Phytomenadione Explained

Tradename:Mephyton, Hemophyt, others
Atc Prefix:B02
Atc Suffix:BA01
Legal Ca:Rx-only
Legal Ca Comment:[1] [2]
Legal Us:OTC
Cas Number:84-80-0
Pubchem:5284607
Drugbank:DB01022
Chemspiderid:4447652
Unii:S5Z3U87QHF
Kegg:D00148
Chebi:18067
Chembl:1550
Synonyms:Vitamin K1, phytonadione, phylloquinone, (E)-phytonadione
Iupac Name:2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione
C:31
H:46
O:2
Smiles:CC1=C(C(=O)c2ccccc2C1=O)C/C=C(\C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Stdinchi:1S/C31H46O2/c1-22(2)12-9-13-23(3)14-10-15-24(4)16-11-17-25(5)20-21-27-26(6)30(32)28-18-7-8-19-29(28)31(27)33/h7-8,18-20,22-24H,9-17,21H2,1-6H3/b25-20+/t23-,24-/m1/s1
Stdinchikey:MBWXNTAXLNYFJB-NKFFZRIASA-N

Phytomenadione, also known as vitamin K1 or phylloquinone, is a vitamin found in food and used as a dietary supplement.[3] It is on the World Health Organization's List of Essential Medicines.[4]

It is used to treat certain bleeding disorders, including warfarin overdose, vitamin K deficiency, and obstructive jaundice. Use is typically recommended by mouth, intramuscular injection or injection under the skin. When given by injection benefits are seen within two hours.[5] It is also recommended for preventing and treating vitamin K deficiency bleeding (VKDB) in infants.[5] Many countries in the world choose intramuscular injections in newborn to keep them safe from VKDB. It is considered a safe treatment and saves many children from death and severe neurologic deficit every year.[6]

Side effects when given by injection may include pain at the site of injection.[5] Severe allergic reactions may occur when it is injected into a vein or muscle, but this has mainly happened when large doses of a certain type of supplement containing castor oil were given intravenously.[7] Use during pregnancy is considered safe,[8] use is also likely okay during breastfeeding.[9] It works by supplying a required component for making a number of blood clotting factors.[5] Food sources include green vegetables, vegetable oil, and some fruit.[10]

Phytomenadione was first isolated in 1939.[11] In 1943 Edward Doisy and Henrik Dam were given a Nobel Prize for its discovery.[11]

Terminology

Phytomenadione is often also called phylloquinone, vitamin K,[12] or phytonadione.

A stereoisomer of phylloquinone is called vitamin k1 (note the difference in capitalization).

Medical uses

It is used to treat certain bleeding disorders,[5] including warfarin overdose (also overdose of similar compounds such as coumatetralyl), vitamin K deficiency, and obstructive jaundice.[5] It is used to prevent and treat vitamin K deficiency bleeding (VKDB) in infants.[5]

In Canada, phytomenadione (Hemophyt) is indicated for the treatment of anticoagulant poisoning in dogs.

Chemistry

Vitamin K is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight.[13] K1 is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent. It is found naturally in a wide variety of green plants, particularly in leaves, since it functions as an electron acceptor during photosynthesis, forming part of the electron transport chain of photosystem I.[14] [15]

Biological function

Animals

The best-known function of vitamin K in animals is as a cofactor in the formation of coagulation factors II (prothrombin), VII, IX, and X by the liver. It is also required for the formation of anticoagulant factors protein C and S. Vitamin K is required for bone protein formation.

In terms of distribution, phylloquinone typically occurs in higher levels in the liver, heart and pancreas, but in lower levels in the brain, kidneys, and lungs.[16]

Plants and cyanobacteria

Vitamin K1 is required for plant photosynthesis, where it participates in the Photosystem I electron transport chain.[17]

Biosynthesis

Vitamin K1 is synthesized from chorismate, a compound produced from shikimate via the shikimate pathway. The conversion of chorismate to vitamin K1 comprises a series of nine steps:[18] [19] [20]

  1. Chorismate is isomerized to isochorismate by isochorismate synthase, or MenF (menaquinone enzyme).
  2. Addition of 2-oxoglutarate to isochorismate by PHYLLO, a multifunctional protein comprising three different enzymatic activities (MenD, H, and C).
  3. Elimination of pyruvate by PHYLLO.
  4. Aromatization to yield o-succinyl benzoate by PHYLLO.
  5. O-succinylbenzoate activation to corresponding CoA ester by MenE.
  6. Naphthoate ring formation by naphthoate synthase (MenB/NS).
  7. Thiolytic release of CoA by a thioesterase (MenH).
  8. Attachment of phytol chain to the naphthoate ring (MenA/ABC4).
  9. Methylation of the precursor at position 3 (MenG).

Notes and References

  1. Web site: Notice: Multiple additions to the Prescription Drug List (PDL) [2023-08-30] ]. . 26 October 2023 . 3 January 2024.
  2. https://pdf.hres.ca/dpd_pm/00071484.PDF
  3. Book: Watson RR . Diet and Exercise in Cystic Fibrosis. 2014. Academic Press. 9780128005880. 187. en. live. https://web.archive.org/web/20161230000443/https://books.google.ca/books?id=hSSOAwAAQBAJ&pg=PA187. 2016-12-30.
  4. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  5. Web site: Phytonadione . The American Society of Health-System Pharmacists. 8 December 2016. live. https://web.archive.org/web/20161229172825/https://www.drugs.com/monograph/phytonadione.html. 29 December 2016.
  6. Web site: American Academy of Pediatrics on vitamin k in the newborn period. 27 July 2018 . Furman L .
  7. Riegert-Johnson DL, Volcheck GW . The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review . Annals of Allergy, Asthma & Immunology . 89 . 4 . 400–406 . October 2002 . 12392385 . 10.1016/S1081-1206(10)62042-X .
  8. Bailey B . Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women? . Birth Defects Research. Part A, Clinical and Molecular Teratology . 67 . 2 . 133–140 . February 2003 . 12769509 . 10.1002/bdra.10007 .
  9. Web site: Phytonadione Use During Pregnancy. Drugs.com. 29 December 2016. live. https://web.archive.org/web/20161229172908/https://www.drugs.com/pregnancy/phytonadione.html. 29 December 2016.
  10. Web site: Office of Dietary Supplements . Vitamin K . U.S. National Institutes of Health . 30 December 2016. 11 February 2016 . live . https://web.archive.org/web/20161231075317/https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/ . 31 December 2016 .
  11. Book: Sneader. Walter. vanc . Drug Discovery: A History. 2005. John Wiley & Sons. 9780471899792. 243. en. live. https://web.archive.org/web/20161230000050/https://books.google.ca/books?id=Cb6BOkj9fK4C&pg=PA243. 2016-12-30.
  12. Haroon Y, Shearer MJ, Rahim S, Gunn WG, McEnery G, Barkhan P . The content of phylloquinone (vitamin K1) in human milk, cows' milk and infant formula foods determined by high-performance liquid chromatography . The Journal of Nutrition . 112 . 6 . 1105–1117 . June 1982 . 7086539 . 10.1093/jn/112.6.1105 .
  13. Web site: Institute of Medicine (US) Panel on Micronutrients . Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc . NCBI . 25 November 2021 . Washington (DC) . National Academies Press (US) .
  14. 10.1016/0014-5793(89)81215-3 . Itoh S, Iwaki M . Vitamin K1 (Phylloquinone) Restores the Turnover of FeS centers of Ether-extracted Spinach PSI Particles . FEBS Letters . 243 . 1 . 47–52 . 1989 . 84602152 . free .
  15. Palace GP, Franke JE, Warden JT . Is phylloquinone an obligate electron carrier in photosystem I? . FEBS Letters . 215 . 1 . 58–62 . May 1987 . 3552735 . 10.1016/0014-5793(87)80113-8 . 42983611 . free . 1987FEBSL.215...58P .
  16. Bus K, Szterk A . Relationship between Structure and Biological Activity of Various Vitamin K Forms . Foods . 10 . 12 . 3136 . December 2021 . 34945687 . 8701896 . 10.3390/foods10123136 . free .
  17. Basset GJ, Latimer S, Fatihi A, Soubeyrand E, Block A . Phylloquinone (Vitamin K1): Occurrence, Biosynthesis and Functions . Mini Reviews in Medicinal Chemistry . 17 . 12 . 1028–1038 . 2017 . 27337968 . 10.2174/1389557516666160623082714 .
  18. Book: Reumann S . Peroxisomes and their Key Role in Cellular Signaling and Metabolism . Biosynthesis of vitamin K1 (phylloquinone) by plant peroxisomes and its integration into signaling molecule synthesis pathways . 69 . 213–29 . 2013 . 23821151 . 10.1007/978-94-007-6889-5_12 . Springer Netherlands . 9789400768888 . Subcellular Biochemistry .
  19. Widhalm JR, van Oostende C, Furt F, Basset GJ . A dedicated thioesterase of the Hotdog-fold family is required for the biosynthesis of the naphthoquinone ring of vitamin K1 . Proceedings of the National Academy of Sciences of the United States of America . 106 . 14 . 5599–5603 . April 2009 . 19321747 . 2660889 . 10.1073/pnas.0900738106 . free . 2009PNAS..106.5599W .
  20. Van Oostende C, Widhalm JR, Furt F, Ducluzeau AL, Basset GJ . Vitamin K1 (Phylloquinone) . Advances in Botanical Research . 2011 . 59 . 229–261 . 10.1016/B978-0-12-385853-5.00001-5 . 9780123858535 .

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