Vitamin E: Interactions with Vitamin K and Other Bioactive Compounds

  • M. Kyla SheaEmail author
  • Sarah L. Booth
Part of the Nutrition and Health book series (NH)


Nutrient functions often depend on those of other nutrients and/or bioactive compounds. These critical nutrient-nutrient interactions are often overlooked in observational studies and challenging to address in randomized clinical trials. As dietary guidance is issued to the general public primarily in the form of food components of the diet, such nutrient-nutrient interactions merit consideration in understanding the functions of a given nutrient. Vitamin E is no exception. An adverse interaction between vitamin E and another fat-soluble vitamin, vitamin K, was first detected over 50 years ago. Given both nutrients’ critical involvement in coagulation, in extreme cases, this interaction can result in abnormal blood clotting. There is also emerging evidence that vitamin E interacts with other bioactive compounds.


Vitamin E Vitamin K Coagulation Nutrient-nutrient interactions Warfarin Ginkgo biloba 


  1. 1.
    Mohajeri MH, Eckert GP, Pauly JR, Butt CM. Pharmacology: the pharmacodynamics of nutrients and nutrient interactions in biological functions. Biomed Res Int. 2015;2015:974572.CrossRefGoogle Scholar
  2. 2.
    Traber MG. Vitamin E and K interactions – a 50-year-old problem. Nutr Rev. 2008;66:624–9.CrossRefGoogle Scholar
  3. 3.
    Suttie JW. Vitamin K in health and disease. Boca Raton: CRC Press, Taylor and Francis Group; 2009.CrossRefGoogle Scholar
  4. 4.
    Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL. Vitamin K contents of meat, dairy, and fast food in the U.S. diet. J Agric Food Chem. 2006;54:463–7.CrossRefGoogle Scholar
  5. 5.
    Fu X, Shen X, Finnan EG, Haytowitz DB, Booth SL. Measurement of multiple vitamin K forms in processed and fresh-cut pork products in the U.S. food supply. J Agric Food Chem. 2016;64:4531–5.CrossRefGoogle Scholar
  6. 6.
    Fu X, Harshman SG, Shen X, et al. Multiple vitamin K forms exist in dairy foods. Curr Dev Nutr. 2017;1:e000638.CrossRefGoogle Scholar
  7. 7.
    Walther B, Karl JP, Booth SL, Boyaval P. Menaquinones, bacteria, and the food supply: the relevance of dairy and fermented food products to vitamin K requirements. Adv Nutr. 2013;4:463–73.CrossRefGoogle Scholar
  8. 8.
    Shea MK, Booth SL. Fat soluble vitamins: an overview. Scientific America Nutrition; 2018 (in press).Google Scholar
  9. 9.
    Cheung A, Suttie JW. Synthesis of menaquinone-2 derivatives as substrates for the liver microsomal vitamin K-dependent carboxylase. Biofactors. 1988;1:61–5.PubMedGoogle Scholar
  10. 10.
    Corrigan JJ Jr, Marcus FI. Coagulopathy associated with vitamin E ingestion. JAMA. 1974;230:1300–1.CrossRefGoogle Scholar
  11. 11.
    Corrigan JJ Jr, Ulfers LL. Effect of vitamin E on prothrombin levels in warfarin-induced vitamin K deficiency. Am J Clin Nutr. 1981;34:1701–5.CrossRefGoogle Scholar
  12. 12.
    Corrigan JJ Jr. The effect of vitamin E on warfarin-induced vitamin K deficiency. Ann N Y Acad Sci. 1982;393:361–8.CrossRefGoogle Scholar
  13. 13.
    Frank J, Weiser H, Biesalski HK. Interaction of vitamins E and K: effect of high dietary vitamin E on phylloquinone activity in chicks. Int J Vitam Nutr Res. 1997;67:242–7.PubMedGoogle Scholar
  14. 14.
    Dowd P, Zheng ZB. On the mechanism of the anticlotting action of vitamin E quinone. Proc Natl Acad Sci U S A. 1995;92:8171–5.CrossRefGoogle Scholar
  15. 15.
    Nowicka B, Kruk J. Occurrence, biosynthesis and function of isoprenoid quinones. Biochim Biophys Acta. 2010;1797:1587–605.CrossRefGoogle Scholar
  16. 16.
    Yamanashi Y, Takada T, Kurauchi R, Tanaka Y, Komine T, Suzuki H. Transporters for the intestinal absorption of cholesterol, vitamin E, and vitamin K. J Atheroscler Thromb. 2017;24:347–59.CrossRefGoogle Scholar
  17. 17.
    Goncalves A, Margier M, Roi S, et al. Intestinal scavenger receptors are involved in vitamin K1 absorption. J Biol Chem. 2014;289:30743–52.CrossRefGoogle Scholar
  18. 18.
    Goncalves A, Roi S, Nowicki M, et al. Fat-soluble vitamin intestinal absorption: absorption sites in the intestine and interactions for absorption. Food Chem. 2015;172:155–60.CrossRefGoogle Scholar
  19. 19.
    Nassir F, Wilson B, Han X, Gross RW, Abumrad NA. CD36 is important for fatty acid and cholesterol uptake by the proximal but not distal intestine. J Biol Chem. 2007;282:19493–501.CrossRefGoogle Scholar
  20. 20.
    Rhainds D, Brissette L. The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. Defining the rules for lipid traders. Int J Biochem Cell Biol. 2004;36:39–77.CrossRefGoogle Scholar
  21. 21.
    Reboul E, Klein A, Bietrix F, et al. Scavenger receptor class B type I (SR-BI) is involved in vitamin E transport across the enterocyte. J Biol Chem. 2006;281:4739–45.CrossRefGoogle Scholar
  22. 22.
    Takada T, Yamanashi Y, Konishi K, et al. NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy. Sci Transl Med. 2015;7:275ra23.CrossRefGoogle Scholar
  23. 23.
    Reboul E, Soayfane Z, Goncalves A, et al. Respective contributions of intestinal Niemann-Pick C1-like 1 and scavenger receptor class B type I to cholesterol and tocopherol uptake: in vivo v. in vitro studies. Br J Nutr. 2012;107:1296–304.CrossRefGoogle Scholar
  24. 24.
    Narushima K, Takada T, Yamanashi Y, Suzuki H. Niemann-pick C1-like 1 mediates alpha-tocopherol transport. Mol Pharmacol. 2008;74:42–9.CrossRefGoogle Scholar
  25. 25.
    Booth SL, Tucker KL, McKeown NM, Davidson KW, Dallal GE, Sadowski JA. Relationships between dietary intakes and fasting plasma concentrations of fat-soluble vitamins in humans. J Nutr. 1997;127:587–92.CrossRefGoogle Scholar
  26. 26.
    Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, DC: National Academy Press; 2001.Google Scholar
  27. 27.
    Gao X, Wilde PE, Lichtenstein AH, Bermudez OI, Tucker KL. The maximal amount of dietary alpha-tocopherol intake in U.S. adults (NHANES 2001–2002). J Nutr. 2006;136:1021–6.CrossRefGoogle Scholar
  28. 28.
    Harshman SG, Finnan EG, Barger KJ, et al. Vegetables and mixed dishes are top contributors to phylloquinone intake in US adults: data from the 2011–2012 NHANES. J Nutr. 2017;147:1308–13.CrossRefGoogle Scholar
  29. 29.
    Institute of Medicine. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academies Press; 2000.Google Scholar
  30. 30.
    Kantor ED, Rehm CD, Du M, White E, Giovannucci EL. Trends in dietary supplement use among US adults from 1999–2012. JAMA. 2016;316:1464–74.CrossRefGoogle Scholar
  31. 31.
    Traber MG. Mechanisms for the prevention of vitamin E excess. J Lipid Res. 2013;54:2295–306.CrossRefGoogle Scholar
  32. 32.
    Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008;100:530–47.CrossRefGoogle Scholar
  33. 33.
    Edson KZ, Prasad B, Unadkat JD, et al. Cytochrome P450-dependent catabolism of vitamin K: omega-hydroxylation catalyzed by human CYP4F2 and CYP4F11. Biochemistry. 2013;52:8276–85.CrossRefGoogle Scholar
  34. 34.
    McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE. CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol. 2009;75:1337–46.CrossRefGoogle Scholar
  35. 35.
    Traber MG. Vitamin E regulatory mechanisms. Annu Rev Nutr. 2007;27:347–62.CrossRefGoogle Scholar
  36. 36.
    Sontag TJ, Parker RS. Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J Biol Chem. 2002;277:25290–6.CrossRefGoogle Scholar
  37. 37.
    Azzi A, Gysin R, Kempna P, et al. Regulation of gene expression by alpha-tocopherol. Biol Chem. 2004;385:585–91.CrossRefGoogle Scholar
  38. 38.
    Landes N, Birringer M, Brigelius-Flohe R. Homologous metabolic and gene activating routes for vitamins E and K. Mol Asp Med. 2003;24:337–44.CrossRefGoogle Scholar
  39. 39.
    Tabb MM, Sun A, Zhou C, et al. Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J Biol Chem. 2003;278:43919–27.CrossRefGoogle Scholar
  40. 40.
    Farley SM, Leonard SW, Labut EM, et al. Vitamin E decreases extra-hepatic menaquinone-4 concentrations in rats fed menadione or phylloquinone. Mol Nutr Food Res. 2012;56:912–22.CrossRefGoogle Scholar
  41. 41.
    Farley SM, Leonard SW, Taylor AW, et al. omega-Hydroxylation of phylloquinone by CYP4F2 is not increased by alpha-tocopherol. Mol Nutr Food Res. 2013;57:1785–93.PubMedGoogle Scholar
  42. 42.
    Al Rajabi A, Booth SL, Peterson JW, et al. Deuterium-labeled phylloquinone has tissue-specific conversion to menaquinone-4 among Fischer 344 male rats. J Nutr. 2012;142:841–5.CrossRefGoogle Scholar
  43. 43.
    Thijssen HH, Drittij-Reijnders MJ. Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4. Br J Nutr. 1994;72:415–25.CrossRefGoogle Scholar
  44. 44.
    Thijssen HH, Drittij-Reijnders MJ, Fischer MA. Phylloquinone and menaquinone-4 distribution in rats: synthesis rather than uptake determines menaquinone-4 organ concentrations. J Nutr. 1996;126:537–43.CrossRefGoogle Scholar
  45. 45.
    Nakagawa K, Hirota Y, Sawada N, et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature. 2010;468:117–21.CrossRefGoogle Scholar
  46. 46.
    Okano T, Shimomura Y, Yamane M, et al. Conversion of phylloquinone (vitamin K1) into menaquinone-4 (vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice. J Biol Chem. 2008;283:11270–9.CrossRefGoogle Scholar
  47. 47.
    Shearer MJ, Newman P. Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res. 2014;55:345–62.CrossRefGoogle Scholar
  48. 48.
    Hanzawa F, Sakuma E, Nomura S, Uchida T, Oda H, Ikeda S. Excess alpha-tocopherol decreases extrahepatic phylloquinone in phylloquinone-fed rats but not menaquinone-4 in menaquinone-4-fed rats. Mol Nutr Food Res. 2014;58:1601–9.CrossRefGoogle Scholar
  49. 49.
    Tovar A, Ameho CK, Blumberg JB, Peterson JW, Smith D, Booth SL. Extrahepatic tissue concentrations of vitamin K are lower in rats fed a high vitamin E diet. Nutr Metab (Lond). 2006;3:29.CrossRefGoogle Scholar
  50. 50.
    Farley SM, Leonard SW, Stevens JF, Traber MG. Deuterium-labeled phylloquinone fed to alpha-tocopherol-injected rats demonstrates sensitivity of low phylloquinone-containing tissues to menaquinone-4 depletion. Mol Nutr Food Res. 2014;58:1610–9.CrossRefGoogle Scholar
  51. 51.
    Booth SL, Golly I, Sacheck JM, et al. Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status. Am J Clin Nutr. 2004;80:143–8.CrossRefGoogle Scholar
  52. 52.
    Horwitt MK. Vitamin E: a reexamination. Am J Clin Nutr. 1976;29:569–78.CrossRefGoogle Scholar
  53. 53.
    Shea MK, Booth SL. Concepts and controversies in evaluating vitamin K status in population-based studies. Nutrients. 2016;8:E8.CrossRefGoogle Scholar
  54. 54.
    Leung VW, Shalansky SJ, Lo MK, Jadusingh EA. Prevalence of use and the risk of adverse effects associated with complementary and alternative medicine in a cohort of patients receiving warfarin. Ann Pharmacother. 2009;43:875–81.CrossRefGoogle Scholar
  55. 55.
    Kim JM, White RH. Effect of vitamin E on the anticoagulant response to warfarin. Am J Cardiol. 1996;77:545–6.CrossRefGoogle Scholar
  56. 56.
    Stanger MJ, Thompson LA, Young AJ, Lieberman HR. Anticoagulant activity of select dietary supplements. Nutr Rev. 2012;70:107–17.CrossRefGoogle Scholar
  57. 57.
    Segal R, Pilote L. Warfarin interaction with Matricaria chamomilla. CMAJ. 2006;174:1281–2.CrossRefGoogle Scholar
  58. 58.
    Broniatowski M, Flasinski M, Hac-Wydro K. Antagonistic effects of alpha-tocopherol and ursolic acid on model bacterial membranes. Biochim Biophys Acta. 2015;1848:2154–62.CrossRefGoogle Scholar
  59. 59.
    Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583–92.CrossRefGoogle Scholar
  60. 60.
    Cheung MC, Zhao XQ, Chait A, Albers JJ, Brown BG. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Thromb Vasc Biol. 2001;21:1320–6.CrossRefGoogle Scholar
  61. 61.
    Singh U, Otvos J, Dasgupta A, de Lemos JA, Devaraj S, Jialal I. High-dose alpha-tocopherol therapy does not affect HDL subfractions in patients with coronary artery disease on statin therapy. Clin Chem. 2007;53:525–8.CrossRefGoogle Scholar
  62. 62.
    Niki E. Interaction of ascorbate and alpha-tocopherol. Ann N Y Acad Sci. 1987;498:186–99.CrossRefGoogle Scholar
  63. 63.
    Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. 2007;167:1610–8.CrossRefGoogle Scholar
  64. 64.
    Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2009;301:52–62.CrossRefGoogle Scholar
  65. 65.
    Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2008;300:2123–33.CrossRefGoogle Scholar
  66. 66.
    Traber MG, Stevens JF. Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radic Biol Med. 2011;51:1000–13.CrossRefGoogle Scholar
  67. 67.
    La Fata G, Seifert N, Weber P, Mohajeri MH. Vitamin E supplementation delays cellular senescence in vitro. Biomed Res Int. 2015;2015:563247.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Sunde RA, Thompson KM, Fritsche KL, Evenson JK. Minimum selenium requirements increase when repleting second-generation selenium-deficient rats but are not further altered by vitamin E deficiency. Biol Trace Elem Res. 2017;177:139–47.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Jean Mayer USDA Human Nutrition Research Center on AgingTufts UniversityBostonUSA

Personalised recommendations