Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy

Hirai, Keita; Yamada, Yuto; Hayashi, Hideki; Tanaka, Masaki; Izumiya, Kohei; Suzuki, Masayuki; Yoshizawa, Misa; Moriwaki, Hisataka; Akimoto, Takehide; Tsuji, Daiki; Inoue, Ken‐ichiro; Itoh, Ken

doi:10.1016/j.thromres.2015.02.019

Cited by 16 publications

(10 citation statements)

References 38 publications

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“…The CYP4F2*3 allele results in a lower hepatic concentration of the variant enzyme, relative to wild-type, which is the basis for its reduced catalytic function [27]. Two other recent genetic studies help substantiate a role for CYP4F2 in vitamin K disposition in vivo [28, 29]. C YP4F2*3 genotype also influences α-tocopherol (vitamin E) levels in plasma [30].…”

Section: Discussionmentioning

confidence: 99%

Dietary and genetic influences on hemostasis in a Yup’ik Alaska Native population

Reyes

Boyer

et al. 2017

PLoS ONE

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Fish and marine animals are important components of the subsistence diet of Alaska Native people, resulting in a high ω3 PUFA intake. The historical record for circumpolar populations highlights a tendency for facile bleeding, possibly related to ω3 PUFA effects on platelet activation and/or vitamin K-dependent clotting factors. To evaluate these two scenarios in Yup’ik people of southwestern Alaska, we examined the association between dietary ω3 PUFA intake and activities of clotting factor II, V, fibrinogen, PT, INR, PTT, and sP-selectin in 733 study participants, using the nitrogen isotope ratio of red blood cells as a biomarker of ω3 PUFA consumption. sP-selectin alone correlated strongly and inversely with ω3 PUFA consumption. Approximately 36% of study participants exhibited PIVKA-II values above the threshold of 2 ng/ml, indicative of low vitamin K status. To assess genetic influences on vitamin K status, study participants were genotyped for common vitamin K cycle polymorphisms in VKORC1, GGCX and CYP4F2. Only CYP4F2*3 associated significantly with vitamin K status, for both acute (plasma vitamin K) and long-term (PIVKA-II) measures. These findings suggest: (i) a primary association of ω3 PUFAs on platelet activation, as opposed to vitamin K-dependent clotting factor activity, (ii) that reduced CYP4F2 enzyme activity associates with vitamin K status. We conclude that high ω3 PUFA intake promotes an anti-platelet effect and speculate that the high frequency of the CYP4F2*3 allele in Yup’ik people (~45%) evolved in response to a need to conserve body stores of vitamin K due to environmental limitations on its availability.

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Section: Discussionmentioning

confidence: 99%

Dietary and genetic influences on hemostasis in a Yup’ik Alaska Native population

Reyes

Boyer

et al. 2017

PLoS ONE

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“…Although breast milk is the preferred dietary mainstay for all neonates, vitamin K levels in breast milk are significantly lower than those in formula milk (median 2.5 mg/L vs. 24-175 mg/L, respectively) [10,11], and there are substantial differences in these levels among individuals [8] (Table 1). Carriers of the vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles are at risk of developing vitamin K deficiency [12,13]. A frequent single nucleotide polymorphism (SNP)-G-1639A-within the VKORC1 promoter has been identified as a major determinant of coumarin sensitivity, reducing the activity of vitamin K epoxide reductase enzyme to 50% of that of the wild GG type.…”

Section: Introductionmentioning

confidence: 99%

“…Carriers of the vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles are at risk of developing vitamin K deficiency [12,13]. A frequent single nucleotide polymorphism (SNP)-G-1639A-within the VKORC1 promoter has been identified as a major determinant of coumarin sensitivity, reducing the activity of vitamin K epoxide reductase enzyme to 50% of that of the wild GG type.…”

Section: Introductionmentioning

confidence: 99%

Vitamin K Deficiency Bleeding in Infancy

Araki

Shirahata

2020

Nutrients

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Vitamin K is essential for the synthesis of few coagulation factors. Infants can easily develop vitamin K deficiency owing to poor placental transfer, low vitamin K content in breast milk, and poor intestinal absorption due to immature gut flora and malabsorption. Vitamin K deficiency bleeding (VKDB) in infancy is classified according to the time of presentation: early (within 24 h), classic (within 1 week after birth), and late (between 2 week and 6 months of age). VKDB in infancy, particularly late-onset VKDB, can be life-threatening. Therefore, all infants, including newborn infants, should receive vitamin K prophylaxis. Exclusive breastfeeding and cholestasis are closely associated with this deficiency and result in late-onset VKDB. Intramuscular prophylactic injections reduce the incidence of early-onset, classic, and late-onset VKDB. However, the prophylaxis strategy has recently been inclined toward oral administration because it is easier, safer, and cheaper to administer than intramuscular injection. Several epidemiological studies have shown that vitamin K oral administration is effective in the prevention of VKDB in infancy; however, the success of oral prophylaxis depends on the protocol regimen and parent compliance. Further national surveillance and studies are warranted to reveal the optimal prophylaxis regimen in term and preterm infants.

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“…16,17 Interestingly, recent in vitro studies have provided evidence that CYP4F2 is a vitamin K 1 oxidase and that CYP4F2*3 carriers have reduced capacity to metabolize vitamin K 1 . [18][19][20] Although there are some suggestions that CYP4F2 polymorphism would affect warfarin dose requirements in humans, 21,22 to date there is no clear evidence of CYP4F2 activity affecting…”

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confidence: 99%

Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F23* Genetic Polymorphism on Pharmacokinetics of Vitamin K₁

Park

Kim

Park

2019

The Journal of Clinical Pharma

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The objective of this study was to evaluate whether cytochrome P450 (CYP)4F2 is involved in the exposure of vitamin K1 through a drug interaction study with ketoconazole, a CYP4F2 inhibitor, and a pharmacogenetic study with CYP4F2*3. Twenty‐one participants with different CYP4F2*3 polymorphisms were enrolled (8 for *1/*1, 7 for *1/*3, and 6 for *3/*3). All participants were treated twice daily for 5 days with 200 mg of ketoconazole or placebo. Finally, a single dose of 10 mg vitamin K1 was administered, plasma levels of vitamin K1 were measured, and its pharmacokinetics was assessed. Ketoconazole elevated the plasma levels of vitamin K1 and increased the average area under the concentration‐time curve (AUCinf) and peak concentration by 41% and 40%, respectively. CYP4F2*3 polymorphism also affected plasma levels of vitamin K1 and its pharmacokinetics in a gene dose–dependent manner. The average AUCinf value was 659.8 ng·h/mL for CYP4F2*1/*1, 878.1 ng·h/mL for CYP4F2*1/*3, and 1125.2 ng·h/mL for CYP4F2*3/*3 (P = .010). This study revealed that ketoconazole and CYP4F2*3 polymorphism substantially increased the exposure of vitamin K1 in humans. These findings provide a plausible explanation for variations in warfarin dose requirements resulting from interindividual variations in vitamin K1 exposure due to CYP4F2‐related drug interactions and genetic polymorphisms.

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Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy

Cited by 16 publications

References 38 publications

Dietary and genetic influences on hemostasis in a Yup’ik Alaska Native population

Dietary and genetic influences on hemostasis in a Yup’ik Alaska Native population

Vitamin K Deficiency Bleeding in Infancy

Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F23* Genetic Polymorphism on Pharmacokinetics of Vitamin K₁

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Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy

Cited by 16 publications

References 38 publications

Dietary and genetic influences on hemostasis in a Yup’ik Alaska Native population

Dietary and genetic influences on hemostasis in a Yup’ik Alaska Native population

Vitamin K Deficiency Bleeding in Infancy

Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F2*3 Genetic Polymorphism on Pharmacokinetics of Vitamin K1

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Product

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Effects of Ketoconazole, a CYP4F2 Inhibitor, and CYP4F23* Genetic Polymorphism on Pharmacokinetics of Vitamin K₁