Common Variants of Cytochrome P450 4F2 Exhibit Altered Vitamin E-Ω-Hydroxylase Specific Activity

Abstract

Human cytochrome P450 4F2 (CYP4F2) catalyzes the ω-hydroxylation of the side chain of tocopherols (TOH) and tocotrienols (T3), the first step in their catabolism to polar metabolites excreted in urine. CYP4F2, in conjunction with α-TOH transfer protein, results in the conserved phenotype of selective retention of α-TOH. The purpose of this work was to determine the functional consequences of 2 common genetic variants in the human CYP4F2 gene on vitamin E-ω-hydroxylase specific activity using the 6 major dietary TOH and T3 as substrate. CYP4F2-mediated ω-hydroxylase specific activity was measured in microsomal preparations from insect cells that express wild-type or polymorphic variants of the human CYP4F2 protein. The W12G variant exhibited a greater enzyme specific activity (pmol product · min(-1) · pmol CYP4F2(-1)) compared with wild-type enzyme for both TOH and T3, 230-275% of wild-type toward α, γ, and δ-TOH and 350% of wild-type toward α, γ, and δ-T3. In contrast, the V433M variant had lower enzyme specific activity toward TOH (42-66% of wild type) but was without a significant effect on the metabolism of T3. Because CYP4F2 is the only enzyme currently shown to metabolize vitamin E in humans, the observed substrate-dependent alterations in enzyme activity associated with these genetic variants may result in alterations in vitamin E status in individuals carrying these mutations and constitute a source of variability in vitamin E status.

Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?

“…Consistent with this finding is the observation that carriers of the 433Met allele have decreased capacity to metabolize vitamin K [87], and tocopherol [88]. At variance with the results of these studies, the CYP4F2 433Met, but not the 433Val allele, increases the urinary excretion of 20-HETE in a mixed sample of hypertensive and normotensive subjects, suggesting an increased, rather than a decreased, metabolizing capacity [75].…”

The Revised Human Liver Cytochrome P450 “Pie”: Absolute Protein Quantification of CYP4F and CYP3A Enzymes Using Targeted Quantitative Proteomics

“…The V433M variant has been implicated in interindividual variability associated with warfarin maintenance dose due to effects on vitamin K 1 metabolism (McDonald et al, 2009). Both variants exhibit altered vitamin E metabolism (Bardowell et al, 2010). Interestingly, the variants have been linked to both increased and decreased catalytic activity, with the effects appearing to be substrate dependent.…”

“…Two functional variants, W12G and V433M, were identified recently (Bardowell et al, 2010). The V433M variant has been implicated in interindividual variability associated with warfarin maintenance dose due to effects on vitamin K 1 metabolism (McDonald et al, 2009).…”

Complexity of vitamin E metabolism

“…Major et al [218] identified a new SNP in the CYP4F2 gene (rs2108622) which encodes the vitamin E ω-hydroxylase. The physiological relevance of this SNP and the SNP rs3093105 has been characterized by Bardowell et al [225] . The CYP4F2 W12G variant leads to a 2.3 to 2.8-fold increased specific enzyme activity for both TOHs and T3s, whereas the CYP4F2 V433M (rs2108622) variant causes reduced enzyme activity for TOHs, without affecting the activity for T3s.…”