The Reductive Activity of Human Liver Microsomes for Vitamin K Epoxides

Masashi Kawano, Takuya Araki, Hideaki Yashima, Tomonori Nakamura, Koujirou Yamamoto

Abstract

Vitamin K (VK) is oxidized to vitamin K epoxide (VK-O) during the production of VK-dependent blood clotting factors. Thereafter, VK-O is reduced to VK by vitamin K epoxide reductase (VKOR) in the liver and reused. This reductive reaction is inhibited by warfarin, an oral anticoagulant. VK in nature is roughly divided into two types, VK1 (phylloquinone) and VK2 (menaquinone). Although their bioavailabilities and elimination half-lives from human blood differ, information on the influence of each VK on the effectiveness of warfarin is limited. In this study, the difference in the metabolism of VK1-O and MK4-O by VKOR was evaluated in an in vitro study using human liver microsomes. The results showed that the substrate affinity (1/Km), and the maximum reaction rate (Vmax) of the VKOR reduction was around 7 and 4 times higher for MK4-O than for VK1-O, respectively. The intrinsic clearance of MK4-O, obtained by dividing the Vmax value by the Km value, was about 30 times greater than that of VK1-O. According to these data, the production of VK-dependent blood coagulation factors can be considered to be dominated mainly by MK4-O, at least under normal conditions. We may thus have to be more careful about controlling the intake of MK4 than VK1 in patients receiving warfarin therapy.

Keywords: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), VKOR, warfarin

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References

Wu S, Chen X, Jin D, Stafford D, Pedersen L, Tie J. Warfarin and vitamin K epoxide reductase: a molecular accounting for observed inhibition. Blood. 2018;132(6):647-57.

Czogalla K, Liphardt K, Honing K, Hornug V, Biswas A, Watzka M, et al. VKORC1 and VKORC1L1 have distinctly different oral anticoagulant dose-response characteristics and binding sites. Blood Adv. 2018;2(6):691-702.

Haque J, McDonald M, Kulman J, Rettie A. A cellular system for quantitation of vitamin K cycle activity: structure-activity effects on vitamin K antagonism by warfarin metabolites. Blood. 2014;123(4):582-9.

Chan Y, Lee H, See L, Tu H, Chao T, Yeh Y, et al. Effectiveness and safety of four direct oral anticoagulants in Asian patients with nonvalvular atrial fibrillation. Chest. 2019;156(3):529-43.

Lutsey P, Walker R, MacLehouse R, Alonso A, Adam T, Zakai N. Direct oral anticoagulants and warfarin for venous thromboembolism treatment: Trends from 2012 to 2017. Res Pract Thromb Haemost. 2019;3(4):668-73.

Farzamikia N, Sakhinia E, Afrasiabirad A. Pharmacogenetics-based warfarin dosing in patients with cardiac valve replacement: The effects of CYP2C9 and VKORC1 gene polymorphisms. Lab Med. 2017;49(1):25-34.

Zhang J, Klein K, Jorgensen A, Francis B, Alfirevic A, Bourgeois S. Effect of genetic variability in the CYP4F2, CYP4F11, and CYP4F12 genes on liver mRNA levels and warfarin response. Front Phamacol. 2017;8:323.

Liang R, Wang C, Zhao H, Huang J, Hu D, Sun Y. Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis. Thrombosis Res. 2012;130(1):38-44.

Yang L, Ge W, Yu F, Zhu H. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement-a systematic review and meta analysis. Thrombosis Res. 2010;125(4):e159-66.

Al-Eitan L, Almasri A, Khasawneh R. Effects of CYP2C9 and VKORC1 polymorphisms on warfarin sensitivity and responsiveness during the stabilization phase of therapy. Saudi Pharm J. 2019;27(4):484-90.

Leblanc C, Dube M, Presse N, Dumas S, Nguyen M, Rouleau-Milloux E, et al. Avoidance of Vitamin K-Rich Foods Is Common among Warfarin Users and Translates into Lower Usual Vitamin K Intakes. L Acad Nutr Diet. 2016;116(6):1000-7.

Homma K, Wakana N, Suzuki Y, Nukui M, Daimatsu T, Tanaka E, et al. Treatment of natto, a fermented soybean preparation, to prevent excessive plasma vitamin K concentrations in patients taking warfarin. J Nutr Sci Vitaminol. 2006;52(5):297-301.

Franco V, Polanczyk CA, Clausell N, Rohde LE. Role of Dietary Vitamin K Intake in Chronic Oral Anticoagulation: Prospective Evidence from Observational and Randomized protocols. Am J Med. 2004;116:651-6.

Karlson B, Leijd B, Hellstrom K. On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment. Acta Med Scand. 1986;220:347-50.

Chow WH, Chow TC, Tse TM, Tai YT, Lee WT. Anticoagulant instability with life-threating complication after dietary modification. Postgrad Med J. 1990;66:855-7.

Holmes M, Hunt B, Shearer M. The role of dietary vitamin K in the management of oral vitamin K antagonists. Blood Rev. 2012;26(1):1-14.

Ferland G, Doucet I, Mainville D. Phylloquinone and menaquinone 4 tissue distribution at different life stages in male and female sprague-dawley rats fed different VK levels since weaning or subjected to a 40% calorie restriction since adulthood. Nutrients. 2016;8(3):141.

Fu X, Harshman S, Shen X, Haytowitz D, Karl J, Wolfe B, et al. Multiple Vitamin K Forms Exist in Dairy Foods. Curr Dev Nutr. 2017;1(6): e000638

Flore R, Ponziani F, Rienzo T, Zocco M, FlexA, Gerardino L, et al. Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis. Eur Rev Med Pharmacol. 2013;17(18):2433-40.

Beaulens J, Booth S, van den Heuvel E, Stoecklin E, Vermeer C. The role menaquinones (vitamin K2) in human health. Br J Nutr. 2013;110(8):1357-68.

Hirota Y, Tsugawa N, Nakagawa K, Suhara Y, Tanaka K, Uchino Y, et al. Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats. J Biol Chem. 2013;288(46):33071-80.

Shearer M, Okano T. Key Pathways and Regulators of Vitamin K Function and Intermediary Metabolism. 2018;38:127-51.

Boraldi F, Garci-Fernandez M, Paolinelli-Devincenzi C, Annovi G, Schurgers L, Vermeer C, et al. Ectopic calcification in β-thalassemia patients is associated with increased oxidative stress and lower MGP carboxylation. Biochim Biophys Acta. 2013;1832(12):2077-84.

Mayer O, Seidlerova J, Bruthans J, Filipovsky J, Timoracka K, Vanek J, et al. Desphospho-uncarboxylated matrix Gla-protein is associated with mortality risk in patients with chronic stable vascular disease. Atherosclerosis. 2014;235(1):162-8.

Dunovska K, Klapkova E, Sopko B, CepovaJ, Prusa R. LC–MS/MS quantitative analysis of phylloquinone, menaquinone-4 and menaquinone-7 in the human serum of a healthy population. PeerJ. 2019;7:e7695.

Al Rajab A, Booth S, Peterson J, Choi S, Suttie J, Shea M, et al. Deuterium-labeled phylloquinone has tissue-specific conversion to menaquinone-4 among Fischer 344 male rats. J Nutr. 2012;142(5):841-5.

Violi F, Lip G, Pignateli P, Pastori D. Interaction between dietary vitamin K intake and anticoagulation by vitamin K antagonists: Is it really true?: A systematic review. Medicine. 2016;95(10):e2895.

McCabe K, Booth S, Fu X, Shobeiri N, Pang J, Adams M, et al. Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease. Kidney Int. 2013;83(5):835-44.

DOI: https://doi.org/10.24198/idjp.v2i1.25302

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