Phytomenadione

Phytomenadione, also known as vitamin K₁ or phylloquinone, is a vitamin found in food and used as a dietary supplement.^[4][5] It is on the World Health Organization's List of Essential Medicines.^[6]

Phytomenadione

Clinical data
Trade names	Mephyton, Hemophyt, others
Other names	Vitamin K1, phytonadione, phylloquinone, (E)-phytonadione
AHFS/Drugs.com	Monograph
Routes of administration	By mouth, subcutaneous, intramuscular, intravenous
ATC code	B02BA01 (WHO) QB02BA01 (WHO)
Legal status
Legal status	CA: ℞-only[1][2] US: WARNING[3]OTC
Identifiers
IUPAC name 2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione
CAS Number	84-80-0
PubChem CID	5284607
DrugBank	DB01022
ChemSpider	4447652
UNII	S5Z3U87QHF
KEGG	D00148
ChEBI	CHEBI:18067
ChEMBL	ChEMBL1550
CompTox Dashboard (EPA)	DTXSID8023472
ECHA InfoCard	100.001.422
Chemical and physical data
Formula	C31H46O2
Molar mass	450.707 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1=C(C(=O)c2ccccc2C1=O)C/C=C(\C)/CCC[C@H](C)CCC[C@H](C)CCCC(C)C
InChI InChI=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 Y Key:MBWXNTAXLNYFJB-NKFFZRIASA-N

It is used to treat certain bleeding disorders,^[5] including warfarin overdose, vitamin K deficiency, and obstructive jaundice.^[5] Use is typically recommended by mouth, intramuscular injection or injection under the skin.^[5] 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.^[7]

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.^[8] Use during pregnancy is considered safe,^[9] use is also likely okay during breastfeeding.^[10] 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.^[11]

Phytomenadione was first isolated in 1939.^[12] In 1943 Edward Doisy and Henrik Dam were given a Nobel Prize for its discovery.^[12]

Terminology

Phytomenadione is often also called phylloquinone, vitamin K,^[13] or phytonadione.

A stereoisomer of phylloquinone is called vitamin k₁ (note the difference in capitalization).^{[citation needed]}

Medical uses

See also: Vitamin K § Medical uses (the section nearly only covers Vitamin K₁, i.e. this compound.)

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.^[1][2]

Chemistry

Vitamin K is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight.^[14] 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.^[15][16]

Biological function

Main article: vitamin K

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.^[17]

Plants and cyanobacteria

Vitamin K₁ is required for plant photosynthesis, where it participates in the Photosystem I electron transport chain.^[18]

Biosynthesis

The biosynthesis of vitamin K1 via the transformation of chorismate occurs in nine steps.

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:^[19][20][21]

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).

References

1. "Notice: Multiple additions to the Prescription Drug List (PDL) [2023-08-30]". Health Canada. 26 October 2023. Retrieved 3 January 2024.
2. https://pdf.hres.ca/dpd_pm/00071484.PDF ^{[bare URL PDF]}
3. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
4. Watson RR (2014). Diet and Exercise in Cystic Fibrosis. Academic Press. p. 187. ISBN 9780128005880. Archived from the original on 2016-12-30.
5. "Phytonadione". The American Society of Health-System Pharmacists. Archived from the original on 29 December 2016. Retrieved 8 December 2016.
6. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
7. Furman L (27 July 2018). "American Academy of Pediatrics on vitamin k in the newborn period".
8. Riegert-Johnson DL, Volcheck GW (October 2002). "The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review". Annals of Allergy, Asthma & Immunology. 89 (4): 400–406. doi:10.1016/S1081-1206(10)62042-X. PMID 12392385.
9. Bailey B (February 2003). "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. doi:10.1002/bdra.10007. PMID 12769509.
10. "Phytonadione Use During Pregnancy". Drugs.com. Archived from the original on 29 December 2016. Retrieved 29 December 2016.
11. "Vitamin K". Office of Dietary Supplements. U.S. National Institutes of Health. 11 February 2016. Archived from the original on 31 December 2016. Retrieved 30 December 2016.
12. Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 243. ISBN 9780471899792. Archived from the original on 2016-12-30.
13. Haroon Y, Shearer MJ, Rahim S, Gunn WG, McEnery G, Barkhan P (June 1982). "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. doi:10.1093/jn/112.6.1105. PMID 7086539.
14. 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". Washington (DC): National Academies Press (US). Retrieved 25 November 2021 – via NCBI.
15. Itoh S, Iwaki M (1989). "Vitamin K₁ (Phylloquinone) Restores the Turnover of FeS centers of Ether-extracted Spinach PSI Particles". FEBS Letters. 243 (1): 47–52. doi:10.1016/0014-5793(89)81215-3. S2CID 84602152.
16. Palace GP, Franke JE, Warden JT (May 1987). "Is phylloquinone an obligate electron carrier in photosystem I?". FEBS Letters. 215 (1): 58–62. Bibcode:1987FEBSL.215...58P. doi:10.1016/0014-5793(87)80113-8. PMID 3552735. S2CID 42983611.
17. Bus K, Szterk A (December 2021). "Relationship between Structure and Biological Activity of Various Vitamin K Forms". Foods. 10 (12): 3136. doi:10.3390/foods10123136. PMC 8701896. PMID 34945687.
18. Basset GJ, Latimer S, Fatihi A, Soubeyrand E, Block A (2017). "Phylloquinone (Vitamin K1): Occurrence, Biosynthesis and Functions". Mini Reviews in Medicinal Chemistry. 17 (12): 1028–1038. doi:10.2174/1389557516666160623082714. PMID 27337968.
19. Reumann S (2013). "Biosynthesis of vitamin K1 (phylloquinone) by plant peroxisomes and its integration into signaling molecule synthesis pathways". Peroxisomes and their Key Role in Cellular Signaling and Metabolism. Subcellular Biochemistry. Vol. 69. Springer Netherlands. pp. 213–29. doi:10.1007/978-94-007-6889-5_12. ISBN 9789400768888. PMID 23821151.
20. Widhalm JR, van Oostende C, Furt F, Basset GJ (April 2009). "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. Bibcode:2009PNAS..106.5599W. doi:10.1073/pnas.0900738106. PMC 2660889. PMID 19321747.
21. Van Oostende C, Widhalm JR, Furt F, Ducluzeau AL, Basset GJ (2011). "Vitamin K1 (Phylloquinone)". Advances in Botanical Research. 59: 229–261. doi:10.1016/B978-0-12-385853-5.00001-5. ISBN 9780123858535.

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