Vitamin K: Difference between revisions
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JAAAAAACKKKYYYYY IS GAAYYYYYYYY |
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{{Hatnote|"Vitamin K" is also a slang term for [[ketamine]], an unrelated anaesthetic.}} |
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VAARRRRAAAAAANNN IS GAAYYYYYYYY |
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{{Use dmy dates|date=September 2013}} |
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HUR HUR HUR HUR |
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{{Infobox drug class |
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| Use = [[Vitamin K deficiency]] |
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| Biological_target = [[Gamma-glutamyl carboxylase]] |
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| ATC_prefix = B02BA |
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| MeshID = D014812 |
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| Drugs.com = {{Drugs.com|enc|vitamin-k}} |
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[[File:Phylloquinone structure.svg|thumb|right|175px|Vitamin K<sub>1</sub> (phylloquinone) - both forms of the vitamin contain a functional [[naphthoquinone]] ring and an aliphatic side-chain. Phylloquinone has a [[Phytane|phytyl]] side-chain.]] |
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[[File:Menaquinone.svg|thumb|right|175px|Vitamin K<sub>2</sub> (menaquinone). In menaquinone, the side-chain is composed of a varying number of [[isoprenoid]] residues. The most common number of these residues is four, since animal enzymes normally produce menaquinone-4 from plant phylloquinone.]] |
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[[File:Phytomenadione (vitamin K1).jpg|thumb|right|175px|A sample of phytomenadione (vitamin K<sub>1</sub>) for injection, also called phylloquinone.]] |
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'''Vitamin K''' is a group of structurally similar, fat-soluble [[vitamin]]s that the human body needs for [[post-translational modification]] of certain proteins required for blood [[coagulation]], and in [[metabolic pathway]]s in bone and other tissue. They are 2-[[methyl]]-[[1,4-naphthoquinone]] (3-) [[Derivative (chemistry)|derivatives]]. This group of vitamins includes two natural [[vitamer]]s: [[phylloquinone|vitamin K<sub>1</sub>]] and [[Vitamin K2|vitamin K<sub>2</sub>]].<ref>{{cite web | title=Vitamin K Overview | url=http://www.umm.edu/altmed/articles/vitamin-k-000343.htm | work=University of Maryland Medical Center}}</ref> |
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Vitamin K<sub>1</sub>, also known as '''phylloquinone''', '''phytomenadione''', or '''phytonadione''', is synthesized by plants, and is found in highest amounts in [[Leaf vegetable|green leafy vegetables]] because it is directly involved in photosynthesis. It may be thought of as the "plant form" of vitamin K. It is active in animals and may perform the classic functions of vitamin K in animals, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K<sub>2</sub>. |
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[[Vitamin K2|Vitamin K<sub>2</sub>]], the main storage form in animals, has several subtypes, which differ in isoprenoid chain length. These vitamin K<sub>2</sub> homologues are called '''menaquinones''', and are characterized by the number of [[Terpenoid|isoprenoid]] residues in their side chains. Menaquinones are abbreviated '''MK-n''', where '''M''' stands for menaquinone, the '''K''' stands for vitamin K, and the '''n''' represents the number of isoprenoid side chain residues. For example, menaquinone-4 (abbreviated MK-4) has four isoprene residues in its side chain. Menaquinone-4 (also known as [[menatetrenone]] from its four isoprene residues) is the most common type of vitamin K<sub>2</sub> in animal products since MK-4 is normally synthesized from vitamin K<sub>1</sub> in certain animal tissues (arterial walls, pancreas, and testes) by replacement of the phytyl tail with an unsaturated geranylgeranyl tail containing four [[isoprene]] units, thus yielding menaquinone-4. This homolog of vitamin K<sub>2</sub> may have enzyme functions that are distinct from those of vitamin K<sub>1</sub>. |
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Bacteria in the colon (large intestine) can also convert K<sub>1</sub> into vitamin K<sub>2</sub>. In addition, bacteria typically lengthen the isopreneoid side chain of vitamin K<sub>2</sub> to produce a range of vitamin K<sub>2</sub> forms, most notably the MK-7 to MK-11 homologues of vitamin K<sub>2</sub>. All forms of K<sub>2</sub> other than MK-4 can only be produced by bacteria, which use these forms in [[anaerobic respiration]]. The MK-7 and other bacteria-derived form of vitamin K<sub>2</sub> exhibit vitamin K activity in animals, but MK-7's extra utility over MK-4, if any, is unclear and is presently a matter of investigation. |
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Three synthetic types of vitamin K are known: vitamins K<sub>3</sub>, K<sub>4</sub>, and K<sub>5</sub>. Although the natural K<sub>1</sub> and all K<sub>2</sub> homologues have proven nontoxic, the synthetic form K<sub>3</sub> ([[menadione]]) has shown toxicity.<ref name=Higdon>{{cite web|last=Higdon|title=Vitamin K|publisher=Linus Pauling Institute, Oregon State University|date=February 2008|url=http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/|accessdate=12 April 2008}}</ref> K<sub>4</sub>, and K<sub>5</sub> are also non toxic. |
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== Discovery of vitamin K<sub>1</sub> == |
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Vitamin K<sub>1</sub> was identified in 1929 by [[Denmark|Danish]] scientist [[Henrik Dam]] when he investigated the role of [[cholesterol]] by feeding chickens a cholesterol-depleted diet.<ref name="Dam">{{cite journal|last=Dam|first=H.|year=1935|title=The Antihæmorrhagic Vitamin of the Chick.: Occurrence And Chemical Nature|journal=Nature|volume=135|issue=3417|pages=652–653|doi=10.1038/135652b0 }}</ref> After several weeks, the animals developed haemorrhages 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.'' |
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==Conversion of vitamin K<sub>1</sub> to vitamin K<sub>2</sub> in animals== |
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The MK-4 form of vitamin K<sub>2</sub> is produced via conversion of vitamin K<sub>1</sub> in the testes, pancreas, and arterial walls.<ref>{{cite journal|last=Newman P.|first=Shearer MJ|title=Metabolism and cell biology of vitamin K|journal=Thrombosis and Haemostasis|year=2008|pages=530–547|doi=10.1160/TH08-03-0147|last2=Newman|first2=Paul}}</ref> While major questions still surround the biochemical pathway for the transformation of vitamin K<sub>1</sub> to MK-4, the conversion is not dependent on gut bacteria, as it occurs 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|doi=10.1016/S0304-4165(97)00089-5}}</ref> and in parenterally-administered K<sub>1</sub> 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|doi=10.1079/BJN19940043}}</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 MK-4 have a remarkable capacity to convert up to 90% of the available K<sub>1</sub> into MK-4.<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|doi=10.1016/S0304-4165(97)00089-5}}</ref> There is evidence that the conversion proceeds by removal of the [[Phytane|phytyl]] tail of K<sub>1</sub> to produce [[menadione]] as an intermediate, which is then condensed with an activated [[geranylgeranylation|geranylgeranyl]] moiety (see also [[prenylation]]) to produce vitamin K<sub>2</sub> in the MK-4 (menatetrione) form.<ref>Al Rajabi, Ala (2011) [http://gradworks.umi.com/34/56/3456517.html The Enzymatic Conversion of Phylloquinone to Menaquinone-4]. Ph.D. thesis, Tufts University, Friedman School of Nutrition Science and Policy.</ref> |
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==Subtypes of vitamin K<sub>2</sub>== |
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{{main|Vitamin K2}} |
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Vitamin K<sub>2</sub> (menaquinone) includes several subtypes. The two subtypes most studied are menaquinone-4 ([[menatetrenone]], MK-4) and menaquinone-7 (MK-7). |
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Menaquinone-7 is different from MK-4 in that it is not produced by human tissue. MK-7 consumption has been shown to reduce the risk of bone fractures and cardiovascular disorders that are crucial health issues worldwide. Recently, leading research teams from Australia, Japan, and Korea are broadening the understanding of MK-7 and its production. It has been reported that MK-7 may be converted from phylloquinone (K<sub>1</sub>) in the colon by ''E. coli'' 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|doi=10.1007/s007740170021}}</ref> However, bacteria-derived menaquinones (MK-7) 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|doi=10.1146/annurev.nu.15.070195.002151}}</ref><ref>{{cite journal|last=Weber|first=P|title=Vitamin K and bone health|journal=Nutrition|year=2001|volume=17|pages=880–887|doi=10.1016/S0899-9007(01)00709-2|pmid=11684396|issue=10}}</ref> MK-4 and MK-7 are both found in the United States in dietary supplements for bone health. |
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The U.S. [[Food and Drug Administration]] (FDA) has not approved any form of vitamin K for the prevention or treatment of [[osteoporosis]]; however, MK-4 has been shown to decrease the incidence of fractures up to 87%.<ref name="Sato 2005">{{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|doi=10.1016/j.bone.2004.09.018|pages=61–8}}</ref> MK-4 (45 mg daily) has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.<ref name="Iwamoto 1999 161–164">{{cite journal|last=Iwamoto|first=I|coauthors=Kosha S, Noguchi S-i|title=A longitudinal study of the effect of vitamin K<sub>2</sub> on bone mineral density in postmenopausal women a comparative study with vitamin D<sub>3</sub> and estrogen-progestin therapy|journal=Maturitas|year=1999|volume=31|issue=2|pages=161–164|pmid=10227010|doi=10.1016/S0378-5122(98)00114-5}}</ref> |
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Vitamin K<sub>2</sub> as MK-4, but not as MK-7 (and also not vitamin K<sub>1</sub>) has also been shown to prevent bone loss and/or fractures in the following circumstances: |
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* caused by corticosteroids (e.g., prednisone, dexamethasone, prednisolone),<ref name="Inoue 2001 11–18">{{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 K<sub>2</sub> (menatetrenone) treatment in children treated with glucocorticoid and alfacalcidol|journal=Endocrine Journal|year=2001|volume=48|issue=1|pages=11–18|pmid=11403096|doi=10.1507/endocrj.48.11}}</ref><ref name="Sasaki 2005 41–47">{{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 K<sub>2</sub> 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|doi=10.1007/s00774-004-0539-6}}</ref><ref name="Yonemura 2004 53–60">{{cite journal|last=Yonemura|first=K|coauthors=Fukasawa H, Fujigaki Y, Hishida A.|title=Protective effect of vitamins K<sub>2</sub> and D<sub>3</sub> 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|doi=10.1053/j.ajkd.2003.09.013}}</ref><ref name="Yonemura 2000 123–128">{{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|doi=10.1007/PL00005832}}</ref> |
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* anorexia nervosa,<ref name="Iketani 2003 259–269">{{cite journal|last=Iketani|first=T|coauthors=Kiriike N, B. Stein M|title=Effect of menatetrenone (vitamin K<sub>2</sub>) treatment on bone loss in patients with anorexia nervosa|journal=Psychiatry Research|year=2003|volume=117|issue=3|pages=259–269|pmid=12686368|doi=10.1016/S0165-1781(03)00024-6}}</ref> |
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* cirrhosis of the liver,<ref name="Shiomi 2002 978–981">{{cite journal|last=Shiomi|first=S|coauthors=Nishiguchi S, Kubo S|title=Vitamin K<sub>2</sub> (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|doi=10.1111/j.1572-0241.2002.05618.x}}</ref> |
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* postmenopausal osteoporosis,<ref name="Iwamoto 1999 161–164"/><ref name="Cockayne 2006 1256–1261">{{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|doi=10.1001/archinte.166.12.1256}}</ref><ref name="Iwamoto 2000 546–551">{{cite journal|last=Iwamoto|first=J|coauthors=Takeda T, Ichimura S|title=Effect of combined administration of vitamin D<sub>3</sub> and vitamin K<sub>2</sub> on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis|journal=Journal of Orthopaedic Science|year=2000|volume=5|issue=6|pages=546–551|pmid=11180916|doi=10.1007/s007760070003}}</ref><ref name="Purwosunu 2006 230–234">{{cite journal|last=Purwosunu|first=Y|coauthors=Muharram, Rachman IA, Reksoprodjo S, Sekizawa A|title=Vitamin K<sub>2</sub> 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|doi=10.1111/j.1447-0756.2006.00386.x}}</ref><ref name="Shiraki 2000 515–522">{{cite journal|last=Shiraki|first=M|coauthors=Shiraki Y, Aoki C, Miura M|title=Vitamin K<sub>2</sub> (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|doi=10.1359/jbmr.2000.15.3.515}}</ref><ref name="Ushiroyama 2002 211–221">{{cite journal|last=Ushiroyama|first=T|coauthors=Ikeda A, Ueki M|title=Effect of continuous combined therapy with vitamin K<sub>2</sub> and vitamin D<sub>3</sub> on bone mineral density and coagulofibrinolysis function in postmenopausal women|journal=Maturitas|year=2002|volume=41|issue=3|pages=211–221|pmid=11886767|doi=10.1016/S0378-5122(01)00275-4}}</ref> |
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* disuse from stroke,<ref name="Sato 1998 291–296">{{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|doi=10.1016/S8756-3282(98)00108-2}}</ref> |
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* [[Alzheimer's disease]],<ref name="Sato 2005 61–68">{{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|doi=10.1016/j.bone.2004.09.018}}</ref> |
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* [[Parkinson disease]],<ref name="Sato 2002 114–118">{{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|doi=10.1016/S8756-3282(02)00783-4}}</ref> |
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* [[primary biliary cirrhosis]]<ref name="Nishiguchi 2001 543–545">{{cite journal|last=Nishiguchi|first=S|coauthors=Shimoi S, Kurooka H|title=Randomized pilot trial of vitamin K<sub>2</sub> for bone loss in patients with primary biliary cirrhosis|journal=Journal of Hepatology|year=2001|volume=35|issue=4|pages=543–545|pmid=11682046|doi=10.1016/S0168-8278(01)00133-7}}</ref> |
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* and leuprolide treatment (for prostate cancer).<ref name="Somekawa 1999 2700–2704">{{cite journal|last=Somekawa|first=Y|coauthors=Chigughi M, Harada M, Ishibashi T|title=Use of vitamin K<sub>2</sub> (menatetrenone) and 1,25-dihydroxyvitamin D<sub>3</sub> 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|doi=10.1210/jc.84.8.2700}}</ref> |
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==Chemical structure== |
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The three synthetic forms of vitamin K are 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=1 February 2007|accessdate=2 April 2009|url=http://www.nlm.nih.gov/medlineplus/ency/article/002407.htm}}</ref> |
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==Physiology== |
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Vitamin K<sub>1</sub>, the precursor of most vitamin K in nature, is a steroisomer of [[phylloquinone]], an important chemical in green plants, where it functions as an electron acceptor in [[photosystem I]] during [[photosynthesis]]. For this reason, vitamin K<sub>1</sub> 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 (roots, fruits, etc.). [[Iceberg lettuce]] contains relatively little. The function of phylloquinone in plants appears to have no resemblance to its later metabolic and biochemical function (as "vitamin K") in animals, where it performs a completely different biochemical reaction. |
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Vitamin K (in animals) 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 domain]]s. Gla residues are usually involved in binding [[calcium in biology|calcium]], and are essential for the biological activity of all known [[Gla domain#Human proteins containing this domain|Gla proteins]].<ref name=Furie>{{cite journal|author=Furie B, Bouchard BA, Furie BC|title=Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid|journal=Blood|volume=93|issue=6|pages=1798–808|date=15 March 1999|pmid=10068650|url=http://bloodjournal.hematologylibrary.org/cgi/content/full/93/6/1798}}</ref> |
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{{As of|2007|alt=At this time}}, 16 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes: |
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*[[coagulation|Blood coagulation]]: [[prothrombin|prothrombin (factor II)]], [[factor VII|factors VII]], [[factor IX|IX]], and [[factor X|X]], and [[protein C|proteins C]], [[protein S|S]], and [[protein Z|Z]]<ref name=Mann>{{cite journal|author=Mann KG|title=Biochemistry and physiology of blood coagulation|journal=Thromb. Haemost.|volume=82|issue=2|pages=165–74|year=1999|pmid=10605701|url=http://www.schattauer.de/index.php?id=1268&pii=th99080165&no_cache=1}}</ref> |
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*[[Bone]] metabolism: [[osteocalcin]], also called bone Gla protein (BGP), [[matrix Gla protein]] (MGP),<ref name="Price">{{cite journal|author=Price PA|title=Role of vitamin-K-dependent proteins in bone metabolism|journal=Annu. Rev. Nutr.|volume=8|pages=565–83|year=1988|pmid=3060178|doi=10.1146/annurev.nu.08.070188.003025}}</ref> periostin,<ref name="Coutu">{{cite journal|author=Coutu DL, Wu JH, Monette A, Rivard GE, Blostein MD, Galipeau J|title=Periostin, a member of a novel family of vitamin K-dependent proteins, is expressed by mesenchymal stromal cells|journal=J. Biol. Chem.|volume=283|issue=26|pages=17991–18001|year=2008|pmid=18450759|doi=10.1074/jbc.M708029200}}</ref> and the recently discovered Gla-rich protein (GRP).<ref>{{cite pmid|18836183}}</ref><ref>{{cite pmid|19893032}}</ref> |
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*Vascular biology: growth arrest-specific protein 6 (Gas6)<ref name="Hafizi">{{cite journal|author=Hafizi S, Dahlbäck B|title=Gas6 and protein S. Vitamin K-dependent ligands for the Axl receptor tyrosine kinase subfamily|journal=FEBS J.|volume=273|issue=23|pages=5231–44|year=2006|pmid=17064312|doi=10.1111/j.1742-4658.2006.05529.x}}</ref> |
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*Unknown function: proline-rich g-carboxy glutamyl proteins (PRGPs) 1 and 2, and transmembrane g-carboxy glutamyl proteins (TMGs) 3 and 4.<ref name="Kulman">{{cite journal|author=Kulman JD, Harris JE, Xie L, Davie EW|title=Proline-rich Gla protein 2 is a cell-surface vitamin K-dependent protein that binds to the transcriptional coactivator Yes-associated protein|journal=Proc. Natl. Acad. Sci. U.S.A.|volume=104|issue=21|pages=8767–72|year=2007|pmid=17502622|doi=10.1073/pnas.0703195104|pmc=1885577}}</ref> |
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Like other lipid-soluble vitamins (A, D, E), vitamin K is stored in the fat tissue of the human body. |
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==Vitamin K absorption and dietary need== |
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Previous theory held that dietary deficiency is extremely rare unless the intestine (small bowel) was heavily damaged, resulting in [[malabsorption]] of the molecule. Another at-risk group for deficiency were those subject to decreased production of K<sub>2</sub> by normal intestinal microbiota, as seen in [[broad spectrum antibiotic]] use.<ref>{{cite web| title=Vitamin K| accessdate=26 May 2009|url= http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitamink.html|work=National Institute of Health}}</ref> Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics.<ref>{{cite journal|last=Conly|first=J|coauthors=Stein K|title=Reduction of vitamin K<sub>2</sub> 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 |author=Ferland G, Sadowski JA, O'Brien ME |title=Dietary induced subclinical vitamin K deficiency in normal human subjects |journal=The Journal of Clinical Investigation |volume=91 |issue=4 |pages=1761–8 |year=1993 |pmid=8473516 |pmc=288156 |doi=10.1172/JCI116386 }}</ref> Those with chronic kidney disease are at risk for vitamin K deficiency, as well as [[vitamin D deficiency]], and particularly those with the [[apoE4]] genotype.<ref name=Holden>{{cite journal|last=Holden|first=RM|coauthors=Morton, AR; Garland, JS; Pavlov, A; Day, AG; Booth, SL|title=Vitamins K and D status in stages 3–5 chronic kidney disease|journal=Clinical journal of the American Society of Nephrology : CJASN|date=April 2010|volume=5|issue=4|pages=590–7|pmid=20167683|doi=10.2215/CJN.06420909|pmc=2849681}}</ref> Additionally, in the elderly there is a reduction in vitamin K<sub>2</sub> production.<ref>{{cite journal |author=Hodges SJ, Pilkington MJ, Shearer MJ, Bitensky L, Chayen J |title=Age-related changes in the circulating levels of congeners of vitamin K<sub>2</sub>, menaquinone-7 and menaquinone-8 |journal=Clinical Science |volume=78 |issue=1 |pages=63–6 |year=1990 |pmid=2153497 }}</ref> |
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Recent research results also demonstrate that the small intestine and large intestine (colon) seem to be inefficient at absorbing vitamin K supplements in rat populations low in Vitamin K.<ref name=Groenen>{{cite journal |author=Groenen-van Dooren MM, Ronden JE, Soute BA, Vermeer C |title=Bioavailability of phylloquinone and menaquinones after oral and colorectal administration in vitamin K-deficient rats |journal=Biochem. Pharmacol. |volume=50 |issue=6 |pages=797–801 |year=1995 |pmid=7575640|doi=10.1016/0006-2952(95)00202-B}}</ref><ref name=Komai>{{cite journal |author=Komai M, Shirakawa H |title=[Vitamin K metabolism. Menaquinone-4 (MK-4) formation from ingested VK analogues and its potent relation to bone function] |language=Japanese |journal=Clin Calcium |volume=17 |issue=11 |pages=1663–72 |year=2007 |pmid=17982185 }}</ref> These results are reinforced by human cohort studies, where a majority of the subjects showed inadequate vitamin K amounts in the body. This was revealed by the presence of large amounts of incomplete [[carboxylation#Carboxylation in biochemistry|gamma-carboxylated protein]]s in the blood, an indirect test for vitamin K deficiency.<ref name=Geleijnse>{{cite journal |author=Geleijnse JM |title=Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study |journal=J. Nutr. |volume=134 |issue=11 |pages=3100–5 |year=2004|pmid=15514282 |url=http://jn.nutrition.org/content/134/11/3100.full.pdf |author2=Vermeer C |author3=Grobbee DE |last4=Schurgers |first4=LJ |last5=Knapen |first5=MH |last6=Van Der Meer |first6=IM |last7=Hofman |first7=A |last8=Witteman |first8=JC }}</ref><ref name=Beulens>{{cite journal |author=Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT |title=High dietary menaquinone intake is associated with reduced coronary calcification |journal=Atherosclerosis |volume=203 |issue=2 |pages=489–93 |year=2009 |pmid=18722618 |doi=10.1016/j.atherosclerosis.2008.07.010 }}</ref><ref name=Nimptsch>{{cite journal |author=Nimptsch K, Rohrmann S, Kaaks R, Linseisen J |title=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) |journal=Am. J. Clin. Nutr. |volume=91 |issue=5 |pages=1348–58 |year=2010 |pmid=20335553 |doi=10.3945/ajcn.2009.28691 |url=http://www.ajcn.org/content/91/5/1348.full.pdf }}</ref> And in an animal model MK-4 was shown to prevent arterial calcifications, pointing to its potential role in prevention of such calcification.<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|doi=10.1159/000075344}}</ref> In this study vitamin K<sub>1</sub> was also tested, in an attempt to make connections between vitamin K<sub>1</sub> intake and calcification reduction. Only vitamin K<sub>2</sub> (as MK-4) was found to influence warfarin-induced calcification in this study. |
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==Recommended amounts== |
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The U.S. [[Dietary Reference Intake]] (DRI) for an Adequate Intake (AI) of vitamin K for a 25-year old [[male]] is 120 [[micrograms]] (μg) per day. The AI for adult women is 90 μg/day, for infants is 10–20 μg/day, and for children and adolescents 15–100 μg/day. To get maximum [[carboxylation]] of [[osteocalcin]], one may have to take up to 1000 μg of vitamin K<sub>1</sub>.<ref>{{cite journal |author=Binkley NC, Krueger DC, Kawahara TN, angelke JA, Chappell RJ, Suttie JW |title=A high phylloquinone intake is required to achieve maximal osteocalcin gamma-carboxylation |journal=Am. J. Clin. Nutr. |volume=76 |issue=5 |pages=1055–60 |year=2002|pmid=12399278 |url=http://www.ajcn.org/content/76/5/1055.full.pdf }}</ref> |
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==Anticoagulant drug interactions== |
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Phylloquinone (K<sub>1</sub>)<ref name="pmid15383473">{{cite journal |author=Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E |title=The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=204S–233S |year=2004 |pmid=15383473 |doi=10.1378/chest.126.3_suppl.204S}}</ref><ref name="pmid12186515">{{cite journal |author=Crowther MA |title=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 |journal=Ann. Intern. Med. |volume=137 |issue=4 |pages=251–4 |year=2002 |pmid=12186515 |author2=Douketis JD |author3=Schnurr T |last4=Steidl |first4=L |last5=Mera |first5=V |last6=Ultori |first6=C |last7=Venco |first7=A |last8=Ageno |first8=W |doi=10.7326/0003-4819-137-4-200208200-00009 }}</ref> or menaquinone (K<sub>2</sub>) are capable of reversing the anticoagulant activity (incorrectly but colloquially referred to as "blood-thinning action") of the powerful [[anticoagulant]] [[warfarin]] (tradename [[warfarin|Coumadin]]). Warfarin works by blocking recycling of vitamin K, so that the body and tissues have lower levels of active vitamin K, and thus a deficiency of the active vitamin. |
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Supplemental vitamin K (for which oral dosing is often more active than injectable dosing in human adults) reverses the vitamin K deficiency caused by warfarin, and therefore modulates or totally reverses the intended anticoagulant action of warfarin and related drugs.{{Citation needed|reason=no reference given|date=May 2013}} Foods containing high amounts of vitamin K ([[green leafy vegetables]]) are avoided when taking warfarin .{{Citation needed|reason=no reference given|date=May 2013}} Sometimes small amounts of vitamin K (one milligram per day) are given orally to patients taking [[warfarin|Coumadin]] so that the action of the drug is more predictable. {{Citation needed|reason=No reference cited for this fact|date=May 2013}} The proper anticoagulant action of the drug is a function of vitamin K intake and drug dose, and (due to differing absorption) must be individualized for each patient.{{Citation needed|reason=no reference given|date=May 2013}} The action of warfarin and vitamin K both require two to five days after dosing to have maximum effect, and neither [[warfarin|Coumadin]] or vitamin K shows much effect in the first 24 hours after they are given.{{Citation needed|reason=no reference given|date=May 2013}} |
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In two separate studies in the rat model, after long term administration of [[warfarin|Coumadin]] to induce calcification of arteries in the rodents, supplemental vitamin K was found to reverse or prevent some of the arterial calcification attendant on the long-term blockade of vitamin K.<ref>{{cite pmid|17138823}}</ref> A second study found that only vitamin K<sub>2</sub> as MK-4, and not vitamin K<sub>1</sub> was effective at preventing warfarin-induced arterial calcification in rats, suggesting differing roles for the two forms of the vitamin in some calcium-dependent processes.<ref>{{cite doi|10.1159/000075344}}</ref> |
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The newer anticoagulants [[dabigatran]] and [[rivaroxaban]] have different mechanisms of action that do not interact with vitamin K, and may be taken with supplemental vitamin K.<ref>[http://www.pradaxapro.com/drug-interactions.jsp Pradaxa Drug Interactions]. Pradaxapro.com (19 March 2012). Retrieved on 21 April 2013.</ref><ref name="pmid9446847">{{cite journal|last=Bauersachs|first=R|coauthors=The EINSTEIN Investigators|title=Oral Rivaroxaban for Symptomatic Venous Thromboembolism|journal=New England Journal of Medicine|year=2010|volume=363|pages=2499–2510|doi=10.1056/NEJMoa1007903|pmid=21128814|issue=26}}</ref> |
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==Food sources== |
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===Vitamin K<sub>1</sub>=== |
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{| class="wikitable" |
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|- |
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!Food |
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!Serving Size |
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!Vitamin K<sub>1</sub><ref name="RheaumeBleueKate">[[#Rheaume-Bleue|Rhéaume-Bleue]], p. 42</ref> Microgram (μg) |
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!Food |
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!Serving Size |
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!Vitamin K<sub>1</sub><ref name="RheaumeBleueKate" /> Microgram (μg) |
|||
|- |
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|[[Kale]], cooked |
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|1/2 cup |
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|531 |
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|[[Parsley]], raw |
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|1/4 cup |
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|246 |
|||
|- |
|||
|[[Spinach]], cooked |
|||
|1/2 cup |
|||
|444 |
|||
|[[Spinach]], raw |
|||
|1 cup |
|||
|145 |
|||
|- |
|||
|[[Collards]], cooked |
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|1/2 cup |
|||
|418 |
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|Collards, raw |
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|1 cup |
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|184 |
|||
|- |
|||
|[[Swiss chard]], cooked |
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|1/2 cup |
|||
|287 |
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|Swiss chard, raw |
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|1 cup |
|||
|299 |
|||
|- |
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|[[Mustard (plant)|Mustard]] greens, cooked |
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|1/2 cup |
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|210 |
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|Mustard greens, raw |
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|1 cup |
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|279 |
|||
|- |
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|[[Turnip]] greens, cooked |
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|1/2 cup |
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|265 |
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|Turnip greens, raw |
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|1 cup |
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|138 |
|||
|- |
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|[[Broccoli]], cooked |
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|1 cup |
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|220 |
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|Broccoli, raw |
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|1 cup |
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|89 |
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|- |
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|[[Brussels sprouts]], cooked |
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|1 cup |
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|219 |
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|[[Endive]], raw |
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|1 cup |
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|116 |
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|- |
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|[[Cabbage]], cooked |
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|1/2 cup |
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|82 |
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|[[Green leaf lettuce]] |
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|1 cup |
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|71 |
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|- |
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|[[Asparagus]] |
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|4 spears |
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|48 |
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|[[Romaine lettuce]], raw |
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|1 cup |
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|57 |
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|- |
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|colspan="6"|''Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force.<ref>[http://www.cc.nih.gov/ccc/patient_education/drug_nutrient/coumadin1.pdf Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K]. National Institutes of Health Clinical Center. cc.nih.gov</ref> |
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|} |
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Vitamin K<sub>1</sub> is found chiefly in leafy green vegetables such as [[dandelion]] greens (which contain 778.4 μg per 100 g, or 741% of the recommended daily amount), [[spinach]], [[swiss chard]], and ''[[Brassica]]'' (''e.g.'' [[cabbage]], [[kale]], [[cauliflower]], [[broccoli]], [[lettuce]], and [[brussels sprout]]s) and often the absorption is greater when accompanied by fats such as butter or oils; some [[fruit]]s, 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.<ref>[http://www.nutritiondata.com/facts-C00001-01c20eX.html Nutrition Facts and Information for Parsley, raw]. Nutritiondata.com. Retrieved on 21 April 2013.</ref> Some vegetable oils, notably soybean, contain vitamin K, but at levels that would require relatively large calorific consumption to meet the [[USDA]]-recommended levels.<ref>[http://www.nutritiondata.com Nutrition facts, calories in food, labels, nutritional information and analysis]. Nutritiondata.com (13 February 2008). Retrieved on 21 April 2013.</ref> |
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Colonic bacteria synthesize a significant portion of humans' vitamin K needs; newborns often receive a vitamin K shot at birth to tide them over until their colons become colonized at five to seven days of age from the consumption of their mother's milk. |
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Phylloquinone's tight binding to thylakoid membranes in chloroplasts makes it less bioavailable. For example, cooked spinach has a 5% bioavailability of phylloquinone, however, fat added to it increases bioavailability to 13% due to the increased solubility of vitamin K in fat.<ref>[http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/vitamink.html Vitamin K]. Vivo.colostate.edu (2 July 1999). Retrieved on 21 April 2013.</ref> |
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===Vitamin K<sub>2</sub>=== |
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{{main|Vitamin K2}} |
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Food sources of vitamin K<sub>2</sub> include fermented or aged cheeses, eggs, meats such as chicken and beef and their fat, livers, and organs, and in fermented vegetables, especially [[natto]], as well as sauerkraut and kefir.<ref>[http://www.livestrong.com/article/299992-vitamin-k2-food-sources/ food sources for vitamin K<sub>2</sub>]. Livestrong.com. Retrieved on 21 April 2013.</ref> |
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{| class="wikitable" |
|||
|- |
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!Food {{convert|100|g|oz}} portion |
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!Microgram (μg) |
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!Proportion of vitamin K<sub>2</sub> |
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!Food {{convert|100|g|oz}} portion |
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!Microgram (μg) |
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!Proportion of vitamin K<sub>2</sub> |
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|- |
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|[[Natto]], cooked |
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|1,103.4 |
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|(90% MK-7, 10% other MK) |
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|Chicken Leg |
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|8.5 |
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|(100% MK-4) |
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|- |
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|Goose [[liver pâté]] |
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| 369.0 |
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|(100% MK-4) |
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|[[Ground beef]] (medium fat) |
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|8.1 |
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|(100% MK-4) |
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|- |
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|Hard cheeses (Dutch [[Gouda cheese|Gouda]] style), raw |
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| 76.3 |
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|(6% MK-4, 94% other MK) |
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|Chicken liver ([[Braising|braised]]) |
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|6.7 |
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|(100% MK-4) |
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|- |
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|Soft cheeses (French [[Brie]] style) |
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|56.5 |
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|(6.5 MK-4, 93.5% other MK) |
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|Hot dog |
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|5.7 |
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|(100% MK-4) |
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|- |
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|[[Egg yolk]], (Netherlands) |
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|32.1 |
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|(98% MK-4, 2% other MK) |
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|Bacon |
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|5.6 |
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|(100% MK-4) |
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|- |
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|Goose leg |
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|31.0 |
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|(100% MK-4) |
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|Calf’s liver (pan-fried) |
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|6.0 |
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|(100% MK-4) |
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|- |
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|Egg yolk (U.S.) |
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|15.5 |
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|(100% MK-4) |
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|[[Sauerkraut]] |
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|4.8 |
|||
|(100% MK-4) |
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|- |
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|Butter |
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|15.0 |
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|(100% MK-4) |
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|[[Whole milk]] |
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|1.0 |
|||
|(100% MK-4) |
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|- |
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|Chicken liver (raw) |
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|14.1 |
|||
|(100% MK-4) |
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|[[Salmon]] (Alaska, Coho, Sockeye, Chum, and King wild (raw)) |
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|0.5 |
|||
|(100% MK-4) |
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|- |
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|Chicken liver (pan-fried) |
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|12.6 |
|||
|(100% MK-4) |
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|Cow’s liver (pan-fried) |
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|0.4 |
|||
|(100% MK-4) |
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|- |
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|[[Cheddar cheese]] (U.S.) |
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|10.2 |
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|(6% MK-4, 94% other MK) |
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|[[Egg white]] |
|||
|0.4 |
|||
|(100% MK-4) |
|||
|- |
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|Meat franks |
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|9.8 |
|||
|(100% MK-4) |
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|[[Skim milk]] |
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|0.0 |
|||
| |
|||
|- |
|||
|Chicken breast |
|||
|8.9 |
|||
|(100% MK-4) |
|||
|- |
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|colspan="6"|''Table from [[#Rheaume-Bleue|Rhéaume-Bleue]], pp. 66–67.</sup> |
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|} |
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Vitamin K<sub>2</sub> (menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products.<ref name="pmid16417305">{{cite journal|author=Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL|title=Vitamin k contents of meat, dairy, and fast food in the U.S. Diet|journal=J. Agric. Food Chem.|volume=54|issue=2|pages=463–7|year=2006|pmid=16417305|doi=10.1021/jf052400h }}</ref> Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans (''[[natto]]''), and in most fermented cheeses.<ref name="pmid10874601">{{cite journal|author=Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M|title=Intake of fermented soybean (natto) increases circulating vitamin K<sub>2</sub> (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals|journal=J. Bone Miner. Metab.|volume=18|issue=4|pages=216–22|year=2000|pmid=10874601|doi= 10.1007/s007740070023}}</ref> In ''natto'', none of the vitamin K is from menaquinone-4, and in cheese only 2–7% is.<ref>{{cite web|url=http://www.westonaprice.org/fat-soluble-activators/x-factor-is-vitamin-k2#fig4|title=On the Trail of the Elusive X-Factor: Vitamin K<sub>2</sub> Revealed }}{{verify source|date=November 2011}}</ref> |
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==Deficiency== |
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{{Main|Vitamin K deficiency}} |
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Average diets are usually not lacking in vitamin K, and primary deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include those who suffer from liver damage or disease (e.g. alcoholics), cystic fibrosis, or inflammatory bowel diseases, or have recently had abdominal surgeries. Secondary vitamin K deficiency can occur in bulimics, those on stringent diets, and those taking anticoagulants. Other drugs associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanisms are still unknown. Vitamin K<sub>1</sub> deficiency can result in [[coagulopathy]], a bleeding disorder.<ref>{{cite web|url=http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/|title=Micronutrient Data Centre: Vitamin K }}</ref> Symptoms of K<sub>1</sub> deficiency include anemia, bruising, and bleeding of the gums or nose in both sexes, and heavy menstrual bleeding in women. |
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Osteoporosis<ref>{{cite journal |pmid=16614424 |year=2006 |author1=Ikeda |first2=M |first3=A |first4=E |first5=S |first6=Y |first7=H |title=Intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese Population-Based Osteoporosis (JPOS) Study |volume=136 |issue=5 |pages=1323–8 |journal=The Journal of nutrition |last2=Iki |last3=Morita |last4=Kajita |last5=Kagamimori |last6=Kagawa |last7=Yoneshima}}</ref><ref>{{cite journal |pmid=12350079 |year=2002 |author1=Katsuyama |first2=S |first3=M |first4=K |first5=S |title=Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women |volume=48 |issue=3 |pages=207–15 |journal=Journal of nutritional science and vitaminology |last2=Ideguchi |last3=Fukunaga |last4=Saijoh |last5=Sunami |doi=10.3177/jnsv.48.207}}</ref> and coronary heart disease<ref>{{cite journal |pmid=10737225 |year=1999 |author1=Sano |first2=H |first3=I |first4=H |first5=S |title=Vitamin K<sub>2</sub> (menatetrenone) induces iNOS in bovine vascular smooth muscle cells: no relationship between nitric oxide production and gamma-carboxylation |volume=45 |issue=6 |pages=711–23 |journal=Journal of nutritional science and vitaminology |last2=Fujita |last3=Morita |last4=Uematsu |last5=Murota |doi=10.3177/jnsv.45.711}}</ref><ref name="autogenerated1">{{cite pmid|19179058}}</ref> are strongly associated with lower levels of K<sub>2</sub> (menaquinone). |
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Vitamin K<sub>2</sub> (MK-7) deficiency is also related to severe aortic calcification and all-cause mortality.<ref>{{cite journal |pmid=15514282 |year=2004 |title=Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study |volume=134 |issue=11 |pages=3100–5 |journal=The Journal of nutrition |author1=Geleijnse |last2=Vermeer |last3=Grobbee |last4=Schurgers |last5=Knapen |last6=van der Meer |first2=C |first3=DE |first4=LJ |first5=MH |first6=IM |last7=Hofman |first7=A |last8=Witteman |first8=JC}}</ref> |
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Menaquinone is not inhibited by salicylates as happens with K<sub>1</sub>, so menaquinone supplementation can alleviate the chronic vitamin K deficiency caused by long-term aspirin use.{{Citation needed|date=July 2009}} |
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==Toxicity== |
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Although [[allergic reaction]] from supplementation is possible, no known toxicity is associated with high doses of the phylloquinone (vitamin K<sub>1</sub>) or menaquinone (vitamin K<sub>2</sub>) forms of vitamin K, so no [[Tolerable upper intake level#Current recommendations|tolerable upper intake level]] (UL) has been set.<ref>{{cite pmid|16200467}}</ref> |
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Blood clotting ([[coagulation]]) studies in humans using 45 mg per day of vitamin K<sub>2</sub> (as MK-4)<ref name="Ushiroyama 2002 211–221"/> and even up to 135 mg/day (45 mg three times daily) of K<sub>2</sub> (as MK-4),<ref>{{cite journal|last=Asakura|first=H|coauthors=Myou S, Ontachi Y, Mizutani T, Kato M, Saito M, Morishita E, Yamazaki M, Nakao S|title=Vitamin K administration to elderly patients with osteoporosis induces no hemostatic activation, even in those with suspected vitamin K deficiency|journal=Osteoporosis International|year=2001|volume=12|issue=12|pages=996–1000|pmid=11846334|doi=10.1007/s001980170007}}</ref> showed no increase in blood clot risk. Even doses in rats as high as 250 mg/kg body weight did not alter the tendency for blood-clot formation to occur.<ref>{{cite journal|last=Ronden|first=JE|coauthors=Groenen-van Dooren MMCL, Hornstra G, Vermeer C|title=Modulation of arterial thrombosis tendency in rats by vitamin K and its side chains|journal=Atherosclerosis|year=1997|volume=132|issue=1|pages=61–67|pmid=9247360|doi=10.1016/S0021-9150(97)00087-7}}</ref> |
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Unlike the safe natural forms of vitamin K<sub>1</sub> and vitamin K<sub>2</sub> and their various [[isomer]]s, a synthetic form of vitamin K, vitamin K<sub>3</sub> ([[menadione]]), is demonstrably toxic. The U.S. FDA has banned this form from over-the-counter sale in the [[United States]] because large doses have been shown to cause allergic reactions, [[hemolytic anemia]], and [[cytotoxicity]] in liver cells.<ref name=Higdon/> |
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==Biochemistry== |
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===Function in animals=== |
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[[File:Vitamin K structures.jpg|thumb|400px|Vitamin K structures. MK-4 and MK-7 are both subtypes of K<sub>2</sub>.]] |
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The function of vitamin K<sub>2</sub> in the animal cell is to add a [[carboxylic acid]] functional group to a [[glutamate]] 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 (carboxylate) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate [[calcium ion]]. The binding of calcium ion in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called vitamin K dependent clotting factors discussed below. |
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Within the cell, vitamin K undergoes electron [[Redox|reduction]] to a reduced form called vitamin K hydroquinone by the enzyme [[vitamin K epoxide reductase]] (VKOR).<ref name="Oldenburg">{{cite journal|author=Oldenburg J, Bevans CG, Müller CR, Watzka M|title=Vitamin K epoxide reductase complex subunit 1 (VKORC1): the key protein of the vitamin K cycle|journal=Antioxid. Redox Signal.|volume=8|issue=3–4|pages=347–53|year=2006|pmid=16677080|doi=10.1089/ars.2006.8.347 }}</ref> Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the [[gamma-glutamyl carboxylase]]<ref name="Suttie">{{cite journal|author=Suttie JW|title=Vitamin K-dependent carboxylase|journal=Annu. Rev. Biochem.|volume=54|pages=459–77|year=1985|pmid=3896125|doi=10.1146/annurev.bi.54.070185.002331 }}</ref><ref name="Presnell">{{cite journal|author=Presnell SR, Stafford DW|title=The vitamin K-dependent carboxylase|journal=Thromb. Haemost.|volume=87|issue=6|pages=937–46|year=2002|pmid=12083499}}</ref> or the vitamin K-dependent carboxylase. The carboxylation reaction only proceeds 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. Vitamin K epoxide is then reconverted to vitamin K by VKOR. The reduction and subsequent reoxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle.<ref name=Stafford>{{cite journal|author=Stafford DW|title=The vitamin K cycle|journal=J. Thromb. Haemost.|volume=3|issue=8|pages=1873–8|year=2005|pmid=16102054|doi=10.1111/j.1538-7836.2005.01419.x }}</ref> Humans are rarely deficient in vitamin K<sub>1</sub> because, in part, vitamin K <sub>1</sub> is continuously recycled in cells.<ref>[[#Rheaume-Bleue|Rhéaume-Bleue]], p. 79.</ref> |
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[[Warfarin]] and other [[4-hydroxycoumarins]] block the action of the VKOR.<ref name="Whitlon">{{cite journal|author=Whitlon DS, Sadowski JA, Suttie JW|title=Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition|journal=Biochemistry|volume=17|issue=8|pages=1371–7|year=1978|pmid=646989|doi= 10.1021/bi00601a003 }}</ref> 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 give the desired degree of clotting suppression, warfarin treatment must be carefully monitored to avoid overdose. |
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===Gamma-carboxyglutamate proteins=== |
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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]] to activate the Axl [[receptor (biochemistry)|receptor]] [[tyrosine kinase]] and stimulate cell proliferation or prevent [[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. |
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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. 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. |
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Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail ''[[Conus geographus]]''.<ref name="Terlau">{{cite journal|author=Terlau H, Olivera BM|title=Conus venoms: a rich source of novel ion channel-targeted peptides|journal=Physiol. Rev.|volume=84|issue=1|pages=41–68|year=2004|pmid=14715910|doi=10.1152/physrev.00020.2003 }}</ref> These snails produce a venom containing hundreds of neuroactive peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain two to five Gla residues.<ref name="Buczek">{{cite journal|author=Buczek O, Bulaj G, Olivera BM|title=Conotoxins and the posttranslational modification of secreted gene products|journal=Cell. Mol. Life Sci.|volume=62|issue=24|pages=3067–79|year=2005|pmid=16314929|doi=10.1007/s00018-005-5283-0 }}</ref> |
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===Methods of assessment=== |
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Vitamin K status can be assessed by: |
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* The prothrombin time (PT) test measures the time required for blood to clot. A blood sample is mixed with citric acid and put in a fibrometer; delayed clot formation indicates a deficiency. This test is insensitive to mild deficiency, as the values do not change until the concentration of prothrombin in the blood has declined by at least 50%.<ref>[http://www.webmd.com/a-to-z-guides/prothrombin-time Prothrombin Time]. webmd.com</ref> |
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* Undercarboxylated prothrombin (PIVKA-II), in a study of 53 newborns, found "PT (prothrombin time) is a less sensitive marker than PIVKA II",<ref>{{cite pmid|22280352}}</ref> and as indicated above, PT is unable to detect subclinical deficiencies that can be detected with PIVKA-II testing. |
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* Plasma phylloquinone was found to be positively correlated with phylloquinone intake in elderly British women, but not men,<ref>{{cite journal|author=Thane CW|title=Plasma phylloquinone (vitamin K<sub>1</sub>) concentration and its relationship to intake in a national sample of British elderly people|journal=Br. J. Nutr.|volume=87|issue=6|pages=615–22|year=2002|pmid=12067432|doi=10.1079/BJNBJN2002582|author2=Bates CJ|author3=Shearer MJ|last4=Unadkat|first4=N.|last5=Harrington|first5=D.J.|last6=Paul|first6=A.A.|last7=Prentice|first7=A.|last8=Bolton-Smith|first8=C. }}</ref> |
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but an article by Schurges ''et al.'' reported no correlation between FFQ {{explain}} and plasma phylloquinone.<ref>{{cite journal|author=McKeown NM|title=Dietary and nondietary determinants of vitamin K biochemical measures in men and women|journal=J. Nutr.|volume=132|issue=6|pages=1329–34|year=2002|pmid=12042454|url=http://jn.nutrition.org/content/132/6/1329.full.pdf|author2=Jacques PF|author3=Gundberg CM|last4=Peterson|first4=JW|last5=Tucker|first5=KL|last6=Kiel|first6=DP|last7=Wilson|first7=PW|last8=Booth|first8=SL }}</ref> |
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* Urinary γ-carboxyglutamic acid 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 and 417 μg for five days did not induce a significant change. Response may be age-specific.<ref>{{cite journal|author=Yamano M, Yamanaka Y, Yasunaga K, Uchida K|title=Effect of vitamin K deficiency on urinary gamma-carboxyglutamic acid excretion in rats|journal=Nippon Ketsueki Gakkai Zasshi|volume=52|issue=6|pages=1078–86|year=1989|pmid=2588957}}</ref> |
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* Undercarboxylated osteocalcin (UcOc) levels have been inversely correlated with stores of vitamin K<ref>{{cite pmid|21944271}}</ref> and bone strength in developing rat tibiae. Another study following 78 postmenopausal Korean women found a supplement regimen of vitamins K and D, and calcium, but not a regimen of vitamin D and calcium, was inversely correlated with reduced UcOc levels.<ref>{{cite pmid|21860562}}</ref> <!-- commercial Metametrix Clinical Laboratory offers a blood test for UcOc <ref>http://www.metametrix.com/test-menu/profiles/vitamins/vitamin-k</ref>--> |
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===Function in bacteria=== |
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Many bacteria, such as ''[[Escherichia coli]]'' found in the [[large intestine]], can synthesize vitamin K<sub>2</sub> (menaquinone-7 or MK-7, up to MK-11),<ref name="Bentley">{{cite journal|author=Bentley R, Meganathan R|title=Biosynthesis of vitamin K (menaquinone) in bacteria|journal=Microbiol. Rev.|volume=46|issue=3|pages=241–80|year=1982|pmid=6127606|pmc=281544|url=http://mmbr.asm.org/content/46/3/241.full.pdf }}</ref> but not vitamin K<sub>1</sub> (phylloquinone). In these bacteria, menaquinone transfers two [[electrons]] between two different small molecules, during oxygen-independent metabolic energy production processes ([[anaerobic respiration]]).<ref name="Haddock">{{cite journal|author=Haddock BA, Jones CW|title=Bacterial respiration|journal=Bacteriol Rev|volume=41|issue=1|pages=47–99|year=1977|pmid=140652|pmc=413996|url=http://mmbr.asm.org/content/41/1/47.full.pdf }}</ref> For example, a small molecule with an excess of electrons (also called an electron donor) such as [[lactic acid|lactate]], [[formate]], or [[NADH]], with the help of an enzyme, passes two electrons to a menaquinone. The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such [[fumarate]] or [[nitrate]] (also called an electron acceptor). Adding two electrons to [[fumarate]] or [[nitrate]] converts the molecule to [[succinate]] or [[nitrite]] + [[water]], respectively. |
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Some of these reactions generate a cellular energy source, [[adenosine triphosphate|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]] (O<sub>2</sub>), which accepts four electrons from an electron donor such as [[NADH]] to be converted to [[water]]. ''E. coli'' can carry out [[aerobic respiration]] and menaquinone-mediated anaerobic respiration. |
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==Vitamin K injection in newborns== |
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The blood clotting factors of newborn babies are roughly 30 to 60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains 1–4 μg/L of vitamin K<sub>1</sub>, while formula-derived milk can contain up to 100 μg/L in supplemented formulas. Vitamin K<sub>2</sub> concentrations in human milk appear to be much lower than those of vitamin K<sub>1</sub>. |
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Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at 0.25 to 1.7%, with a prevalence of two to 10 cases per 100,000 births.<ref>{{cite journal|author=Shearer MJ|title=Vitamin K|journal=Lancet|volume=345|issue=8944|pages=229–34|year=1995|pmid=7823718|doi= 10.1016/S0140-6736(95)90227-9 }}</ref> Premature babies have even lower levels of the vitamin, so they are at a higher risk from this deficiency. |
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Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalizations, blood transfusions, brain damage, and death. Supplementation can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular administration is more effective in preventing late vitamin K deficiency bleeding than oral administration.<ref>''Wintrobe's Clinical Hematology'', 11th Edition. J.P. Greer, Foerster J., Lukens, J.N., Rodgers, G.M., Paraskevas, F., and Glader, B., editor. Philadelphia, PA, USA: Lippincott Williams and Wilkens.</ref><ref name="pediatrics.aappublications.org">{{cite journal|title=Controversies concerning vitamin K and the newborn. American Academy of Pediatrics Committee on Fetus and Newborn|journal=Pediatrics|volume=112|issue=1 Pt 1|pages=191–2|year=2003|pmid=12837888|doi=10.1542/peds.112.1.191|url=http://pediatrics.aappublications.org/content/112/1/191.full.pdf |author1=American Academy of Pediatrics Committee on Fetus and Newborn}}</ref> |
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===USA=== |
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As a result of the occurrences of vitamin K deficiency bleeding, the Committee on Nutrition of the American Academy of Pediatrics has recommended 0.5 to 1.0 mg vitamin K<sub>1</sub> be administered to all newborns shortly after birth.<ref name="pediatrics.aappublications.org"/> |
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===UK=== |
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{{unreferenced section|date=November 2011}} |
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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. |
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===Controversy=== |
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Controversy arose in the early 1990s regarding this practice, when two studies suggested a relationship between [[wikt:parenteral|parenteral]] administration of vitamin K and childhood cancer,{{Citation needed|date=July 2010}} 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.<ref>{{cite journal |author=McMillan DD |title=Routine administration of vitamin K to newborns |journal=Paediatr Child Health |volume=2 |issue=6 |pages=429–31 |year=1997|url=http://www.cps.ca/documents/position/administration-vitamin-K-newborns}}</ref> |
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==Vitamin K and bone health== |
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Both physiological and observational evidence indicate vitamin K plays a role in bone growth and the maintenance of bone density, but a large study attempting to delay the onset of osteoporosis by vitamin K supplementation proved ineffective.<ref name="VKSUP">{{cite journal |doi=10.1371/journal.pmed.0050196|pmc=2566998 |pmid=18922041 |journal=PLoS Med. |title=Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial |issue=10|pages=1–12 |author=Cheung AM, Tile L, Lee Y, Tomlinson G, Hawker G, Scher J, Hu H, Vieth R, Thompson L, Jamal S, Josse R|year=2008 |editor1-last=Torgerson |volume=5}}</ref> |
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Vitamin K takes part in the post-translational modification as a cofactor in γ-carboxylation of vitamin K-dependant proteins (VKDPs). VKDPs have glutamate residues (Glu). Biophysical studies suggest that supplemental vitamin K promotes [[Osteoblast|osteotrophic]] processes and slows [[osteoclast]]ic processes via calcium bonding. Study of Atkins et al.<ref>{{cite journal | author = Gerald JA | year = 2009 | title = Vitamin K promotes mineralization, osteoblast‐to‐osteocyte transition, and an anticatabolic phenotype by γ‐carboxylation‐dependent and independent mechanisms | journal = Am J Physiol Cell Physiol | volume = 297 | pages = C1358–C1367 | doi = 10.1152/ajpcell.00216.2009 | pmid = 19675304 | issue = 6| author2 = Katie JW | author3 = Asiri R W | last4 = Bonewald | first4 = L. F. | last5 = Findlay | first5 = D. M.}}</ref> revealed [[phylloquinone]], [[menatetrenone]] (MK-4) and [[menadione]] promote ''in vitro'' mineralization by human primary osteoblasts. Other studies have shown [[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, 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.<ref>Drenckhahn, D. & Kugler, P (2003), "Knochengewebe". In Benninhoff & D. Drenhahn, ''Anatomie Band'' 1:147. Munich, Germany: Urban & Fisher</ref><ref name="womentowomen">{{cite web |url= http://www.womentowomen.com/bonehealth/keynutrients-vitamink.aspx |title= Key vitamins for bone health — vitamins K<sub>1</sub> and K<sub>2</sub> |author= Brown, Susan E. |publisher= womentowomen.com |accessdate=11 August 2010}}</ref> Vitamin D is reported to regulate the OC transcription by osteoblast thereby showing that vitamin K and vitamin D work in tandem for the bone metabolism and development. Lian and his group discovered two nucleotide substitution regions they named "osteocalcin box" in the rat and human osteocalcin genes.<ref>{{cite journal | author = Lian J, Stewart C, Puchacz E, Mackowiak S, Shalhoub V, Collart D, Zambetti G & Stein G | year = 1989 | title = Structure of the rat osteocalcin gene and regulation of vitamin D-dependent expression | journal = Proc. Natl. Acad. Sci. USA | volume = 86 | pages = 1143–1147 | doi = 10.1073/pnas.86.4.1143 | pmid = 2784002 | issue = 4 | pmc = 286642}}</ref> 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. |
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===Vitamin K<sub>1</sub> and bone health=== |
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Data from the 1998 Nurses Health Study, an [[observational study]], indicated an inverse relationship between dietary vitamin K<sub>1</sub> 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.<ref name="womentowomen" /><ref name=Kanai1997/>{{failed verification|date=August 2013}} The Framingham Heart Study<ref>{{cite journal | author = Booth SL, Tucker KL, Chen H, Hannan MT, Gagnon DR, Cupples LA, Wilson PW, Ordovas J, Schaefer EJ, Dawson-Hughes B, Kiel DP| year = 2000 | title = Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women | journal = Am J Clin Nutr | volume = 71 | pages = 1201–1208 | pmid = 10799384 | issue = 5}}</ref> is another study that showed a similar result. Subjects in the highest quartile of vitamin K<sub>1</sub> intake (median K<sub>1</sub> intake of 254 μg/ day) had a 35% lower risk of hip fracture than those in the lowest quartile. 254 μg/day is above the US Daily Reference Intake (DRI) of 90 μg/day for women and 120 μg/day for men. (See above) |
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In the face of this evidence, a large multicentre, randomized, placebo-controlled trial was performed to test the supplementation of vitamin K in postmenopausal women with osteopenia. Despite heavy doses of vitamin K<sub>1</sub>, no differences were found in bone density between the supplemented and placebo groups.<ref name="VKSUP" /> |
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===Vitamin K<sub>2</sub> (MK-4) and bone health=== |
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MK-4 has been shown in numerous studies to reduce fracture risk, and stop and reverse bone loss. In Japan, MK-4 in the dose of 45 mg daily is recognized as a treatment for [[osteoporosis]]<ref name=Kanai1997>{{cite journal |doi=10.1016/S0020-7292(96)02790-7 |title=Serum vitamin K level and bone mineral density in post-menopausal women |year=1997 |last1=Kanai |first1=T |journal=International Journal of Gynecology & Obstetrics |volume=56 |page=25 |last2=Takagi |first2=T. |last3=Masuhiro |first3=K. |last4=Nakamura |first4=M. |last5=Iwata |first5=M. |last6=Saji |first6=F.}}</ref><ref>{{cite journal |pmid=9925126 |url=http://www.ajcn.org/content/69/1/74.full.pdf |journal=American Journal of Clinical Nutrition |title=Vitamin K intake and hip fractures in women: a prospective study |volume=69 |issue=1 |pages=74–9 |author=Feskanich, Diane |first2=P |first3=W |first4=H |first5=S |first6=G |year=1999 |last2=Weber |last3=Willett |last4=Rockett |last5=Booth |last6=Colditz}}</ref> under the trade name [[Glakay]].<ref>[http://www.eisai.jp/medical/products/di/EPI/GLA_SC_EPI.pdf Glakay prescribing information]. Eisai Co., Ltd..</ref> MK-4 has been shown to decrease fractures up to 87%.<ref name="Sato 2005"/> In the amount of 45 mg daily MK-4 has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.<ref name="Iwamoto 1999 161–164"/> |
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MK-4 (but not MK-7 or vitamin K<sub>1</sub>) prevented bone loss and/or fractures in the following circumstances: |
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* caused by corticosteroids (e.g., [[prednisone]], [[dexamethasone]], [[prednisolone]])<ref name="Inoue 2001 11–18"/><ref name="Sasaki 2005 41–47"/><ref name="Yonemura 2004 53–60"/><ref name="Yonemura 2000 123–128"/> |
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* [[anorexia nervosa]]<ref name="Iketani 2003 259–269"/> |
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* cirrhosis of the liver<ref name="Shiomi 2002 978–981"/> |
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* postmenopausal osteoporosis<ref name="Iwamoto 1999 161–164"/><ref name="Cockayne 2006 1256–1261"/><ref name="Iwamoto 2000 546–551"/><ref name="Purwosunu 2006 230–234"/><ref name="Shiraki 2000 515–522"/><ref name="Ushiroyama 2002 211–221"/> |
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* disuse from stroke<ref name="Sato 1998 291–296"/> |
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* [[Alzheimer's disease]]<ref name="Sato 2005 61–68"/> |
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* [[Parkinson disease]]<ref name="Sato 2002 114–118"/> |
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* [[primary biliary cirrhosis]]<ref name="Nishiguchi 2001 543–545"/> |
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* leuprolide treatment (for prostate cancer).<ref name="Somekawa 1999 2700–2704"/> |
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===Vitamin K<sub>2</sub> (MK-7) and bone health=== |
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Menaquinone-7 (MK-7), which is abundant in fermented soybeans (natto), has been demonstrated to stimulate osteoblastic bone formation and to inhibit osteoclastic bone resorption.<ref>{{cite journal |author=Yamaguchi M |title=Regulatory mechanism of food factors in bone metabolism and prevention of osteoporosis |journal=Yakugaku Zasshi |volume=126 |issue=11 |pages=1117–37 |year=2006 |pmid=17077614|doi=10.1248/yakushi.126.1117}}</ref> In another study, use of MK-7 caused significant elevations of serum Y-carboxylated [[osteocalcin]] concentration, a biomarker of bone formation. MK-7 also completely inhibited a decrease in the calcium content of bone tissue by inhibiting the bone-resorbing factors [[parathyroid hormone]] and prostaglandin E<sub>2</sub>.<ref>{{cite journal |author=Tsukamoto Y |title=Studies on action of menaquinone-7 in regulation of bone metabolism and its preventive role of osteoporosis |journal=BioFactors |volume=22 |issue=1–4 |pages=5–19 |year=2004 |pmid=15630245 |doi=10.1002/biof.5520220102}}</ref> |
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On 19 February 2011, HSA (Singapore) approved a health supplement that contains vitamin K<sub>2</sub> (MK-7) and vitamin D<sub>3</sub> for increasing bone mineral density.<ref>[http://iabpi.com/component/content/article/69-fitness-natto-essence Ref. no. HPRG (HSU) 2011-02-0016]. Iabpi.com (16 March 2011). Retrieved on 21 April 2013.</ref> |
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== Vitamin K<sub>2</sub> (MK-7) and coronary heart disease == |
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A study by Gast et al. (2009),<ref name="autogenerated1"/> reports "an inverse association between vitamin K(2) and risk of CHD with a Hazard Ratio (HR) of 0.91 [95% CI 0.85–1.00] per 10 μg/d vitamin K(2) intake. This association was mainly due to vitamin K(2) subtypes MK-7, MK-8 and MK-9. Vitamin K(1) intake was not significantly related to CHD. The authors conclude that "a high intake of menoquinones, especially MK-7, MK-8 and MK-9, could protect against CHD. However, more research is necessary to define optimal intake levels of vitamin K intake for the prevention of CHD." |
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==Vitamin K and Alzheimer's disease== |
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Research into the antioxidant properties of vitamin K indicates that the concentration of vitamin K is lower in the circulation of carriers of the [[Apolipoprotein E|APOE4]] gene, and recent studies have shown its ability to inhibit [[Neuron|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.<ref>{{cite journal |doi=10.1054/mehy.2001.1307 |pmid=11461163 |year=2001 |author=Allison AC|title=The possible role of vitamin K deficiency in the pathogenesis of Alzheimer's disease and in augmenting brain damage associated with cardiovascular disease |volume=57 |issue=2 |pages=151–5 |journal=Medical hypotheses}}</ref> |
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==Vitamin K used topically== |
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Vitamin K may be applied topically, typically as a 5% cream, to diminish postoperative bruising from cosmetic surgery and injections, to treat broken capillaries (spider veins), to treat [[rosacea]], and to aid in the fading of [[hyperpigmentation]] and dark under-eye circles.<ref>{{cite journal|last=Cohen|first=JL|coauthors=Bhatia, AC|title=The role of topical vitamin K oxide gel in the resolution of postprocedural purpura|journal=Journal of drugs in dermatology : JDD|date=November 2009|volume=8|issue=11|pages=1020–4|pmid=19894369}}</ref><ref>{{cite journal|last=Leu|first=S|coauthors=Havey, J; White, LE; Martin, N; Yoo, SS; Rademaker, AW; Alam, M|title=Accelerated resolution of laser-induced bruising with topical 20% arnica: a rater-blinded randomized controlled trial|journal=The British journal of dermatology|date=September 2010|volume=163|issue=3|pages=557–63|pmid=20412090|doi=10.1111/j.1365-2133.2010.09813.x}}</ref> |
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==Vitamin K and cancer== |
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{{medref|section|date=January 2014}} |
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While researchers in Japan were studying the role of vitamin K<sub>2</sub> as the menaquinone-4 (MK-4) form in the prevention of bone loss in females with liver disease, they discovered another possible effect. This two-year study that involved 21 women with viral [[liver cirrhosis]] found that women in the supplement group were 90% less likely to develop [[liver cancer]].<ref>"[http://www.nutraingredients.com/Research/Vitamin-K-found-to-protect-against-liver-cancer Vitamin K Found to Protect Against Liver Cancer]". utraingredients.com (21 July 2004)</ref><ref>{{cite journal|author=Saxena SP, Israels ED, Israels LG|title=Novel vitamin K-dependent pathways regulating cell survival|journal=Apoptosis|volume=6|issue=1–2|pages=57–68|year=2001|pmid=11321042|doi=10.1023/A:1009624111275 }}</ref> A German study performed on men with [[prostate cancer]] found a significant inverse relationship between vitamin K<sub>2</sub> consumption and advanced prostate cancer.<ref>{{cite journal|author=Nimptsch K, Rohrmann S, Linseisen J|title=Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition. (EPIC-Heidelberg)|journal=Am. J. Clin. Nutr.|volume=87|issue=4|pages=985–92|year=2008|pmid=18400723|url=http://www.ajcn.org/content/87/4/985.full.pdf }}</ref> |
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In 2006, a clinical trial showed that K<sub>2</sub> as the menaquinone-4 (MK-4) (called [[menatetrenone]] in the study) might be able to reduce recurrence of liver cancer after surgery. It should be noted that this was a small pilot study and other similar studies did not show much effect. MK-4 is now being tested along with other drugs to reduce liver cancer and has shown promising early results.<ref name="ACC">[http://www.cancer.org/Treatment/TreatmentsandSideEffects/ComplementaryandAlternativeMedicine/HerbsVitaminsandMinerals/vitamin-k American Cancer Society: Vitamin K]. Cancer.org. Retrieved on 21 April 2013.</ref> |
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==Vitamin K and diabetes in the elderly== |
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A research shows that total diabetes risk of individual who have highest circulating levels of vitamin K<sub>1</sub> were 51% lower than those with the lowest levels. The researchers conclude that dietary phylloquinone intake is associated with reduced risk of type 2 diabetes.<ref>{{cite pmid|23034962}}</ref> |
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==Vitamin K and non-Hodgkin lymphoma== |
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A research shows that the risk of developing non-Hodgkin lymphoma was decreased by 45 percent for the study participants who had the highest vitamin K levels compared to participants with the lowest levels of the vitamin.<ref>Cerhan J. 101st Annual Meeting of the American Association for Cancer Research (AACR). 2012</ref> |
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==Vitamin K as antidote for poisoning by 4-hydroxycoumarin drugs== |
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Vitamin K is part of the suggested treatment regime for poisoning by [[rodenticide]].<ref>{{cite web |url=http://emedicine.medscape.com/article/818130-treatment#a1126 |accessdate=March 2014 |title=Rodenticide Toxicity Treatment & Management |author=Lung D |editor=Tarabar A}}</ref> |
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[[Vitamin K antagonist|Vitamin K antagonists]] are substances that reduce blood clotting by reducing the active form of vitamin K. They are used as rat poisons and as medications to prevent [[thrombosis]]. Examples include [[4-Hydroxycoumarins|4-hydroxycoumarins]] such as the pharmaceutical [[warfarin]], and also anticoagulant-mechanism poisons such as [[bromadiolone]], which are commonly found in [[rodenticides]].{{cn|date=March 2014}} |
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4-Hydroxycoumarin drugs possess [[anticoagulant|anticoagulatory]] and rodenticidal properties because they inhibit recycling of vitamin K and thus cause simple deficiency of active vitamin K. This deficiency results in decreased vitamin K-dependent synthesis of some clotting factors by the liver. Death is usually a result of internal hemorrhage. Treatment for rodenticide poisoning 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, after poisoning (this is necessary for the more potent 4-hydoxycoumarins used as rodenticides, which act by being fat-soluble and thus having a longer residence time in the body). If caught early, prognosis is good even when great amounts of the drug or poison are ingested, as these drugs are not true vitamin K antagonists, so the same amount of fresh vitamin K administered each day is sufficient for any dose of poison (although as noted, this must be continued for a longer time with more potent poisons). No matter how large the dose of these agents, they can do no more than prevent vitamin K from being recycled, and this metabolic problem may always be simply reversed by giving sufficient vitamin K (often 5 mg per day) to ensure that enough fresh vitamin K resides in the tissues to carry out its normal functions, even when efficient use of it by the body is prevented by the poison.{{mcn|date=March 2014}} |
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==Vitamin K and brain sulfatides== |
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A recent study has shown that rats who are fed excess amounts of vitamin K had greater amounts of brain [[sulfatide]] concentrations.<ref>{{cite pmid|8914944}}</ref> This study indicates that vitamin K has more uses than originally thought, thus furthering the importance of daily vitamin K intake. The same study showed that a diet with insufficient vitamin K levels decreased the brain sulfatide concentrations in rats at the (p < . 01) significance level. Another study involving rats has indicated that different species, strains and genders of rats required different amounts of vitamin K intake, depending on how much was stored in their livers.<ref>{{cite pmid|7310534}}</ref> This may indicate that different humans should have different needs for their vitamin K intake. A third study looked at the way rats and chicks are able to recycle parts of vitamin K. The study found that chicks are about 10% less efficient in recycling the vitamin K than their rat counterparts.<ref>{{cite pmid|1453219}}</ref> This evidences also helps to confirm that vitamin K levels are unique to each species, and the previous study shows that required vitamin K intake also varies within species. |
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==History of discovery== |
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In 1929, [[Denmark|Danish]] scientist [[Carl Peter Henrik Dam|Henrik Dam]] investigated the role of [[cholesterol]] by feeding chickens a cholesterol-depleted diet.<ref name="Dam"/> 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.<ref name="MacCorquodale">{{cite journal|last=MacCorquodale|first=D. W.|coauthors=Binkley, S. B.; Thayer, S. A.; Doisy, E. A.|year=1939|title=On the constitution of Vitamin K<sub>1</sub>|journal=Journal of the American Chemical Society|volume=61|issue=7|pages=1928–1929|doi=10.1021/ja01876a510 }} |
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</ref> Dam and Doisy shared the 1943 [[Nobel Prize]] for medicine for their work on vitamin K (K<sub>1</sub> and K<sub>2</sub>) published in 1939. Several laboratories synthesized the compound(s) in 1939.<ref name="Fieser">{{cite journal|last=Fieser|first=L. F.|year=1939|title=Synthesis of Vitamin K<sub>1</sub>|journal=Journal of the American Chemical Society|volume=61|issue=12|pages=3467–3475|doi=10.1021/ja01267a072 }}</ref> |
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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]]).<ref name="dam-nobel">Dam, Henrik (12 December 1946). [http://nobelprize.org/nobel_prizes/medicine/laureates/1943/dam-lecture.pdf The discovery of vitamin K, its biological functions and therapeutical application.] Nobel Prize lecture</ref> |
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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.<ref name="Warner">{{cite journal|last=Warner|first=E. D.|coauthors=Brinkhous, K. M.; Smith, H. P.|year=1938|journal=Proceedings of the Society of Experimental Biology and Medicine|volume=37|page=628|doi=10.3181/00379727-37-9668P|title=Bleeding Tendency of Obstructive Jaundice}}</ref> |
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The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo ''et al.'',<ref name=Stenflo>{{cite journal|author=Stenflo J, Fernlund P, Egan W, Roepstorff P|title=Vitamin K Dependent Modifications of Glutamic Acid Residues in Prothrombin|journal=Proc. Natl. Acad. Sci. U.S.A.|volume=71|issue=7|pages=2730–3|year=1974|pmid=4528109|pmc=388542|doi= 10.1073/pnas.71.7.2730 }}</ref> Nelsestuen ''et al.'',<ref name=Nelsestuen>{{cite journal|author=Nelsestuen GL, Zytkovicz TH, Howard JB|title=The mode of action of vitamin K. Identification of gamma-carboxyglutamic acid as a component of prothrombin|journal=J. Biol. Chem.|volume=249|issue=19|pages=6347–50|year=1974|pmid=4214105|url=http://www.jbc.org/content/249/19/6347.full.pdf }}</ref> and Magnusson ''et al.''<ref name=Magnusson>{{cite journal|author=Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A|title=Primary structure of the vitamin K-dependent part of prothrombin|journal=FEBS Lett.|volume=44|issue=2|pages=189–93|year=1974|pmid=4472513|doi=10.1016/0014-5793(74)80723-4 }}</ref>) isolated the vitamin K-dependent coagulation factor [[prothrombin|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. |
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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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==References== |
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{{reflist|colwidth=30em}} |
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==Bibliography== |
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*{{cite book|ref=Rheaume-Bleue|author=Rhéaume-Bleue, Kate|title=Vitamin K<sub>2</sub> and the Calcium Paradox|publisher= John Wiley & Sons, Canada|year=2012|isbn=1118065727}} |
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==External links== |
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*{{pauling|id=vitamins/vitaminK|title=Vitamin K|author=Jane Higdon}} |
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*[http://ars.usda.gov/is/AR/archive/jan00/green0100.htm Vitamin K: Another Reason to Eat Your Greens] |
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*[http://ctds.info/vitamink.html Vitamin K: Signs of Deficiency] |
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*[http://www.merck.com/mmpe/sec01/ch004/ch004m.html Vitamin K: Vitamin Deficiency, Dependency, and Toxicity]: Merck Manual Professional |
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*[http://aims.org.uk/Journal/Vol13No2/vitk.htm An Alternative Perspective on Vitamin K Prophylaxis] |
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*[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321262/pdf/FNR-56-5329.pdf Vitamin K: the effect on health beyond coagulation – an overview], Cees Vermeer, " |
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{{vitamin}} |
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{{Enzyme cofactors}} |
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{{Antihemorrhagics}} |
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[[Category:Antihemorrhagics]] |
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[[Category:Naphthoquinones]] |
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[[Category:Terpenes and terpenoids]] |
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[[Category:Vitamers]] |
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[[Category:Vitamin K| ]] |
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Revision as of 14:15, 13 April 2014
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