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Vitamin K₂ (menaquinone). In menaquinone the side chain is composed of a varying number of isoprenoid residues.

Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation but also involved in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives. This group of vitamins includes Vitamin K₁ and vitamin K₂.

Vitamin K₁ is also known as phylloquinone or phytomenadione (also called phytonadione). Plants synthesize vitamin K₁ while bacteria can produce a range of vitamin K₂ forms, including the conversion of K₁ to K₂ by bacteria in the small intestines. No known toxicity exists for vitamins K₁ and K₂.

Vitamin K₂ (menaquinone), is itself a category of vitamin K that includes many types of vitamin K₂. The two subtypes of vitamin K₂ that have been most studied are menaquinone-4 (menatetrenone, MK4) and menaquinone-7 (MK7). MK4 is produced via conversion of vitamin K₁ in the body, in the testes, pancreas and arterial walls.^[1] While major questions still surround the biochemical pathway for the transformation of vitamin K₁ to MK4, studies demonstrate that the conversion is not dependent on gut bacteria, occuring in germ-free rats^[2]^[3] and in parenterally-administered K1 in rats.^[4]^[5] In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available K1 into MK4.^[6]^[7]

In contrast to MK4, MK7 is not produced by humans but is converted from phylloquinone in the intestines by gut bacteria.^[8] However, bacteria-derived menaquinones appear to contribute minimally to overall vitamin K status.^[9]^[10] MK4 and MK7 are both found in the United States in dietary supplements for bone health. The US FDA has not approved any form of vitamin K for the prevention or treatment of osteoporosis; however, MK4 has been shown to decrease fractures up to 87%,^[11] speed fracture healing and prevent and reverse bone loss from medications. In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.^[12] prevented bone loss and/or fractures caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),^[13]^[14]^[15]^[16] anorexia nervosa,^[17] cirrhosis of the liver,^[18] postmenopausal osteoporosis,^[19]^[20]^[21]^[22]^[23]^[24], disuse from stroke,^[25] Alzheimer’s disease,^[26] Parkinson disease,^[27] primary biliary cirrhosis^[28] and leuprolide treatment (for prostate cancer).^[29]

The old theory says that dietary deficiency is extremely rare unless the intestines are heavily damaged, are unable to absorb the molecule, or are subject to decreased production by normal flora, as seen in broad spectrum antibiotic use.^[30] Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared to those not taking these antibiotics.^[31] Diets low in vitamin K also decrease the body's vitamin K concentration.^[32] Additionally, in the elderly there is a reduction in vitamin K2 production.^[33]

Recent research results also demonstrate that the bowels seems to be inefficient at absorbing vitamins K.^[34]^[35] These results are reinforced by human cohort studies, where a majority of the subjects showed inadequate vitamins K amounts in the body. This was revealed by the presence of large amounts of incomplete gamma-carboxylated proteins in the blood, an indirect test for vitamins K deficiency.^[36]^[37]^[38] And in an animal model MK4 was shown to prevent arterial calcifications, pointing to its potential role in cardiovascular disease prevention.^[39] In this study vitamin K₁ was also tested and shown to not prevent arterial calfications.

There are three synthetic forms of vitamin K, vitamins K₃, K₄, and K₅, which are used in many areas including the pet food industry (vitamin K₃) and to inhibit fungal growth (vitamin K₅).^[40]

Chemical structure

All members of the vitamin K group of vitamins share a methylated naphthoquinone ring structure, and vary in the aliphatic side chain attached at the 3-position (see figure 1). Phylloquinone (also known as vitamin K₁) invariably contains in its side chain four isoprenoid residues, one of which is unsaturated.

Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids.

It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur.

Physiology

Vitamin K is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate residues (abbreviated 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. The Gla-residues are essential for the biological activity of all known Gla-proteins.^[41]

At this time^[update] 15 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:

Blood coagulation: (prothrombin (factor II), factors VII, IX, X, protein C, protein S, and protein Z).^[42]
Bone metabolism: osteocalcin, also called bone Gla-protein (BGP), matrix gla protein (MGP),^[43] and periostin.^[44]
Vascular biology: growth arrest-specific protein 6 (Gas6)^[45]
unknown function: proline-rich g-carboxy glutamyl proteins (PRGPs) 1 and 2, and transmembrane g-carboxy glutamyl proteins (TMGs) 3 and 4.^[46]

Like other liposoluble vitamins (A, D, E), vitamin K is stored in the fat tissue of the human body.

Recommended amounts

The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) of vitamin K for a 25-year old male is 120 micrograms/day. The Adequate Intake (AI) for adult women is 90 micrograms/day, for infants is 10–20 micrograms/day, for children and adolescents 15–100 micrograms/day. In 2002 it was found that to get maximum carboxylation of osteocalcin, one may have to take up to 1000 μg of vitamin K₁.^[47]

Toxicity

Although allergic reaction from supplementation is possible, there is no known toxicity associated with high doses of the phylloquinone (vitamin K₁) or menaquinone (vitamin K₂) forms of vitamin K and therefore no tolerable upper intake level (UL) has been set. ^{[citation needed]}

However, a synthetic form of vitamin K, vitamin K₃ (menadione), is demonstrably toxic. In fact, the FDA has banned this synthetic form of the vitamin from over-the-counter supplements because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.^[48]

Drug interactions

Phylloquinone (K₁)^[49]^[50] or menaquinone (K₂) are capable of blocking the blood thinning action of anticoagulants like warfarin, which work by interfering with the action of vitamin K. They also reverse the tendency of these drugs to cause arterial calcification in the long term.

Sources

Vitamin K₁ is found chiefly in leafy green vegetables such as spinach, swiss chard, and Brassica (e.g. cabbage, kale, cauliflower, broccoli, and brussels sprouts); some fruits such as avocado, kiwifruit and grapes are also high in vitamin K. By way of reference, two tablespoons of parsley contain 153% of the recommended daily amount of vitamin K.^[51] Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large calorific consumption to meet the USDA recommended levels.^[52] Colonic bacteria synthesize a significant portion of humans' vitamin K needs- this is one of the reasons why newborns often receive a vitamin K shot at birth- in order to tide them over until day 5-7 when their colon becomes colonized.

It is believed that phylloquinone's tight binding to the thylakoid membranes in the chloroplasts is the reason behind the poor bioavailability of vitamin K in green plants. For example, cooked spinach has a 5 percent bioavailability of phylloquinone. However when one adds fat to the spinach, the bioavailability increases to 13 percent due to the increased solubility of vitamin K in fat.^[53]

Menaquinone-4 and menaquinone-7 (vitamin K₂) are found in meat, eggs, dairy,^[54] and natto.^[55] MK-4 is synthesized by animal tissues, the rest (mainly MK-7) are synthesized by bacteria during fermentation. In natto 0% of vitamin K is from MK-4 and in cheese 2–7%.^[56]

Deficiency

Average diets are usually not lacking in vitamin K and primary vitamin K deficiency is rare in healthy adults. As previously mentioned, newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include individuals who suffer from liver damage or disease (e.g. alcoholics), people with cystic fibrosis, inflammatory bowel diseases or those who have recently had abdominal surgeries. Groups that may suffer from secondary vitamin K deficiency include bulimics, those on stringent diets, and those taking anticoagulants. Other drugs that have been associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanism is still unknown. There is no difference between the sexes as both males and females are affected equally. Symptoms of deficiency include heavy menstrual bleeding in women, anemia, bruising, and bleeding of the gums or nose. They could also have disorders such as coagulopathy.^[56]

Osteoporosis^[57]^[58] and coronary heart disease^[59]^[60] are strongly associated with lower levels of K₂ (menaquinone). Menaquinone is not inhibited by salicylates as happens with K₁, so menaquinone supplementation can alleviate the chronic vitamin K deficiency caused by long term aspirin use.^{[citation needed]}

Biochemistry

Discovery

In 1929, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet.^[61] After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that—together with the cholesterol—a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K.^[62] Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K₁ and K₂) published in 1939. Several laboratories synthesized the compound(s) in 1939.^[63]

For several decades the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg).^[64]

The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.^[65]

Function

The function of vitamin K in the cell is to convert glutamate in proteins to gamma-carboxyglutamate (gla).

Within the cell, vitamin K undergoes electron reduction to a reduced form of vitamin K (called vitamin K hydroquinone) by the enzyme vitamin K epoxide reductase (or VKOR).^[66] Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase^[67]^[68] or the vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to vitamin K by vitamin K epoxide reductase. These two enzymes comprise the so-called vitamin K cycle.^[69] One of the reasons humans are rarely deficient in vitamin K is that vitamin K is continually recycled in our cells.

Warfarin and other coumarin drugs block the action of the vitamin K epoxide reductase.^[70] This results in decreased concentrations of vitamin K and vitamin K hydroquinone in the 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 suppression of the clotting, warfarin treatment must be carefully monitored to avoid over-dosing. (See the warfarin article.)

Gamma-carboxyglutamate proteins, or Gla-proteins

At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting protein Z. The bone Gla-protein osteocalcin, the calcification inhibiting matrix gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a growth factor that activates the Axl receptor tyrosine kinase and stimulates cell proliferation or prevents apoptosis in some cells. In all cases in which their function was known, the presence of the Gla-residues in these proteins turned out to be essential for functional activity.

Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.

Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus.^[71] These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2–5 Gla residues.^[72]

Methods of assessment

Prothrombin time test:

Measures the time required for blood to clot

Blood sample mixed with citric acid and put in a fibrometer.

Delayed clot formation indicates a deficiency.

Unfortunately insensitive to mild deficiency as the values do not change until the concentration of prothrombin in the blood has declined by at least 50 percent ^[73]

Plasma Phylloquinone:

Was found to be positively correlated with phylloquinone intake in elderly British women, but not men ^[74]

However an article by Schurges et al. reported no correlation between FFQ and plasma phylloquinone ^[75]

Urinary γ-carboxyglutamic acid:

Urinary Gla responds to changes in dietary vitamin K intake.

Several days are required before any change can be observed.

In a study by Booth et al. increases of phylloquinone intakes from 100 μg to between 377–417 μg for 5 days did not induce a significant change Response may be age-specific ^[76]

Function in bacteria

Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K₂ (menaquinone),^[77] but not vitamin K₁ (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called anaerobic respiration.^[78] 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, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate will convert the molecule to succinate or nitrite + water, respectively. Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except that the final electron acceptor is not molecular oxygen, but say fumarate or nitrate (In aerobic respiration, the final oxidant is molecular oxygen (O₂) , which accepts four electrons from an electron donor such as NADH to be converted to water.) Escherichia coli can carry out aerobic respiration and menaquninone-mediated anaerobic respiration.

Vitamin K injection in newborns

The blood clotting factors of newborn babies are roughly 30 to 60 percent that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains between 1 and 4 micrograms/litre of vitamin K₁, while formula derived milk can contain up to 100 micrograms/litre in supplemented formulas. Vitamin K₂ concentrations in human milk appear to be much lower than those of vitamin K₁. It is estimated that there is a 0.25 to 1.7 percent occurrence of vitamin K deficiency bleeding in the first week of the infant's life with a prevalence of 2-10 cases per 100,000 births.^[79] Premature babies have even lower levels of the vitamin and are at a higher risk from this deficiency.

USA

As a result of the occurrences of vitamin K deficiency bleeding, the Committee on Nutrition of the American Academy of Pediatrics has recommended that 0.5 to 1.0 mg vitamin K₁ be administered to all newborns shortly after birth.^[80]

UK

In the UK, vitamin K is administered to newborns as either a single injection at birth or three orally administered doses given at birth and then over the baby's first month.

Controversy

Controversy arose in the early 1990s regarding this practice when two studies were shown suggesting a relationship between parenteral administration of vitamin K and childhood cancer (14)^{[verification needed]}^{[citation needed]}. However, poor methods and small sample sizes led to the discrediting of these studies and a review of the evidence published in 2000 by Ross and Davies found no link between the two.^[81]^{[verification needed]}

Dietary vitamin K and bone health

The role vitamin K plays in bone metabolism triggered a new thinking in its use as a therapeutic agent in diseases related with bone like osteoporosis. Vit. K takes part in the post translational modification as a co‐factor in γ‐ carboxylation of Vit. K dependant proteins (VKDPs). VKDPs have glutamate residues (Glu). There is physiological and observational evidence that vitamin K plays a role in bone growth and the maintenance of bone density, but efforts to delay the onset of osteoporosis by vitamin K supplementation have proven ineffective.

Biophysical studies have indicated that supplemental vitamin K promotes osteotrophic processes and slows osteoclastic processes via calcium bonding. Study of Atkins et al.(Gerald JA, Katie JW, Asiri R W, et al. (2009) Vitamin K promotes mineralization, osteoblast‐to‐osteocyte transition, and an anticatabolic phenotype by γ‐carboxylation‐dependent and independent mechanisms. Am J Physiol Cell Physiol 297, C1358–C1367) revealed that phylloquinone (Vitamin K1), menatetrenone (Vit. K2) and manadione (Vit. K1) promote in vitro mineralisaton by human primary osteoblasts.Other studies have shown that vitamin K antagonists (usually a class of anticoagulants) lead to early calcification of the epiphysis and epiphysial line in mice and other animals, causing seriously decreased bone growth. This is due to defects in osteocalcin and matrix gla protein. Their primary function is to prevent overcalcification of the bone and cartilage. Vitamin K is important in the process of carboxylating glutamic acid (Glu) in these proteins to gamma-carboxyglutamic acid (Gla), which is necessary for their function.^[82]^[83] Vitamin D is reported to regulate the OC transcribtion by osteoblast thereby showing that Vit. K and Vik. D works in tandem for the bone metabolism and development. Lian and his group (Lian J, Stewart C, Puchacz E, Mackowiak S, Shalhoub V, Collart D, Zambetti G & Stein G (1989) Structure of the rat osteocalcin gene and regulation of vitamin D‐dependent expression. Proc Natl Acad Sci 86, 1143–1147) discovered two nucleotide substitution regions which they named "osteocalcin box" in the rat and human osteocalcin genes. They found a region 600 nucleotides immediately upstream from the transcription start site that support a 10‐fold stimulated transcription of the gene by 1, 25‐dihydroxy vitamin D.

Data from the 1998 Nurses Health Study, an observational study, indicated an inverse relationship between dietary vitamin K₁ and the risk of hip fracture. After being given 110 micrograms/day of vitamin K, women who consumed lettuce one or more times per day had a significantly lower risk of hip fracture than women who consumed lettuce one or fewer times per week. In addition to this, high intakes of vitamin D but low intakes of vitamin K were suggested to pose an increased risk of hip fracture.^[83]^[84] Firmingham Heart Study (Booth SL, Tucker K, Chen H, et al. (2000) Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr 71, 1201–1208.) is another study that showed the similar result. Subjects in the highest quartile of Vit. K1 intake (median K1 intake of 254 μg/ day) has 35% lower risk of hip fracture than those in the lowest quartile. Comparing with the daily recommended intake (DRI) of 90 and 120 μg/ day, both the above intakes are higher than existing DRI indicating the need for the revision of DRI taking into consideration the role it plays in bone health.

However, a large multicentre randomized placebo-controlled trial was performed to test the supplementation of vitamin K in post-menopausal women with osteopenia. Despite heavy doses of vitamin K₁, no differences were found in bone density between the supplemented and placebo groups.^[85]

In Japan, a form of vitamin K₂ is recognized as a treatment for osteoporosis.^[84]^[86] However the long term effects and benefits are unknown and it remains controversial.

Vitamin K and Alzheimer's disease

Research into the antioxidant properties of vitamin K indicates that the concentration of vitamin K is lower in the circulation of carriers of the APOE4 gene, and recent studies have shown its ability to inhibit nerve cell death due to oxidative stress. It has been hypothesized that vitamin K may reduce neuronal damage and that supplementation may hold benefits to treating Alzheimer's disease, although more research is necessary in this area.^[87]

Vitamin K used topically

Vitamin K may be applied topically, typically as a 5% cream, to diminish postoperative bruising from cosmetic surgery and injections, broken capillaries (spider veins), to treat rosacea and to aid in the fading of hyperpigmentation and dark under-eye circles.^{[citation needed]}

Vitamin K and cancer

While researchers in Japan were studying the role of vitamin K₂ in the prevention of bone loss in females with liver disease, they discovered another possible effect of this phytonutrient. This two year study which involved 21 women with viral liver cirrhosis found that women in the supplement group were 90 percent less likely to develop liver cancer.^[88]^[89] A German study performed on men with prostate cancer found a significant inverse relationship between vitamin K₂ consumption and advanced prostate cancer.^[90]

Vitamin K as antidote for poisoning by 4-hydroxcoumarin drugs

Vitamin K is a true antidote for poisoning by 4-hydroxycoumarin anticoagulant drugs (sometimes loosely referred to as coumarins). These include the pharmaceutical warfarin, and also anticoagulant-mechanism poisons such as bromadiolone, which are commonly found in rodenticides. 4-hydroxycoumarin drugs possess anticoagulatory and rodenticidal properties because they inhibit vitamin K-dependent synthesis of some clotting factors by the liver. Death is usually a result of internal hemorrhage. Treatment usually consists of repeated intravenous doses of vitamin K, followed by doses in pill form for a period of at least two weeks, though possibly up to 2 months, afterwards (in the case of the more potent 4-hydoxycoumarins used as rodenticides). If caught early, prognosis is good, even when great amounts of the drug or poison are ingested.

History of discovery

The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al.,^[91] Nelsestuen et al.,^[92] and Magnusson et al.^[93]) isolated the vitamin K-dependent coagulation factor prothrombin (Factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that while warfarin-treated cows had a form of prothrombin that contained 10 glutamate amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.

The biochemistry of how vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world.

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^ Sato, Y (2002). "Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency". Bone. 31 (1): 114–118. PMID 12110423. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Nishiguchi, S (2001). "Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis". Journal of Hepatology. 35 (4): 543–545. PMID 11682046. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Somekawa, Y (1999). "Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide". The Journal of clinical endocrinology and metabolism. 84 (8): 2700–2704. PMID 10443663. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ "Vitamin K". Retrieved 2009-05-26.
^ Conly, J (1994). "Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials". Clinical and investigative medicine. Médecine clinique et experimentale. 17 (6): 531–539. PMID 7895417. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Ferland, G (1993). "Dietary induced subclinical vitamin K deficiency in normal human subjects". Clinical and investigative medicine. Médecine clinique et experimentale. 91 (4): 1761–1768. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Hodges, SJ (1990). "Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8". Clin Sci (Lond). 78 (1): 63–66. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Groenen-van Dooren MM et coll. ”Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats”. Biochem Pharmacol. 1995 Sep 7;50(6):797-801.
^ Komai M, Shirakawa H. Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function. Clin Calcium. 2007 Nov;17(11):1663-72.Komai M, Shirakawa H. Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function. Clin Calcium. 2007 Nov;17(11):1663-72.
^ Geleijnse J. M. et coll. Dietary Intake of Menaquinone is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study. The American Society for Nutritional Sciences J. Nutr. 134:3100-3105, November 2004.
^ Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009 Apr;203(2):489-93.
^ Nimptsch K, Rohrmann S, Kaaks R, Linseisen J. Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr. 2010 May;91(5):1348-58. Epub 2010 Mar 24.
^ Spronk, HMH (2003). "Tissue-Specific Utilization of Menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats". Journal of vascular research. 40 (6): 531–537. PMID 14654717. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ McGee, W (2007-02-01). "Vitamin K". MedlinePlus. Retrieved 2009-04-02.
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^ Mann KG (1999). "Biochemistry and physiology of blood coagulation". Thromb. Haemost. 82 (2): 165–74. PMID 10605701.
^ Price PA (1988). "Role of vitamin-K-dependent proteins in bone metabolism". Annu. Rev. Nutr. 8: 565–83. doi:10.1146/annurev.nu.08.070188.003025. PMID 3060178.
^ Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J (2008). "Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells". J. Biol. Chem. 283 (26): 17991–18001. doi:10.1074/jbc.M708029200. PMID 18450759.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ Hafizi S, Dahlbäck B (2006). "Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily". FEBS J. 273 (23): 5231–44. doi:10.1111/j.1742-4658.2006.05529.x. PMID 17064312.
^ Kulman JD, Harris JE, Xie L, Davie EW (2007). "Proline-rich Gla protein 2 is a cell-surface vitamin K-dependent protein that binds to the transcriptional coactivator Yes-associated protein". Proc. Natl. Acad. Sci. U.S.A. 104 (21): 8767–72. doi:10.1073/pnas.0703195104. PMID 17502622.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Neil C Binkley, Diane C Krueger, Tisha N Kawahara, Jean A Engelke, Richard J Chappell and John W Suttie. "A high phylloquinone intake is required to achieve maximal osteocalcin {gamma}-carboxylation". American Journal of Clinical Nutrition. 76 (5).{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Higdon (February 2008). "Vitamin K". Linus Pauling Institute, Oregon State University. Retrieved 2008-04-12.
^ Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E (2004). "The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest. 126 (3 Suppl): 204S–233S. doi:10.1378/chest.126.3_suppl.204S. PMID 15383473.{{cite journal}}: CS1 maint: multiple names: authors list (link) (summary)
^ Crowther MA, Douketis JD, Schnurr T; et al. (2002). "Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of [[warfarin]]-associated coagulopathy. A randomized, controlled trial" (PDF). Ann. Intern. Med. 137 (4): 251–4. PMID 12186515. {{cite journal}}: Explicit use of et al. in: |author= (help); URL–wikilink conflict (help)CS1 maint: multiple names: authors list (link)
^ Nutrition Facts and Information for Parsley, raw
^ Nutrition facts, calories in food, labels, nutritional information and analysis – NutritionData.com
^ NutritionData.com
^ Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL (2006). "Vitamin k contents of meat, dairy, and fast food in the u.s. Diet". J. Agric. Food Chem. 54 (2): 463–7. doi:10.1021/jf052400h. PMID 16417305. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M (2000). "Intake of fermented soybean (natto) increases circulating vitamin K₂ (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals". J. Bone Miner. Metab. 18 (4): 216–22. doi:10.1007/s007740070023. PMID 10874601.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b "On the Trail of the Elusive X-Factor: Vitamin K2 Revealed". Cite error: The named reference "urlOn the Trail of the Elusive X-Factor: Vitamin K2 Revealed" was defined multiple times with different content (see the help page).
^ Ikeda; Iki, M; Morita, A; Kajita, E; Kagamimori, S; Kagawa, Y; Yoneshima, H (2006). "Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study". The Journal of nutrition. 136 (5): 1323–8. PMID 16614424.
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^ Dam, Henrik (December 12, 1946). The discovery of vitamin K, its biological functions and therapeutical application. Nobel Prize lecture
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^ Suttie JW (1985). "Vitamin K-dependent carboxylase". Annu. Rev. Biochem. 54: 459–77. doi:10.1146/annurev.bi.54.070185.002331. PMID 3896125.
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^ Stafford DW (2005). "The vitamin K cycle". J. Thromb. Haemost. 3 (8): 1873–8. doi:10.1111/j.1538-7836.2005.01419.x. PMID 16102054. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Whitlon DS, Sadowski JA, Suttie JW (1978). "Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition". Biochemistry. 17 (8): 1371–7. doi:10.1021/bi00601a003. PMID 646989. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Terlau H, Olivera BM (2004). "Conus venoms: a rich source of novel ion channel-targeted peptides". Physiol. Rev. 84 (1): 41–68. doi:10.1152/physrev.00020.2003. PMID 14715910. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Buczek O, Bulaj G, Olivera BM (2005). "Conotoxins and the posttranslational modification of secreted gene products". Cell. Mol. Life Sci. 62 (24): 3067–79. doi:10.1007/s00018-005-5283-0. PMID 16314929. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ No Author. http://www.webmd.com/a-to-z-guides/prothrombin-time
^ Thane CW, Bates CJ, Shearer MJ; et al. (2002). "Plasma phylloquinone (vitamin K1) concentration and its relationship to intake in a national sample of British elderly people". Br. J. Nutr. 87 (6): 615–22. doi:10.1079/BJNBJN2002582. PMID 12067432. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ McKeown NM, Jacques PF, Gundberg CM; et al. (2002). "Dietary and nondietary determinants of vitamin K biochemical measures in men and women". J. Nutr. 132 (6): 1329–34. PMID 12042454. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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^ American Academy of Pediatrics Committee on Fetus and Newborn (2003). "Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn". Pediatrics. 112 (1 Pt 1): 191–2. PMID 12837888. {{cite journal}}: Unknown parameter |month= ignored (help)
^ "Routine administration of vitamin K to newborns", Journal of Paediatrics and Child Health (1997) 2(6):429–31
^ Drenckhahn, D. & Kugler, P (2003), "Knochengewebe". In Benninhoff & D. Drenhahn, Anatomie Band 1:147. Munich, Germany: Urban & Fisher
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^ ^a ^b Kanai, T (1997). "Serum vitamin K level and bone mineral density in post-menopausal women". International Journal of Gynecology & Obstetrics. 56: 25. doi:10.1016/S0020-7292(96)02790-7.
^ Cheung, AM; Weber, P; Willett, WC; Rockett, H; Booth, SL; Colditz, GA; Hu, H; Vieth, R; Thompson, L (2008). "Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial". PLoS Med. 5 (10): e196. doi:10.1371/journal.pmed.0050196. PMC 2566998. PMID 18922041.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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External links

Jane Higdon, "Vitamin K", Micronutrient Information Center, Linus Pauling Institute, Oregon State University
Vitamin K: Another Reason to Eat Your Greens
Vitamin K: Signs of Deficiency
Vitamin K: Vitamin Deficiency, Dependency, and Toxicity: Merck Manual Professional
An Alternative Perspective on Vitamin K Prophylaxis
Health Benefits of Vitamin K₂
Vitamin K content: USDA National Nutrient Database for Standard Reference, Release 19

[1] Sell, DR (1990). "End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen". Journal of Clinical Investigation. 85 (2): 380–384. PMID 2298912. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[2] Davidson, RT (1998). "Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria1". Journal of Nutrition. 128 (2): 220–223. PMID 9446847. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[3] Ronden, JE (1998). "Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat". Biochimica et Biophysica Acta (BBA) - General Subjects. 1379 (1): 69–75. PMID 9468334. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[4] Thijssen, HHW (1994). "Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4". British Journal of Nutrition. 72 (3): 415–425. PMID 7947656. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[5] Will, BH (1992). "Comparative Metabolism and Requirement of Vitamin K in Chicks and Rats". Journal of Nutrition. 122 (12): 2354–2360. PMID 1453219. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[6] Davidson, RT (1998). "Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria". Journal of Nutrition. 128 (2): 220–223. PMID 9446847. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[7] Ronden, JE (1998). "Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat". Biochimica et Biophysica Acta (BBA) - General Subjects. 1379 (1): 69–75. PMID 9468334. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[8] Vermeer, C (2001). "Role of K vitamins in the regulation of tissue calcification". Journal of bone and mineral metabolism. 19 (4): 201–206. PMID 11448011. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[9] Suttie, JW (1995). "The importance of menaquinones in human nutrition". Annual Review of Nutrition. 15: 399–417. PMID 8527227.

[10] Weber, P (2001). "Vitamin K and bone health". Nutrition. 17: 880–887.

[11] Sato, Y (2005). "Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease". Bone. 36 (1). PMID 15664003. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[12] Iwamoto, I (1999). "A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy". Maturitas. 31 (2): 161–164. PMID 10227010. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[13] Inoue, T (2001). "Inverse correlation between the changes of lumbar bone mineral density and serum undercarboxylated osteocalcin after vitamin K2 (menatetrenone) treatment in children treated with glucocorticoid and alfacalcidol". Endocrine Journal. 48 (1): 11–18. PMID 11403096. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[14] Sasaki, N, Kusano E, Takahashi H, Ando Y, Yano K, Tsuda E, Asano Y (2005). "Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG)". Journal of bone and mineral metabolism. 23 (1): 41–47. PMID 15616893. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: multiple names: authors list (link)

[15] Yonemura, K (2004). "Protective effect of vitamins K2 and D3 on prednisolone-induced loss of bone mineral density in the lumbar spine". American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation. 43 (1): 53–60. PMID 14712427. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[16] Yonemura, K (2000). "Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis". Calcified Tissue International. 66 (2): 123–128. PMID 10652960. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[17] Iketani, T (2003). "Effect of menatetrenone (vitamin K2) treatment on bone loss in patients with anorexia nervosa". Psychiatry Research. 117 (3): 259–269. PMID 12686368. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[18] Shiomi, S (2002). "Vitamin K2 (menatetrenone) for bone loss in patients with cirrhosis of the liver". The American Journal of Gastroenterology. 97 (4): 978–981. PMID 12003435. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[19] Cockayne, S (2006). "Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials". Archives of Internal Medicine. 166 (12): 1256–1261. PMID 16801507. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[20] Iwamoto, I (1999). "A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy". Maturitas. 31 (2): 161–164. PMID 10227010. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[21] Iwamoto, J (2000). "Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis". Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association. 5 (6): 546–551. PMID 11180916. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[22] Purwosunu, Y (2006). "Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia". The journal of obstetrics and gynaecology research. 32 (2): 230–234. PMID 16594930. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[23] Shiraki, M (2000). "Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis". Journal of Bone and Mineral Research. 15 (3): 515–522. PMID 10750566. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[24] Ushiroyama, T (2002). "Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women". Maturitas. 41 (3): 211–221. PMID 11886767. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[25] Sato, Y (1998). "Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients". Bone. 23 (3): 291–296. PMID 9737352. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[26] Sato, Y (2005). "Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease". Bone. 36 (1): 61–68. PMID 15664003. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[27] Sato, Y (2002). "Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency". Bone. 31 (1): 114–118. PMID 12110423. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[28] Nishiguchi, S (2001). "Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis". Journal of Hepatology. 35 (4): 543–545. PMID 11682046. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[29] Somekawa, Y (1999). "Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide". The Journal of clinical endocrinology and metabolism. 84 (8): 2700–2704. PMID 10443663. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[30] "Vitamin K". Retrieved 2009-05-26.

[31] Conly, J (1994). "Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials". Clinical and investigative medicine. Médecine clinique et experimentale. 17 (6): 531–539. PMID 7895417. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[32] Ferland, G (1993). "Dietary induced subclinical vitamin K deficiency in normal human subjects". Clinical and investigative medicine. Médecine clinique et experimentale. 91 (4): 1761–1768. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[33] Hodges, SJ (1990). "Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8". Clin Sci (Lond). 78 (1): 63–66. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[Groenen-34] Groenen-van Dooren MM et coll. ”Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats”. Biochem Pharmacol. 1995 Sep 7;50(6):797-801.

[Komai-35] Komai M, Shirakawa H. Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function. Clin Calcium. 2007 Nov;17(11):1663-72.Komai M, Shirakawa H. Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function. Clin Calcium. 2007 Nov;17(11):1663-72.

[Geleijnse-36] Geleijnse J. M. et coll. Dietary Intake of Menaquinone is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study. The American Society for Nutritional Sciences J. Nutr. 134:3100-3105, November 2004.

[Beulens-37] Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009 Apr;203(2):489-93.

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[48] Higdon (February 2008). "Vitamin K". Linus Pauling Institute, Oregon State University. Retrieved 2008-04-12.

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[pmid12186515-50] Crowther MA, Douketis JD, Schnurr T; et al. (2002). "Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of [[warfarin]]-associated coagulopathy. A randomized, controlled trial" (PDF). Ann. Intern. Med. 137 (4): 251–4. PMID 12186515. {{cite journal}}: Explicit use of et al. in: |author= (help); URL–wikilink conflict (help)CS1 maint: multiple names: authors list (link)

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[58] Katsuyama; Ideguchi, S; Fukunaga, M; Saijoh, K; Sunami, S (2002). "Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women". Journal of nutritional science and vitaminology. 48 (3): 207–15. PMID 12350079.

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[dam-nobel-64] Dam, Henrik (December 12, 1946). The discovery of vitamin K, its biological functions and therapeutical application. Nobel Prize lecture

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@@ Line 7: / Line 7: @@
 Vitamin K<sub>1</sub> is also known as [[phylloquinone]] or phytomenadione (also called phytonadione). Plants synthesize vitamin K<sub>1</sub> while bacteria can produce a range of vitamin K<sub>2</sub> forms, including the conversion of K<sub>1</sub> to K<sub>2</sub> by bacteria in the small intestines. No known toxicity exists for vitamins K<sub>1</sub> and K<sub>2</sub>.
-Vitamin K<sub>2</sub> (menaquinone), is itself a category of vitamin K that includes many types of vitamin K<sub>2</sub>. The two types of vitamin K<sub>2</sub> subtypes studied are menqquinone-4 ([[menatetrenone]], MK4) and menaquinone-7 (MK7). MK4 is produced via conversion of vitamin K<sub>1</sub> in the body, in the testes, pancreas and arterial walls.<ref>{{cite journal|last=Sell|first=DR|coauthors=Monnier VM|title=End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen|journal=Journal of Clinical Investigation|year=1990|volume=85|issue=2|pages=380-384|pmid=2298912}}</ref> While major questions still surround the biochemical pathway for the transformation of vitamin K<sub>1</sub> to MK4, studies demonstrate that the conversion is not dependent on gut bacteria, occuring in germ-free rats<ref>{{cite journal|last=Davidson|first=RT|coauthors=Foley AL, Engelke JA, Suttie JW|title=Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria1|journal=Journal of Nutrition|year=1998|volume=128|issue=2|pages=220-223|pmid=9446847}}</ref><ref>{{cite journal|last=Ronden|first=JE|coauthors=Drittij-Reijnders M-J, Vermeer C, Thijssen HHW.|title=Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|year=1998|volume=1379|issue=1|pages=69-75|pmid=9468334}}</ref> and in parenterally-administered K1 in rats.<ref>{{cite journal|last=Thijssen|first=HHW|coauthors=Drittij-Reijnders MJ|title=Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4|journal=British Journal of Nutrition|year=1994|volume=72|issue=3|pages=415-425|pmid=7947656}}</ref><ref>{{cite journal|last=Will|first=BH|coauthors=Usui Y, Suttie JW|title=Comparative Metabolism and Requirement of Vitamin K in Chicks and Rats|journal=Journal of Nutrition|year=1992|volume=122|issue=12|pages=2354-2360|pmid=1453219}}</ref> In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available K1 into MK4.<ref>{{cite journal|last=Davidson|first=RT|coauthors=Foley AL, Engelke JA, Suttie JW|title=Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria|journal=Journal of Nutrition|year=1998|volume=128|issue=2|pages=220-223|pmid=9446847}}</ref><ref>{{cite journal|last=Ronden|first=JE|coauthors=Drittij-Reijnders M-J, Vermeer C, Thijssen HHW|title=Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|year=1998|volume=1379|issue=1|pages=69-75|pmid=9468334}}</ref>
+Vitamin K<sub>2</sub> (menaquinone), is itself a category of vitamin K that includes many types of vitamin K<sub>2</sub>. The two subtypes of vitamin K<sub>2</sub> that have been most studied are menaquinone-4 ([[menatetrenone]], MK4) and menaquinone-7 (MK7). MK4 is produced via conversion of vitamin K<sub>1</sub> in the body, in the testes, pancreas and arterial walls.<ref>{{cite journal|last=Sell|first=DR|coauthors=Monnier VM|title=End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen|journal=Journal of Clinical Investigation|year=1990|volume=85|issue=2|pages=380-384|pmid=2298912}}</ref> While major questions still surround the biochemical pathway for the transformation of vitamin K<sub>1</sub> to MK4, studies demonstrate that the conversion is not dependent on gut bacteria, occuring in germ-free rats<ref>{{cite journal|last=Davidson|first=RT|coauthors=Foley AL, Engelke JA, Suttie JW|title=Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria1|journal=Journal of Nutrition|year=1998|volume=128|issue=2|pages=220-223|pmid=9446847}}</ref><ref>{{cite journal|last=Ronden|first=JE|coauthors=Drittij-Reijnders M-J, Vermeer C, Thijssen HHW.|title=Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|year=1998|volume=1379|issue=1|pages=69-75|pmid=9468334}}</ref> and in parenterally-administered K1 in rats.<ref>{{cite journal|last=Thijssen|first=HHW|coauthors=Drittij-Reijnders MJ|title=Vitamin K distribution in rat tissues: dietary phylloquinone is a source of tissue menaquinone-4|journal=British Journal of Nutrition|year=1994|volume=72|issue=3|pages=415-425|pmid=7947656}}</ref><ref>{{cite journal|last=Will|first=BH|coauthors=Usui Y, Suttie JW|title=Comparative Metabolism and Requirement of Vitamin K in Chicks and Rats|journal=Journal of Nutrition|year=1992|volume=122|issue=12|pages=2354-2360|pmid=1453219}}</ref> In fact, tissues that accumulate high amounts of MK4 have a remarkable capacity to convert up to 90% of the available K1 into MK4.<ref>{{cite journal|last=Davidson|first=RT|coauthors=Foley AL, Engelke JA, Suttie JW|title=Conversion of Dietary Phylloquinone to Tissue Menaquinone-4 in Rats is Not Dependent on Gut Bacteria|journal=Journal of Nutrition|year=1998|volume=128|issue=2|pages=220-223|pmid=9446847}}</ref><ref>{{cite journal|last=Ronden|first=JE|coauthors=Drittij-Reijnders M-J, Vermeer C, Thijssen HHW|title=Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat|journal=Biochimica et Biophysica Acta (BBA) - General Subjects|year=1998|volume=1379|issue=1|pages=69-75|pmid=9468334}}</ref>
+In contrast to MK4, MK7 is not produced by humans but is converted from phylloquinone in the intestines by gut bacteria.<ref>{{cite journal|last=Vermeer|first=C|coauthors=Braam L|title=Role of K vitamins in the regulation of tissue calcification|journal=Journal of bone and mineral metabolism|year=2001|volume=19|issue=4|pages=201-206|pmid=11448011}}</ref> However, bacteria-derived menaquinones appear to contribute minimally to overall vitamin K status.<ref>{{cite journal|last=Suttie|first=JW|title=The importance of menaquinones in human nutrition|journal=Annual Review of Nutrition|year=1995|volume=15|pages=399-417|pmid=8527227}}</ref><ref>{{cite journal|last=Weber|first=P|title=Vitamin K and bone health|journal=Nutrition|year=2001|volume=17|pages=880-887}}</ref> MK4 and MK7 are both found in the United States in dietary supplements for bone health. The US FDA has not approved any form of vitamin K for the prevention or treatment of osteoporosis; however, MK4 has been shown to decrease fractures up to 87%,<ref>{{cite journal|last=Sato|first=Y|coauthors=Kanoko T, Satoh K, Iwamoto J|title=Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease|journal=Bone|year=2005|volume=36|issue=1|pmid=15664003}}</ref> speed fracture healing and prevent and reverse bone loss from medications. In the amount of 45 mg daily MK4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of [[osteoporosis]].<ref>{{cite journal|last=Iwamoto|first=I|coauthors=Kosha S, Noguchi S-i|title=A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy|journal=Maturitas|year=1999|volume=31|issue=2|pages=161-164|pmid=10227010}}</ref> prevented bone loss and/or fractures caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),<ref>{{cite journal|last=Inoue|first=T|coauthors=Sugiyama T, Matsubara T, Kawai S, Furukawa S|title=Inverse correlation between the changes of lumbar bone mineral density and serum undercarboxylated osteocalcin after vitamin K2 (menatetrenone) treatment in children treated with glucocorticoid and alfacalcidol.|journal=Endocrine Journal|year=2001|volume=48|issue=1|pages=11-18|pmid=11403096}}</ref><ref>{{cite journal|last=Sasaki|first=N, Kusano E, Takahashi H, Ando Y, Yano K, Tsuda E, Asano Y|coauthors=Kusano E, Takahashi H, Ando Y, Yano K, Tsuda E, Asano Y|title=Vitamin K2 inhibits glucocorticoid-induced bone loss partly by preventing the reduction of osteoprotegerin (OPG)|journal=Journal of bone and mineral metabolism|year=2005|volume=23|issue=1|pages=41-47|pmid=15616893}}</ref><ref>{{cite journal|last=Yonemura|first=K|coauthors=Fukasawa H, Fujigaki Y, Hishida A.|title=Protective effect of vitamins K2 and D3 on prednisolone-induced loss of bone mineral density in the lumbar spine|journal=American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation|year=2004|volume=43|issue=1|pages=53-60|pmid=14712427}}</ref><ref>{{cite journal|last=Yonemura|first=K|coauthors=Kimura M, Miyaji T, Hishida A|title=Short-term effect of vitamin K administration on prednisolone-induced loss of bone mineral density in patients with chronic glomerulonephritis|journal=Calcified Tissue International|year=2000|volume=66|issue=2|pages=123-128|pmid=10652960}}</ref>  anorexia nervosa,<ref>{{cite journal|last=Iketani|first=T|coauthors=Kiriike N, B. Stein M|title=Effect of menatetrenone (vitamin K2) treatment on bone loss in patients with anorexia nervosa|journal=Psychiatry Research|year=2003|volume=117|issue=3|pages=259-269|pmid=12686368}}</ref>  cirrhosis of the liver,<ref>{{cite journal|last=Shiomi|first=S|coauthors=Nishiguchi S, Kubo S|title=Vitamin K2 (menatetrenone) for bone loss in patients with cirrhosis of the liver|journal=The American Journal of Gastroenterology|year=2002|volume=97|issue=4|pages=978-981|pmid=12003435}}</ref> postmenopausal osteoporosis,<ref>{{cite journal|last=Cockayne|first=S|coauthors=Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ|title=Vitamin K and the Prevention of Fractures: Systematic Review and Meta-analysis of Randomized Controlled Trials|journal=Archives of Internal Medicine|year=2006|volume=166|issue=12|pages=1256-1261|pmid=16801507}}</ref><ref>{{cite journal|last=Iwamoto|first=I|coauthors=Kosha S, Noguchi S-i|title=A longitudinal study of the effect of vitamin K2 on bone mineral density in postmenopausal women a comparative study with vitamin D3 and estrogen-progestin therapy.|journal=Maturitas|year=1999|volume=31|issue=2|pages=161-164|pmid=10227010}}</ref><ref>{{cite journal|last=Iwamoto|first=J|coauthors=Takeda T, Ichimura S|title=Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis|journal=Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association|year=2000|volume=5|issue=6|pages=546-551|pmid=11180916}}</ref><ref>{{cite journal|last=Purwosunu|first=Y|coauthors=Muharram, Rachman IA, Reksoprodjo S, Sekizawa A|title=Vitamin K2 treatment for postmenopausal osteoporosis in Indonesia|journal=The journal of obstetrics and gynaecology research|year=2006|volume=32|issue=2|pages=230-234|pmid=16594930}}</ref><ref>{{cite journal|last=Shiraki|first=M|coauthors=Shiraki Y, Aoki C, Miura M|title=Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis|journal=Journal of Bone and Mineral Research|year=2000|volume=15|issue=3|pages=515-522|pmid=10750566}}</ref><ref>{{cite journal|last=Ushiroyama|first=T|coauthors=Ikeda A, Ueki M|title=Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women|journal=Maturitas|year=2002|volume=41|issue=3|pages=211-221|pmid=11886767}}</ref>, disuse from stroke,<ref>{{cite journal|last=Sato|first=Y|coauthors=Honda Y, Kuno H, Oizumi K|title=Menatetrenone ameliorates osteopenia in disuse-affected limbs of vitamin D- and K-deficient stroke patients|journal=Bone|year=1998|volume=23|issue=3|pages=291-296|pmid=9737352}}</ref> [[Alzheimer’s disease]],<ref>{{cite journal|last=Sato|first=Y|coauthors=Kanoko T, Satoh K, Iwamoto J|title=Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease|journal=Bone|year=2005|volume=36|issue=1|pages=61-68|pmid=15664003}}</ref> [[Parkinson disease]],<ref>{{cite journal|last=Sato|first=Y|coauthors=Honda Y, Kaji M|title=Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency|journal=Bone|year=2002|volume=31|issue=1|pages=114-118|pmid=12110423}}</ref> [[primary biliary cirrhosis]]<ref>{{cite journal|last=Nishiguchi|first=S|coauthors=Shimoi S, Kurooka H|title=Randomized pilot trial of vitamin K2 for bone loss in patients with primary biliary cirrhosis|journal=Journal of Hepatology|year=2001|volume=35|issue=4|pages=543-545|pmid=11682046}}</ref> and leuprolide treatment (for prostate cancer).<ref>{{cite journal|last=Somekawa|first=Y|coauthors=Chigughi M, Harada M, Ishibashi T|title=Use of vitamin K2 (menatetrenone) and 1,25-dihydroxyvitamin D3 in the prevention of bone loss induced by leuprolide|journal=The Journal of clinical endocrinology and metabolism|year=1999|volume=84|issue=8|pages=2700-2704|pmid=10443663}}</ref>
-The old theory says that dietary deficiency is extremely rare unless the intestines are heavily damaged, are [[malabsorption|unable to absorb]] the molecule, or are subject to decreased production by normal flora, as seen in [[broad spectrum antibiotic]] use.<ref>{{cite web| title=Vitamin K| accessdate=2009-05-26|url= http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitamink.html}}</ref> However, recent research results shows that this might not be the case; the bowel seems to be inefficient in the absorption of vitamins K.<ref name=Groenen>Groenen-van Dooren MM et coll. ”Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats”. Biochem Pharmacol. 1995 Sep 7;50(6):797-801.</ref><ref name=Komai>Komai M, Shirakawa H. Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function. Clin Calcium. 2007 Nov;17(11):1663-72.Komai M, Shirakawa H. Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function. Clin Calcium. 2007 Nov;17(11):1663-72.</ref> These results are reinforced by human cohorts studies, where a majority of the subjects showed inadequate vitamins K amounts in the body. This was revealed by the presence of large amounts of incomplete gamma-carboxylated proteins in the blood, an indirect test for vitamins K deficiency.<ref name=Geleijnse>Geleijnse J. M. et coll. Dietary Intake of Menaquinone is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study. The American Society for Nutritional Sciences J. Nutr. 134:3100-3105, November 2004.</ref><ref name=Beulens>Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009 Apr;203(2):489-93.</ref><ref name=Nimptsch>Nimptsch K, Rohrmann S, Kaaks R, Linseisen J. Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr. 2010 May;91(5):1348-58. Epub 2010 Mar 24.</ref>
+The old theory says that dietary deficiency is extremely rare unless the intestines are heavily damaged, are [[malabsorption|unable to absorb]] the molecule, or are subject to decreased production by normal flora, as seen in [[broad spectrum antibiotic]] use.<ref>{{cite web| title=Vitamin K| accessdate=2009-05-26|url= http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitamink.html}}</ref> Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared to those not taking these antibiotics.<ref>{{cite journal|last=Conly|first=J|coauthors=Stein K|title=Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials|journal=Clinical and investigative medicine. Médecine clinique et experimentale|year=1994|volume=17|issue=6|pages=531-539|pmid=7895417}}</ref> Diets low in vitamin K also decrease the body's vitamin K concentration.<ref>{{cite journal|last=Ferland|first=G|coauthors=Sadowski JA, O'Brien ME|title=Dietary induced subclinical vitamin K deficiency in normal human subjects|journal=Clinical and investigative medicine. Médecine clinique et experimentale|year=1993|volume=91|issue=4|pages=1761-1768}}</ref> Additionally, in the elderly there is a reduction in vitamin K2 production.<ref>{{cite journal|last=Hodges|first=SJ|coauthors=Pilkington MJ, Shearer MJ, Bitensky L, Chayen J|title=Age-related changes in the circulating levels of congeners of vitamin K2, menaquinone-7 and menaquinone-8|journal=Clin Sci (Lond)|year=1990|volume=78|issue=1|pages=63-66}}</ref>
+Recent research results also demonstrate that the bowels seems to be inefficient at absorbing vitamins K.<ref name=Groenen>Groenen-van Dooren MM et coll. ”Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats”. Biochem Pharmacol. 1995 Sep 7;50(6):797-801.</ref><ref name=Komai>Komai M, Shirakawa H. Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function. Clin Calcium. 2007 Nov;17(11):1663-72.Komai M, Shirakawa H. Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function. Clin Calcium. 2007 Nov;17(11):1663-72.</ref> These results are reinforced by human cohort studies, where a majority of the subjects showed inadequate vitamins K amounts in the body. This was revealed by the presence of large amounts of incomplete gamma-carboxylated proteins in the blood, an indirect test for vitamins K deficiency.<ref name=Geleijnse>Geleijnse J. M. et coll. Dietary Intake of Menaquinone is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study. The American Society for Nutritional Sciences J. Nutr. 134:3100-3105, November 2004.</ref><ref name=Beulens>Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009 Apr;203(2):489-93.</ref><ref name=Nimptsch>Nimptsch K, Rohrmann S, Kaaks R, Linseisen J. Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Am J Clin Nutr. 2010 May;91(5):1348-58. Epub 2010 Mar 24.</ref> And in an animal model MK4 was shown to prevent arterial calcifications, pointing to its potential role in cardiovascular disease prevention.<ref>{{cite journal|last=Spronk|first=HMH|coauthors=Soute BAM, Schurgers LJ, Thijssen HHW, De Mey JGR, Vermeer C|title=Tissue-Specific Utilization of Menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats|journal=Journal of vascular research|year=2003|volume=40|issue=6|pages=531-537|pmid=14654717}}</ref> In this study vitamin K<sub>1</sub> was also tested and shown to not prevent arterial calfications.
 There are three synthetic forms of vitamin K, vitamins K<sub>3</sub>, K<sub>4</sub>, and K<sub>5</sub>, which are used in many areas including the pet food industry (vitamin K<sub>3</sub>) and to inhibit fungal growth (vitamin K<sub>5</sub>).<ref>{{cite web|last=McGee|first=W |publisher=[[MedlinePlus]]|title=Vitamin K|date=2007-02-01|accessdate=2009-04-02|url=http://www.nlm.nih.gov/medlineplus/ency/article/002407.htm}}</ref>