PHYTOMENADIONE

Phytomenadione prevents deficiency bleeding in infants.
Phytomenadione is used in the liver as the intermediate VKH2 to deprotonate a glutamate residue and then is reprocessed into Phytomenadione through a Phytomenadione oxide intermediate.

CAS Number: 84-80-0
EC Number (EINECS): 201-564-2
Molecular Formula: C31H46O2
Molar mass: 450.707 g•mol−1

SYNONYMS:
VITAMIN K1, phytonadione, 84-80-0, Phytomenadione, Phylloquinone, Phytylmenadione, 3-Phytylmenadione, Mephyton, Monodion, Synthex P, Phyllochinon, Kinadion, Kephton, Mono-Kay, Combinal K1, Fitomenadiona, Kativ N, alpha-Phylloquinone, trans-Phylloquinone, K-Ject, 2-Methyl-3-phytyl-1,4-naphthoquinone, Antihemorrhagic vitamin, Phyllochinonum, Phytomenadionum, Phytonadionum, Aqua mephyton, Fitomenadione, Vitamin K 1, Orakay, 2',3'-trans-Vitamin K1, 2-Methyl-3-phytyl-1,4-naphthochinon, Kanavit, Neokay, NSC-270681, DTXSID8023472, Konakion mm, Vitamin K1(20), Konakion mm paed, S5Z3U87QHF, 2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]naphthalene-1,4-dione, CHEBI:18067, 2-Methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,4-naphthalenedione, 2-methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-yl]naphthalene-1,4-dione, DTXCID003472, 2-Methyl-3-[(2E)-3,7,11,15-tetramethyl-2-hexadecenyl]naphthoquinone, NSC270681, vitaminum k1, 2-Methyl-3-((2E)-3,7,11,15-tetramethyl-2-hexadecenyl)naphthoquinone, Phylloquinone e-, 2-methyl-3-((2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-yl)naphthalene-1,4-dione, 2-methyl-3-((E,7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl)naphthalene-1,4-dione, Vitamin K1 Injectable, RefChem:6141, VEDA-K1, VETA-K1, VITAMIN K1 PHYTONADIONE, VITAMIN K1-PHYTONADIONE, PHYTONADIONE PHYTONADIONE, VITAMIN K1, PHYTONADIONE, B02BA01, A034SE7857, 2-Methyl-3-((2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-yl)-1,4-naphthoquinone, Aquamephyton, Konakion, 79083-00-4, Aqua-Mephytin, 11104-38-4, Phylloquinone e-form, 1,4-Naphthalenedione,2-methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-yl]-, 2-Methyl-3-((7R,11R,E)-3,7,11,15-tetramethylhexadec-2-en-1-yl)naphthalene-1,4-dione, MFCD00214063, NSC 270681, VitaminK1, 1,4-Naphthoquinone, 2-methyl-3-phytyl-, Phythyl-menadion, MLF3D1712D, Phytonadione, (E)-(+/-)-, C31H46O2, 1,4-Naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-, (R-(R*,R*-(E)))-, 2-methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethylhexadec-2-en-1-yl]-1,4-dihydronaphthalene-1,4-dione, 1,4-Naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-, 2-Methyl-3-phythyl-1,4-naphthochinon, CAS-84-80-0, rel-2-Methyl-3-((7R,11R,E)-3,7,11,15-tetramethylhexadec-2-en-1-yl)naphthalene-1,4-dione, Phytonadione, K1, 1,4-Naphthalenedione, 2-methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-, [R-[R*,R*-(E)]]-, Phyllochinon [German], Fitomenadione [DCIT], Vitamin K1 (VAN), Phytonadione [USP:JAN], UNII-S5Z3U87QHF, Phytomenadione, Phytonadione, Vitamin K1, Phylloquinone, Fitomenadiona [INN-Spanish], Phytomenadionum [INN-Latin], a-Phylloquinone, Phytonadione RS, HSDB 3162, (E)-phytonadione, Vitamin K?, Phytomenadione CRS, NCGC00159423-02, EINECS 201-564-2, EINECS 234-330-3, EINECS 279-052-3, Vitamin K1 (contains up to 20% cis isomer), vitamin K1, 11, Vitamin K1 (generic), Vitamin K1 (Standard), Phytomenadion/Vitamin K1, PHYTONADIONE [JAN], 2-Methyl-3-phytyl-1,4-naphthochinon [German], phylloquinone,2-METHYL-3-PHYTYL-1,4-NAPHTHOQUINONE, Phylloquinone,Phytomenadione, SCHEMBL3882, Vitamin K1 (Phylloquinone), Vitamin K1, viscous liquid, CHEMBL1550, UNII-MLF3D1712D, PHYTONADIONE, (E)-, PHYLLOQUINONE, (E)-, MLS001074732, BIDD:GT0793, PHYTOMENADIONE, (E)-, orb1309849, 2-Methyl-3-[(2E)-3,7,11,15-tetramethyl-2-hexadecenyl]naphthoquinone #, BDBM24782, HY-N0684R, MSK1513, [r-[r*,R*-(E)]]-2-Methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,4-napthalenedione, [r-[r*,R*-(E)]]-2-Methyl-3-(3-7,11,15-tetramethyl-2-hexadecenyl)-1,4-naphthalenedione, PHYLLOQUINONE E-FORM [MI], GLXC-21157, HMS2094G09, HMS2270J10, Pharmakon1600-01505485, 10485-69-5, HY-N0684, Tox21_111655, BDBM50553259, EBC-09051, LMPR02030028, NSC760373, s4698, 2-Methyl-3-phytyl-1,4-napthoquinone, AKOS015841892, Tox21_111655_1, CCG-213568, CS-6376, DB01022, FV28716, NSC-760373, (R*,R*-(E))-(1)-2-Methyl-3-(3,7,11,15-tetramethylhexadec-2-enyl)-1,4-naphthoquinone, NCGC00159423-03, Phylloquinone (K1), analytical standard, AC-34846, AS-13734, SMR000112043, SBI-0206926.P001, trans-Phytomenadione 100 microg/mL in Ethanol, AB00698065_04, 214V063, EN300-22411510, F814464, Q186093, SR-05000001941, C31H46O2 (2-methyl-3-phytyl-1,4-naphthoquinone), SR-05000001941-1, BRD-K76661572-001-07-6, BRD-K76661572-001-08-4, Z2568644345, 84C51B31-3CE2-476B-BE66-A84BDD46A513, VITAMIN K1, 2-METHYL-3-PHYTYL-1,4-NAPHTHOQUINONE, Phytomenadione, European Pharmacopoeia (EP) Reference Standard, Phytonadione, United States Pharmacopeia (USP) Reference Standard, 2-Methyl-3-(3,7,11,15-tetramethyl-2-hexadecenyl)-1,4-naphthalened- ione, Vitamin K1, BioXtra, >=99.0% (sum of isomers, HPLC), mixtur of isomers, 1,4-Naphthalenedione, 2-methyl-3-((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-yl)-, 1,4-Naphthalenedione, 2-methyl-3-((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecenyl)-, Phytonadione, Pharmaceutical Secondary Standard, Certified Reference Material, 1,4-NAPHTHALENEDIONE, 2-METHYL-3-((2E,7R,11R)-3,7,11,15-TETRAMETHYL-2-HEXADECEN-1-YL)-, REL-, 2-METHYL-3-((2E,7R,11R)-3,7,11,15-TETRAMETHYL-2-HEXADECENYL)-1,4-NAPHTHALENEDIONE, 2-Methyl-3-[(2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecenyl]-1,4-naphthalenedione,Konakion,Mephyton, Vitamin K1, 2-Methyl-3-phytyl-1,4-naphthoquinone, 3-Phytylmenadione, Phylloquinone, Vitamin K1(20), Vitamin K₁, phylloquinone, phytonadione, phytomenadione, α-phylloquinone, trans-phylloquinone, NSC 270681, K-ativn, Konakion, aqua-mephyton, K-Ject, 2-methyl-3-phytyl-1,4-naphthoquinone, Vitamin K₁, phylloquinone, phytonadione, phytomenadione, α-phylloquinone, 2-methyl-3-phytyl-1,4-naphthoquinone, 3-phytylmenadione, Phyllochinon, Phythyl-menadion, trans-Phylloquinone, Kativn K1, Konakion, Aqua-Mephyton, Mephyton, Kinadion, Combinal K1, Mono-Kay, Monodion, Phyllochinonum, Phytomenadionum, Vitamin K₁ (phytomenadione), 2-Methyl-3-phytyl-1,4-naphthoquinone

Phytomenadione is a family of structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements.
The human body requires Phytomenadione for post-synthesis modification of certain proteins that are required for blood coagulation ("K" from Danish koagulation, for "coagulation") and for controlling binding of calcium in bones and other tissues.

The complete synthesis involves final modification of these so-called "Gla proteins" by the enzyme gamma-glutamyl carboxylase that uses Phytomenadione as a cofactor.
Chemically, the Phytomenadione family comprises 2-methyl-1,4-naphthoquinone derivatives.

Phytomenadione includes two natural vitamers: vitamin 1 and vitamin 2 (menaquinone).
Vitamin 2, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms.

The two most studied are menaquinone-4 (MK-4) and menaquinone-7 (MK-7).
Phytomenadione refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements.
"Phytomenadione" includes several chemical compounds.

These are similar in structure in that they share a quinone ring, but differ in the length and degree of saturation of the carbon tail and the number of repeating isoprene units in the side chain.
Plant-sourced forms are primarily Phytomenadione.

Animal-sourced foods are primarily Vitamin2.
Phytomenadione has several roles.
Phytomenadione is an essential nutrient absorbed from food.

Phytomenadione is a product synthesized and marketed as part of a multi-vitamin or as a single-vitamin dietary supplement.
Phytomenadione is a prescription medication for specific purposes.
Phytomenadione is a member of the class of Phytomenadiones that consists of 1,4-naphthoquinone having methyl and phytyl groups at positions 2 and 3 respectively.

The parent of the class of Phytomenadiones.
Phytomenadione has a role as a cofactor, a plant metabolite and a human metabolite.
Phytomenadione is a vitamin K and a member of Phytomenadiones.

Vitamin K1, also called Phytomenadione or phytonadione, is a fat soluble vitamin.
Phytomenadione is a cofactor of the enzyme γ-carboxylase, which modifies and activates precursors to coagulation factors II, VII, IX, and X.
Phytomenadione is indicated in the treatment of coagulation disorders due to faulty formation of coagulation factors II, VII, IX, and X caused by deficiency or interference in the activity of vitamin K.

Phytomenadione has been synthesized since at least 1939, and was approved by the FDA prior to 1955.
Phytomenadione is a Vitamin K and Warfarin Reversal Agent.
The physiologic effect of Phytomenadione is by means of Increased Prothrombin Activity and Reversed Anticoagulation Activity.

Phytomenadione is colorful foods high in vitamin k on white background
Phytomenadione is a fat-soluble vitamin that comes in two forms.
The main type is called Phytomenadione, found in green leafy vegetables like collard greens, kale, and spinach.

The other type, menaquinones, are found in some animal foods and fermented foods.
Menaquinones can also be produced by bacteria in the human body.
Phytomenadione is found throughout the body including the liver, brain, heart, pancreas, and bone.

Phytomenadione is broken down very quickly and excreted in urine or stool.
Because of this, Phytomenadione rarely reaches toxic levels in the body even with high intakes, as may sometimes occur with other fat-soluble vitamins.

Phytomenadione was first isolated in 1939.
In 1943 Edward Doisy and Henrik Dam were given a Nobel Prize for Phytomenadione's discovery.
Phytomenadione is often also called Phytomenadione, vitamin K, or phytonadione.

USES and APPLICATIONS of PHYTOMENADIONE:
Nutritional & Medical: Dietary Vitamin Supplement: Ensures adequate Phytomenadione levels in diets.
Medical Treatment: Phytomenadione is used clinically as phytonadione to treat Phytomenadione deficiency, warfarin overdose, and hypoprothrombinemia.

Newborn Prophylaxis: Phytomenadione prevents deficiency bleeding in infants.
In Food & Nutrition: Phytomenadione is found in green leafy vegetables (e.g., spinach, kale) and dietary oils.
Phytomenadione is used in the liver as the intermediate VKH2 to deprotonate a glutamate residue and then is reprocessed into Phytomenadione through a Phytomenadione oxide intermediate.

The presence of uncarboxylated proteins indicates a Phytomenadione deficiency.
Carboxylation allows them to bind (chelate) calcium ions, which they cannot do otherwise.
Without Phytomenadione, blood coagulation is seriously impaired, and uncontrolled bleeding occurs.

Research suggests that deficiency of Phytomenadione may also weaken bones, potentially contributing to osteoporosis, and may promote calcification of arteries and other soft tissues.
Phytomenadione is made by plants, and is found in highest amounts in green leafy vegetables, being directly involved in photosynthesis.

It is active as a vitamin in animals and performs the classic functions of Phytomenadione, including its activity in the production of blood-clotting proteins.
Animals may also convert it to vitamin2, variant MK-4.

Bacteria in the gut flora can also convert K1 into K2.
All forms of K2 other than MK-4 can only be produced by bacteria, which use these during anaerobic respiration.
Vitamin3 (menadione), a synthetic form of Phytomenadione, was used to treat Phytomenadione deficiency, but because it interferes with the function of glutathione, it is no longer used in this manner in human nutrition.

Veterinary uses: In Canada, Phytomenadione (Hemophyt) is indicated for the treatment of anticoagulant poisoning in dogs.
Phytomenadione helps to make various proteins that are needed for blood clotting and the building of bones.
Prothrombin is a Phytomenadione-dependent protein directly involved with blood clotting.

Osteocalcin is another protein that requires Phytomenadione to produce healthy bone tissue.
Phytomenadione is a fat-soluble vitamin, commonly called Vitamin K₁.
Phytomenadione plays a critical biological role in blood clotting, bone metabolism, and other physiological processes.

Phytomenadione is naturally found in green leafy vegetables and is an essential micronutrient for humans and animals.
Phytomenadione, also known as vitamin K1, Phytomenadione, or phytonadione, is a vitamin found in food and used as a dietary supplement.
Phytomenadione is on the World Health Organization's List of Essential Medicines.

Phytomenadione is used to treat certain bleeding disorders, including warfarin overdose, vitamin K deficiency, and obstructive jaundice.
Use Phytomenadione is typically recommended by mouth, intramuscular injection or injection under the skin.
When given by injection benefits are seen within two hours.

Phytomenadione is also recommended for preventing and treating vitamin K deficiency bleeding in infants.
Many countries in the world choose intramuscular injections in newborn to keep them safe from vitamin K deficiency bleeding.
It is considered a safe treatment and saves many children from death and severe neurologic deficit every year.

-Medical uses of Phytomenadione:
Phytomenadione is used to treat certain bleeding disorders, including warfarin overdose (also overdose of similar compounds such as coumatetralyl), vitamin K deficiency, and obstructive jaundice.
Phytomenadione is used to prevent and treat vitamin K deficiency bleeding in infants.

-Medical uses of Phytomenadione: 
Treating vitamin deficiency in newborns
Phytomenadione is given as an injection to newborns to prevent Phytomenadione deficiency bleeding.
The blood clotting factors of newborn babies are roughly 30–60% that of adult values.

This appears to be a consequence of poor transfer of the vitamin across the placenta, and thus low fetal plasma Phytomenadione.
Occurrence of Phytomenadione deficiency bleeding in the first week of the infant's life is estimated at between 1 in 60 and 1 in 250.
Human milk contains 0.85–9.2 μg/L (median 2.5 μg/L) of Phytomenadione1, while infant formula is formulated in range of 24–175 μg/L.

Late onset bleeding, with onset 2 to 12 weeks after birth, can be a consequence of exclusive breastfeeding, especially if there was no preventive treatment.
Late onset prevalence reported at 35 cases per 100,000 live births in infants who had not received prophylaxis at or shortly after birth.

Phytomenadione deficiency bleeding occurs more frequently in the Asian population compared to the Caucasian population.
Bleeding in infants due to Phytomenadione deficiency can be severe, leading to hospitalization, brain damage, and death.

Intramuscular injection, typically given shortly after birth, is more effective in preventing Phytomenadione deficiency bleeding than oral administration, which calls for weekly dosing up to three months of age.

-Managing warfarin therapy:
Warfarin is an anticoagulant drug.
It functions by inhibiting an enzyme that is responsible for recycling Phytomenadione to a functional state.

As a consequence, proteins that should be modified by Phytomenadione are not, including proteins essential to blood clotting, and are thus not functional.
The purpose of the drug is to reduce risk of inappropriate blood clotting, which can have serious, potentially fatal consequences.
The proper anticoagulant action of warfarin is a function of Phytomenadione intake and drug dose.

Due to differing absorption of the drug and amounts of Phytomenadione in the diet, dosing must be monitored and customized for each patient.
Some foods are so high in Phytomenadione1 that medical advice is to avoid those entirely.
Examples include collard greens, spinach, and turnip greens.

For foods with a modestly high vitamin content, consumption should be kept as consistent as possible.
This ensures that the combination of vitamin intake and warfarin keeps the anti-clotting activity in the therapeutic range.
Phytomenadione is a treatment for bleeding events caused by overdose of the drug.

The vitamin can be administered by mouth, intravenously or subcutaneously.
Oral Phytomenadione is used in situations when a person's International normalized ratio is greater than 10 but there is no active bleeding.
The newer anticoagulants apixaban, dabigatran and rivaroxaban are not Phytomenadione antagonists.

-Treating rodenticide poisoning uses of Phytomenadione:
Coumarin is used in the pharmaceutical industry as a precursor reagent in the synthesis of a number of synthetic anticoagulant pharmaceuticals.
One subset, 4-hydroxycoumarins, act as Phytomenadione antagonists.
They block the regeneration and recycling of Phytomenadione.

Some of the 4-hydroxycoumarin anticoagulant class of chemicals are designed to have high potency and long residence times in the body.
These are used specifically as second generation rodenticides.
Death occurs after a period of several days to two weeks, usually from internal hemorrhaging.

For humans, and for animals that have consumed either the rodenticide or rats poisoned by the rodenticide, treatment is prolonged administration of large amounts of Phytomenadione.
This dosing must sometimes be continued for up to nine months in cases of poisoning by superwarfarin rodenticides such as brodifacoum.
Oral Phytomenadione is preferred over other itroutes of administration because it has fewer side effects.

-Non-human uses of Phytomenadione:
Menadione, a natural compound sometimes referred to as vitamin3, is used in the pet food industry because once consumed it is converted to vitamin2.

The US Food and Drug Administration has banned this form from sale as a human dietary supplement because overdoses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.

4-amino-2-methyl-1-naphthol is a synthetic menadione analog often called vitamin5.
It has been used as a medicine for Phytomenadione deficiency.
Research with K5 suggests it may inhibit fungal growth in fruit juices.

CHARACTERISTICS & BENEFITS of PHYTOMENADIONE:
*Essential Nutrient: 
Vital for blood clotting and bone health.

*Low Toxicity: 
Safe at nutritional levels; deficiency risk is of greater concern than toxicity.

*Biological Activity: 
Phytomenadione helps regulate calcium-binding proteins.

SUMMARY OF KEY PROPERTIES of PHYTOMENADIONE:
Phytomenadione is a fat-soluble vitamin with chemical formula C₃₁H₄₆O₂, used as a nutrient and medical therapeutic agent (e.g., treating coagulopathy).
Phytomenadione is a yellow viscous liquid, insoluble in water, light sensitive, and plays a biological role in blood coagulation and bone health.

CHEMICAL PROPERTIES of PHYTOMENADIONE:
*Class: 
Fat-soluble vitamin, a 1,4-naphthoquinone derivative

*Functional Features: 
Quinone ring system with a long isoprenoid (phytyl) side chain
Vikipedi

*Stability:
Phytomenadione is stable in air and moisture but decomposes in sunlight and by strong bases

*Reactivity: 
Phytomenadione forms quinone derivatives through reduction/oxidation reactions during biological cycles

BIOLOGICAL FUNCTIONS of PHYTOMENADIONE:
Phytomenadione is a cofactor for the enzyme γ-glutamyl carboxylase, enabling post-translational carboxylation of specific proteins.
Phytomenadione activates key blood clotting factors (II/prothrombin, VII, IX, X) essential for hemostasis.
Phytomenadione is involved in bone metabolism and vascular health through modification of bone matrix proteins.
Phytomenadione plays a role in photosynthesis electron transport in plants.

DIETARY RECOMMENDATIONS of PHYTOMENADIONE:
The US National Academy of Medicine does not distinguish between K1 and K2 – both are counted as Phytomenadione.
When recommendations were last updated in 1998, sufficient information was not available to establish an estimated average requirement or recommended dietary allowance, terms that exist for most vitamins.

In instances such as these, the academy defines adequate intakes (AIs) as amounts that appear to be sufficient to maintain good health, with the understanding that at some later date, AIs will be replaced by more exact information.

The current AIs for adult women and men ages 19 and older are 90 and 120 μg/day, respectively, for pregnancy is 90 μg/day, and for lactation is 90 μg/day.
For infants up to 12 months, the AI is 2.0–2.5 μg/day.

For children ages 1–18 years the AI increases with age from 30 to 75 μg/day.
As for safety, the academy sets tolerable upper intake levels (known as "upper limits") for vitamins and minerals when evidence is sufficient.
Phytomenadione has no upper limit, as human data for adverse effects from high doses are not sufficient.

In the European Union, adequate intake is defined the same way as in the US.
For women and men over age 18 the adequate intake is set at 70 μg/day, for pregnancy 70 μg/day, and for lactation 70 μg/day.
For children ages 1–17 years, adequate intake values increase with age from 12 to 65 μg/day.

Japan set adequate intakes for adult women at 65 μg/day and for men at 75 μg/day.
The European Union and Japan also reviewed safety and concluded – as had the United States – that there was insufficient evidence to set an upper limit for Phytomenadione.

For US food and dietary supplement labeling purposes, the amount in a serving is expressed as a percentage of daily value.
For Phytomenadione labeling purposes, 100% of the daily value was 80 μg, but on 27 May 2016 it was revised upwards to 120 μg, to bring it into agreement with the highest value for adequate intake.

Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales.
A table of the old and new adult daily values is provided at Reference Daily Intake.

CHEMISTRY of PHYTOMENADIONE:
The structure of Phytomenadione, vitamin1, is marked by the presence of a phytyl sidechain.
Phytomenadione has an (E) trans double bond responsible for its biological activity, and two chiral centers on the phytyl sidechain.

Phytomenadione appears as a yellow viscous liquid at room temperature due to its absorption of violet light in the UV-visible spectra obtained by ultraviolet–visible spectroscopy.
The structures of menaquinones, vitamin2, are marked by the polyisoprenyl side chain present in the molecule that can contain four to 13 isoprenyl units.

MK-4 is the most common form.
The large size of Phytomenadione gives many different peaks in mass spectroscopy, most of which involve derivatives of the naphthoquinone ring base and the alkyl side chain.

PHYTOMENADIONE DEFICIENCY:
Because Phytomenadione aids mechanisms for blood clotting, its deficiency may lead to reduced blood clotting.
In severe cases, Phytomenadione can result in increased bleeding and increased prothrombin time.
Normal diets are usually not deficient in Phytomenadione, indicating that deficiency is uncommon in healthy children and adults.

An exception may be infants who are at an increased risk of deficiency regardless of Phytomenadione status of the mother during pregnancy and breast feeding due to poor transfer of the vitamin to the placenta and low amounts of the vitamin in breast milk.

Secondary deficiencies can occur in people who consume adequate amounts, but have malabsorption conditions, such as cystic fibrosis or chronic pancreatitis, and in people who have liver damage or disease.
Secondary Phytomenadione deficiency can also occur in people who have a prescription for a Phytomenadione antagonist drug, such as warfarin.
A drug associated with increased risk of Phytomenadione deficiency is cefamandole, although the mechanism is unknown.

METHODS OF ASSESSMENT of PHYTOMENADIONE:
An increase in prothrombin time, a coagulation assay, has been used as an indicator of Phytomenadione status, but it lacks sufficient sensitivity and specificity for this application.

Serum Phytomenadione is the most commonly used marker of Phytomenadione status.
Concentrations <0.15 μg/L are indicative of deficiency.

Disadvantages include exclusion of the other Phytomenadione vitamers and interference from recent dietary intake.
Phytomenadione is required for the gamma-carboxylation of specific glutamic acid residues within the Gla domain of the 17 Phytomenadione–dependent proteins.

Thus, a rise in uncarboxylated versions of these proteins is an indirect but sensitive and specific marker for Phytomenadione deficiency.
If uncarboxylated prothrombin is being measured, this "Protein induced by Phytomenadione Absence/antagonism (PIVKA-II)" is elevated in Phytomenadione deficiency.

The test is used to assess risk of Phytomenadione–deficient bleeding in newborn infants.
Osteocalcin is involved in calcification of bone tissue.
The ratio of uncarboxylated osteocalcin to carboxylated osteocalcin increases with Phytomenadione deficiency.

Vitamin 2 has been shown to lower this ratio and improve lumbar vertebrae bone mineral density.
Matrix Gla protein must undergo Phytomenadione dependent phosphorylation and carboxylation.
Elevated plasma concentration of dephosphorylated, uncarboxylated MGP is indicative of Phytomenadione deficiency.

SYNTHETIC FORMS of PHYTOMENADIONE:
Some synthetic compounds also have Phytomenadione activity in humans.
One synthetic drug with Phytomenadione activity still used in developed countries (the UK) is menadiol sodium diphosphate.
Unlike natural Phytomenadione, it is water-soluble and can be absorbed without the help of bile salts.

BIOCHEMISTRY of PHYTOMENADIONE:
Function in animals
Phytomenadione is distributed differently within animals depending on its specific homologue.
Phytomenadione1 is mainly present in the liver, heart and pancreas, while MK-4 is better represented in the kidneys, brain and pancreas.

The liver also contains longer chain homologues MK-7 to MK-13.
The function of vitamin2 in the animal cell is to add a carboxylic acid functional group to a glutamate (Glu) amino acid residue in a protein, to form a gamma-carboxyglutamate (Gla) residue.

This is a somewhat uncommon posttranslational modification of the protein, which is then known as a Gla protein.
The presence of two −COOH (carboxylic acid) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate calcium ions.

The binding of calcium ions in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called Phytomenadione–dependent clotting factors discussed below.
Within the cell, Phytomenadione participates in a cyclic process.

The vitamin undergoes electron reduction to a reduced form called Phytomenadione hydroquinone (quinol), catalyzed by the enzyme Phytomenadione epoxide reductase (VKOR).
Another enzyme then oxidizes Phytomenadione hydroquinone to allow carboxylation of Glu to Gla.
This enzyme is called gamma-glutamyl carboxylase or the Phytomenadione–dependent carboxylase.

The carboxylation reaction only proceeds if the carboxylase enzyme is able to oxidize Phytomenadione hydroquinone to Phytomenadione epoxide at the same time.
The carboxylation and epoxidation reactions are said to be coupled.
Phytomenadione epoxide is then restored to Phytomenadione by VKOR.

The reduction and subsequent reoxidation of Phytomenadione coupled with carboxylation of Glu is called the Phytomenadione cycle.
Humans are rarely deficient in Phytomenadione because, in part, Phytomenadione2 is continuously recycled in cells.
Warfarin and other 4-hydroxycoumarins block the action of VKOR.

This results in decreased concentrations of Phytomenadione and Phytomenadione hydroquinone in tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient.
This results in the production of clotting factors with inadequate Gla.

Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury.
As it is impossible to predict what dose of warfarin will give the desired degree of clotting suppression, warfarin treatment must be carefully monitored to avoid underdose and overdose.

ABSORPTION of PHYTOMENADIONE:
Phytomenadione is absorbed through the jejunum and ileum in the small intestine.
The process requires bile and pancreatic juices.
Estimates for absorption are on the order of 80% for Phytomenadione in its free form (as a dietary supplement) but much lower when present in foods.

For example, the absorption of Phytomenadione from kale and spinach, foods identified as having a high Phytomenadione content, are on the order of 4% to 17% regardless of whether raw or cooked.
Less information is available for absorption of Vitamin 2 from foods.

The intestinal membrane protein Niemann–Pick C1-like 1 (NPC1L1) mediates cholesterol absorption.
Animal studies show that it also factors into absorption of vitamins E and K1.

The same study predicts potential interaction between SR-BI and CD36 proteins as well.
The drug ezetimibe inhibits NPC1L1 causing a reduction in cholesterol absorption in humans, and in animal studies, also reduces vitamin E and Phytomenadione1 absorption.

An expected consequence would be that administration of ezetimibe to people who take warfarin, a Phytomenadione antagonist, would potentiate the warfarin effect.
This has been confirmed in humans.

PHYSIOLOGY of PHYTOMENADIONE:
In animals, Phytomenadione is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate (Gla) residues.
The modified residues are often (but not always) situated within specific protein domains called Gla domains.
Gla residues are usually involved in binding calcium, and are essential for the biological activity of all known Gla proteins.
17 human proteins with Gla domains have been discovered.
They play key roles in the regulation of three physiological processes.

Blood coagulation: 
prothrombin (factor II), factors VII, IX, and X, and proteins C, S, and Z.

Bone metabolism: 
osteocalcin, matrix Gla protein (MGP), periostin, and Gla-rich protein.

Vascular biology: 
Matrix Gla protein, growth arrest–specific protein 6 (Gas6).

Unknown functions: 
proline-rich γ-carboxyglutamyl proteins 1 and 2, and transmembrane γ-carboxy glutamyl proteins 3 and 4.

FOOD SOURCES of PHYTOMENADIONE:
Green leafy vegetables including collard and turnip greens, kale, spinach, broccoli, Brussels sprouts, cabbage, lettuces
Soybean and canola oil
Salad dressings made with soybean or canola oil
Fortified meal replacement shakes
Menaquinones
Natto (fermented soybeans)
Smaller amounts in meat, cheese, eggs

CHEMISTRY of PHYTOMENADIONE:
Phytomenadione is a fat-soluble vitamin that is stable in air and moisture but decomposes in sunlight.
Phytomenadione is a polycyclic aromatic ketone, based on 2-methyl-1,4-naphthoquinone, with a 3-phytyl substituent.
Phytomenadione 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.

BIOLOGICAL FUNCTION of PHYTOMENADIONE:
*Animals
The best-known function of Phytomenadione in animals is as a cofactor in the formation of coagulation factors II (prothrombin), VII, IX, and X by the liver.
Phytomenadione is also required for the formation of anticoagulant factors protein C and S.

Phytomenadione is required for bone protein formation.
In terms of distribution, Phytomenadione typically occurs in higher levels in the liver, heart and pancreas, but in lower levels in the brain, kidneys, and lungs.

*Plants and cyanobacteria
Phytomenadione is required for plant photosynthesis, where it participates in the Photosystem I electron transport chain.

*Biosynthesis
Phytomenadione is synthesized from chorismate, a compound produced from shikimate via the shikimate pathway.
The conversion of chorismate to Phytomenadione comprises a series of nine steps.

SOURCES of PHYTOMENADIONE:
Phytomenadione is primarily from plants, especially leafy green vegetables.
Small amounts are provided by animal-sourced foods.
Vitamin2 is primarily from animal-sourced foods, with poultry and eggs much better sources than beef, pork or fish.

One exception to the latter is nattō, which is made from bacteria-fermented soybeans.
Phytomenadione is a rich food source of Vitamin 2 variant MK-7, made by the bacteria.

FUNCTION IN PLANTS AND CYANOBACTERIA of PHYTOMENADIONE:
Phytomenadione is an important chemical in green plants (including land plants and green algae) and some species of cyanobacteria, where it functions as an electron acceptor transferring one electron in photosystem I during photosynthesis.
For this reason, Phytomenadione is found in large quantities in the photosynthetic tissues of plants (green leaves, and dark green leafy vegetables such as romaine lettuce, kale, and spinach), but it occurs in far smaller quantities in other plant tissues.

FUNCTION IN OTHER BACTERIA, PHYTOMENADIONE:
Many bacteria, including Escherichia coli found in the large intestine, can synthesize vitamin 2 (MK-7 up to MK-11), but not Phytomenadione.
In the vitamin  2 (menaquinone)–synthesizing bacteria, menaquinone transfers two electrons between two different small molecules during oxygen-independent metabolic energy production processes (anaerobic respiration).

For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, passes two electrons to menaquinone.

The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such as fumarate or nitrate (also called an electron acceptor).
Adding two electrons to fumarate or nitrate converts the molecule to succinate or nitrite plus water, respectively.

Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except the final electron acceptor is not molecular oxygen, but fumarate or nitrate.

In aerobic respiration, the final oxidant is molecular oxygen, which accepts four electrons from an electron donor such as NADH to be converted to water.
E. coli, as facultative anaerobes, can carry out both aerobic respiration and menaquinone-mediated anaerobic respiration.

PHYSICAL and CHEMICAL PROPERTIES of PHYTOMENADIONE:
Formula: C31H46O2
Molar mass: 450.707 g•mol−1
Molecular Weight: 450.7 g/mol
XLogP3-AA: 10.9
Hydrogen Bond Donor Count: 0
Hydrogen Bond Acceptor Count: 2
Rotatable Bond Count: 14
Exact Mass: 450.349780706 Da
Monoisotopic Mass: 450.349780706 Da
Topological Polar Surface Area: 34.1 Ų
Heavy Atom Count: 33

Formal Charge: 0
Complexity: 696
Isotope Atom Count: 0
Defined Atom Stereocenter Count: 2
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 1
Undefined Bond Stereocenter Count: 0
Covalently-Bonded Unit Count: 1
Compound Is Canonicalized: Yes
Physical state: viscous

Color: dark, yellow, green
Odor: No data available
Melting point/freezing point: Melting point/ range: -20 °C
Initial boiling point and boiling range: No data available
Flammability (solid, gas): No data available
Upper/lower flammability or explosive limits: No data available
Flash point: > 113 °C - closed cup
Autoignition temperature: No data available

Decomposition temperature: No data available
pH: No data available
Viscosity: Viscosity, kinematic: No data available
Viscosity: Viscosity, dynamic: No data available
Water solubility: No data available
Partition coefficient n-octanol/water: No data available
Vapor pressure: No data available
Density: 0,984 g/cm3 at 20 °C
Relative density: No data available

Relative vapour density: No data available
Particle characteristics: No data available
Explosive properties: No data available
Oxidizing properties: No data available
Other safety information: No data available
IUPAC Name: 2-methyl-3-[(E,7R,11R)-3,7,11,15-tetramethylhexadec-2-enyl]-1,4-naphthoquinone
Common Name: Phytomenadione
Other Name: Vitamin K₁

CAS Number: 84-80-0
EC Number (EINECS): 201-564-2
Molecular Formula: C₃₁H₄₆O₂
Molecular Weight: ~450.70 g/mol
PubChem CID: 5284607
ChemSpider ID: 4447652
Appearance: Viscous liquid, yellow to dark yellow
Odor: Odorless
State at 25 °C: Liquid (viscous)
Melting Point: ~-20 °C
Boiling Point: ~140 °C at 0 mmHg (under vacuum)

Flash Point: >110 °C (closed cup)
Density / Specific Gravity: ~0.984 g/mL at 25 °C
Solubility: Insoluble in water; miscible in organic solvents (ethanol, acetone, chloroform, hexane)
Refractive Index: ~1.527
Light Sensitivity: Sensitive to light (decomposes)
Empirical Formula (Hill Notation): C31H46O2
CAS Number: 84-80-0
Molecular Weight: 450.70
UNSPSC Code: 12352115
EC Index Number: 201-564-2
MDL number: MFCD00214063

FIRST AID MEASURES of PHYTOMENADIONE:
-Description of first-aid measures
*General advice:
Show this material safety data sheet to the doctor in attendance.
*If inhaled:
After inhalation: 
Fresh air.
*In case of skin contact: 
Take off immediately all contaminated clothing. 
Rinse skin with
water/ shower.
*In case of eye contact:
After eye contact: 
Rinse out with plenty of water. 
Call in ophthalmologist. 
Remove contact lenses.
*If swallowed:
After swallowing: 
Immediately make victim drink water (two glasses at most). 
Consult a physician.
-Indication of any immediate medical attention and special treatment needed.
No data available

ACCIDENTAL RELEASE MEASURES of PHYTOMENADIONE:
-Environmental precautions:
Do not let product enter drains.
-Methods and materials for containment and cleaning up:
Cover drains. 
Collect, bind, and pump off spills. 
Observe possible material restrictions. 
Take up dry. 
Dispose of properly. 
Clean up affected area.

FIRE FIGHTING MEASURES of PHYTOMENADIONE:
-Extinguishing media:
*Suitable extinguishing media:
Carbon dioxide (CO2) 
Foam 
Dry powder
*Unsuitable extinguishing media:
For this substance/mixture no limitations of extinguishing agents are given.
-Further information:
Prevent fire extinguishing water from contaminating surface water or the ground water system.

EXPOSURE CONTROLS/PERSONAL PROTECTION of PHYTOMENADIONE:
-Control parameters:
--Ingredients with workplace control parameters:
-Exposure controls:
--Personal protective equipment:
*Eye/face protection:
Use equipment for eye protection. 
Safety glasses
*Body Protection:
protective clothing
*Respiratory protection:
Recommended Filter type: Filter A 
-Control of environmental exposure:
Do not let product enter drains.

HANDLING and STORAGE of PHYTOMENADIONE:
-Conditions for safe storage, including any incompatibilities:
*Storage conditions:
Tightly closed. 
Dry.

STABILITY and REACTIVITY of PHYTOMENADIONE:
-Chemical stability:
The product is chemically stable under standard ambient conditions (room temperature).
-Possibility of hazardous reactions:
No data available