CYP4F2 Is a Vitamin K₁ Oxidase: An Explanation for Altered Warfarin Dose in Carriers of the V433M Variant

Abstract

Genetic polymorphisms in VKORC1 and CYP2C9, genes controlling vitamin K 1 (VK1) epoxide reduction and (S)-warfarin metabolism, respectively, are major contributors to interindividual variability in warfarin dose. The V433M polymorphism (rs2108622) in CYP4F2 has also been associated with warfarin dose and speculatively linked to altered VK1 metabolism. Therefore, the purpose of the present study was to determine the role of CYP4F2 and the V433M polymorphism in the metabolism of VK1 by human liver. In vitro metabolic experiments with accompanying liquid chromatography-tandem mass spectrometry analysis demonstrated that recombinant CYP4F2 (Supersomes) and human liver microsomes supplemented with NADPH converted VK1 to a single product. A screen of all commercially available P450 Supersomes showed that only CYP4F2 was capable of metabolizing VK1 to this product.Steady-state kinetic analysis with recombinant CYP4F2 and with human liver microsomes revealed a substrate K m of 8 to 10 M. Moreover, anti-CYP4F2 IgG, as well as several CYP4F2-selective chemical inhibitors, substantially attenuated the microsomal reaction. Finally, human liver microsomes genotyped for rs2108622 demonstrated reduced vitamin K 1 oxidation and lower CYP4F2 protein concentrations in carriers of the 433M minor allele. These data demonstrate that CYP4F2 is a vitamin K 1 oxidase and that carriers of the CYP4F2 V433M allele have a reduced capacity to metabolize VK1, secondary to an rs2108622-dependent decrease in steady-state hepatic concentrations of the enzyme. Therefore, patients with the rs2108622 polymorphism are likely to have elevated hepatic levels of VK1, necessitating a higher warfarin dose to elicit the same anticoagulant response.

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].…”

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

“…9,19,20 CYP4F2 codes for a vitamin K 1 oxidase that causes a decrease in the metabolism of vitamin K 1 . 21 Several studies have shown that carriers of the derived T allele at the non-synonymous SNP rs2108622 require higher warfarin doses than subjects with the ancestral C allele. 22 Studies on European populations have indicated that CYP4F2 rs2108622 may account for an additional 1-7% of observed variation in warfarin dosing.…”

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…CYP4F2 is another genetic factor in warfarin processing. CYP4F2 contributes to vitamin K1 oxidation, and some variants could result in reduced enzyme activity [79] . An association between the CYP4F2 variant (rs2108622) and warfarin dose was subsequently confirmed in a meta-analysis involving more than 9000 participants from 30 studies [80] .…”