result in substantial alterations in vitamin E‐ω‐hydroxylase specific activity

Abstract

Human cytochrome P450 CYP4F2 catalyzes the ω‐hydroxylation of the side chain of tocopherols (TOHs) and tocotrienols (T3s), the first step in their catabolism to polar metabolites which are excreted in urine. CYP4F2 exhibits strong substrate preference for vitamin E forms other than α‐TOH, and in conjunction with α‐TOH transfer protein results in the conserved phenotype of selective accumulation of α‐TOH. The purpose of this work was to determine the functional effect of two genetic variants in the human CYP4F2 gene on TOH‐ω‐hydroxylase specific activity. CYP4F2 TOH‐ω‐hydroxylase specific activity was measured in microsomal preparations from insect cells infected with baculovirus containing human wild‐type or polymorphic CYP4F2 DNA expressing the respective enzyme variants. The W12G variant exhibited a 130–175% increase in enzyme activity (pmol product/min/pmol CYP4F2) toward α, γ, δ‐TOH and a 250–253% increase in enzyme activity toward α, γ, δ‐T3. The V433M variant exhibited a 36–58% decrease in enzyme activity towards TOHs and a non‐significant decrease in activity toward T3s. Since CYP4F2 is the only known enzyme to mediate vitamin E metabolism in humans, the observed substantial enhancement and impairment in enzyme activity due to these two genetic variants may result in alterations in vitamin E status in individuals carrying these mutations. Supported in part by NIH grant DK067494.Grant Funding Source: NIH grant DK067494