Vitamin K2. Monograph.
[No authors listed]
Altern Med Rev. 2009 Sep;14(3):284-93. Review.
PMID: 19803553
In 1945, Dr. Weston Price described "a new vitamin-like activator" that played an influential role in the utilization of minerals, protection from tooth decay, growth and development, reproduction, protection against heart disease and the function of the brain.
Using a chemical test, he determined that this compound—which he called Activator X—occurred in the butterfat, organs and fat of animals consuming rapidly growing green grass, and also in certain sea foods such as fish eggs.
Vitamin K2 is produced by animal tissues, including the mammary glands, from vitamin K1, which occurs in rapidly growing green plants.
A growing body of published research confirms Dr. Price's discoveries, namely that vitamin K2 is important for the utilization of minerals, protects against tooth decay, supports growth and development, is involved in normal reproduction, protects against calcification of the arteries leading to heart disease, and is a major component of the brain
Miksi verisuonet kalkkeutuvat ja luusto haurastuu kalkin puutteessa?
Miksi vihreitä kasviksia pitäisi syödä useita kertoja päivässä.
Kasvit muodostavat lyhytketjuista fyllokinonia eli K1-vitamiinia. Bakteerit muodostavat pitempiketjuisia menakinoneja (MK) eli K2-vitamiineja. Bakteerien tuottamat menakinonit erotetaan toisistaan sivuketjujen pituuden mukaan toisistaan lyhenteellä MK-n jossa n voi olla 5-13. Bakteerit syntetisoivat pitkäketjuisia muotoja käymisprosesseissa joko suolistossa tai käyttämällä valmistetuissa ruoka-aineissa kuten esimerkiksi eräissä hapanmaitotuotteissa ja juustoissa sekä eräissä hapatetuissa tuotteissa, varsinkin Japanissa yleisissä hapatetuissa soijapavuissa (natto). Nisäkkäillä useiden elinten solut kykenevät muuntamaan K1-vitamiinista K2-vitamiinia (MK-4).
Menakinoni-4:ää (MK-4) syntetisoidaan eri puolilla elimistöä fyllokinonista, mutta sen merkitys tunnetaan vielä huonosti. Sitä tavataan runsaasti esimerkiksi aivoissa, mutta sen tehtäviä siellä ei tiedetä. Ravinnosta MK-4:ää saadaan varsinkin kananmunista ja lihasta, MK-8:aa ja MK-9:ää taas juustoista. Japanissa MK-7:ää saadaan erityisen runsaasti hapatetusta natto-soijasta. Eräälle tietyn bacillus subtilis -bakteerin syntetisoimalle erityisen paljon MK-7- vitamiinia tuottavalle nattokannalle onkin myönnetty terveysvaikutteisen elintarvikkeen asema Japanissa. Hyvin pitkäsivuketjuiset menakinonit MK-10 – MK-13) ovat Bacteroides-suvun anaerobisten bakteerien tuottamia. Niitä ei ole merkittävissä määrin ruoka-aineissa, mutta silti niitä on ihmisen ja eläinten maksassa. Tämä viittaa siihen, että niiden alkuperä on suolistossa.
K-vitamiinia on kahta eri muotoa 1) fyllokinoni, joka tunnetaan myös nimellä fytonadioni (K1-vitamiini), sitä on runsaasti vihreissä vihanneksissa, kuten pinaatissa, parsakaalissa, lehtisalaatissa. 2) menakinonit (K2-vitamiini) ovat K-vitamiinin muotoja, joita valmistuu muun muassa suolistossamme bakteerikäymisen tuloksena. Menakinoneita (MK-n) on myös jonkinverran ruuassamme: MK-4 on lihassa, MK-7, MK-8 ja MK-9 on runsaasti käymisprosessilla valmistetuissa ruuissa, kuten juustossa. Myös synteettistä K3-vitamiinia voidaan valmistaa, mutta sitä ei suositella ihmisen käyttöön.
Toisen kuuden viikon jakson jälkeen havaittiin, että varfariinia ja vähän K1-vitamiinia saanessa koe-eläinryhmässä valtimoiden kalkkeutuminen jatkui edelleen, samoin kävi koe-eläinryhmälle, joka sai vain normaaleja määriä K-vitamiinia. Sensijaan runsaasti K-vitamiinia saaneissa ryhmissä kalkin kertyminen estyi ja lopulta ylimääräistä kalkkia alkoi jopa poistua runsaasti valtimoista (vähintään 37 %)
Tutkijoiden loppupäätelmä oli, että ”ainakin eläinmalleissa K-vitamiini voi poistaa valtimoihin kertynyttä kalkkia”. Heidän mukaansa ”tutkimuksen sovellutusmahdollisuudet ihmisten hoidossa saattavat olla erittäin merkittävät”.
Research has uncovered the fact that vitamin K also plays a crucial role in maintaining bone health. It was found that the amount of vitamin K required to halt bone absorption leading to osteoporosis requires much greater intakes than that required for blood clot regulation. Further, it appears that bone and vascular tissue (like coronary arteries) maintain a preference for a different form of vitamin K than that required for blood clotting regulation. Rather than vitamin K1 needed for clotting, vitamin K2 is the form preferred by bones and arteries (Schurgers LJ et al 2001). It appears that much of the information generated over the years for vitamin K focused on the K1 form, ignoring the K2 form necessary for bone and vascular health.
Normal deposition of calcium occurs only in bone and in teeth. Abnormal deposition of calcium in the body occurs in three places: the inner lining of the arteries of the body (the intima) that causes atherosclerotic plaque; the muscle layer of arteries (“medial calcification”); and heart valves. K2 appears to be the form of vitamin K responsible for controlling these phenomena.
Deficiency of K2 in both mice and humans is associated with coronary calcification; low vitamin K2 levels are associated with increased activity of Gla matrix protein, an enzyme that causes calcium deposition in artery walls. People who take warfarin (Coumadin®), a potent blocker of vitamin K2, experience more arterial and heart valve calcification.
The 2004 Rotterdam Heart Study was the experience that really brought this concept closer to our interests. This well-conducted study of 4800 Dutch demonstrated an association of vitamin K2 intake with 57% reduction in cardiovascular events and lesser degrees of aortic calcification (another surrogate for atherosclerosis). Benefit appeared to be associated with a daily K2 intake of 32.7 micrograms per day (Geleijnse JM et al 2004). An important corollary of this study is that it suggests that a vitamin K2-mediated reduction in coronary calcification is accompanied by reduced likelihood of heart attack and other events.
Tissue phylloquinone and menaquinones in rats are affected by age and gender.
Huber AM, Davidson KW, O'Brien-Morse ME, Sadowski JA.
J Nutr. 1999 May;129(5):1039-44.
PMID: 10222397
The results suggest that in extrahepatic tissues, certain menaquinones may be the predominant form of vitamin K. The specific tissue distribution and the general decline of MK-4 and MK-6 in extrahepatic tissues during aging suggest a vitamin K tissue dynamic that is affected not only by diet, but also by gender, age and the specific roles of phylloquinone, MK-4 and MK-6 in metabolism. All of these factors must be taken into account in establishing the nutrient requirement for vitamin K.
Age and dietary form of vitamin K affect menaquinone-4 concentrations in male Fischer 344 rats.
Booth SL, Peterson JW, Smith D, Shea MK, Chamberland J, Crivello N.
J Nutr. 2008 Mar;138(3):492-6.
PMID: 18287355
These data suggest that dihydrophylloquinone, which differs from phylloquinone in its side phytyl chain, is absorbed but its intake results in less MK-4 in certain tissues. Dihydrophylloquinone may be used in models for the study of tissue-specific vitamin K deficiency
Conversion of phylloquinone (Vitamin K1) into menaquinone-4 (Vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice.\nOkano T, Shimomura Y, Yamane M, Suhara Y, Kamao M, Sugiura M, Nakagawa K.\nJ Biol Chem. 2008 Apr 25;283(17):11270-9. Epub 2007 Dec 14. \nPMID: 18083713 \ndoi: 10.1074/jbc.M702971200 \n\nOur results suggest that cerebral menaquinone-4 originates from phylloquinone intake and that there are two routes of accumulation, one is the release of menadione from phylloquinone in the intestine followed by the prenylation of menadione into menaquinone-4 in tissues, and another is cleavage and prenylation within the cerebrum.
Conversion of dietary phylloquinone to tissue menaquinone-4 in rats is not dependent on gut bacteria.
Davidson RT, Foley AL, Engelke JA, Suttie JW.
J Nutr. 1998 Feb;128(2):220-3.
PMID: 9446847
These data offer conclusive proof that the tissue-specific formation of MK-4 from K is a metabolic transformation that does not require bacterial transformation to menadione as an intermediate in the process
Role of vitamin K2 in the treatment of postmenopausal osteoporosis.
Iwamoto J, Takeda T, Sato Y.
Curr Drug Saf. 2006 Jan;1(1):87-97. Review.
PMID: 18690918
Effect of low dose vitamin K2 (MK-4) supplementation on bio-indices in postmenopausal Japanese women.
Koitaya N, Ezaki J, Nishimuta M, Yamauchi J, Hashizume E, Morishita K, Miyachi M, Sasaki S, Ishimi Y.
J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):15-21.
PMID: 19352059
It has been reported that treatment with a pharmacological dose (45 mg/d) of menaquinone-4 (MK-4) prevents bone loss in postmenopausal women. However, it is not known whether supplementation with low dose MK-4 has beneficial effects on bone metabolism in healthy women. The aim of this study is to examine the effects of the supplementation of 1.5 mg/d MK-4 for 4 wk on bone and lipid metabolism in healthy postmenopausal Japanese women. The study was performed as a randomized double blind placebo-controlled trial. The participants aged 53-65 y were randomly assigned to 2 groups and supplemented with 1.5 mg/d of MK-4 or a placebo for 4 wk (n=20 for each group). The most marked effects of MK-4 intake were observed on serum osteocalcin (OC) concentrations. Serum undercarboxylated OC (ucOC) concentration decreased, and the gamma-carboxylated OC (GlaOC) and GlaOC/GlaOC+ucOC ratio that indicates the degree of OC gamma-carboxylation increased significantly at 2 and 4 wk compared with that at baseline in the MK-4 group. The serum ucOC and GlaOC concentrations in the MK-4 group were significantly different from those in the placebo group at 2 wk. These results suggest that supplementation with 1.5 mg/d MK-4 accelerated the degree of OC gamma-carboxylation. The concentrations of serum lipids and other indices were not different between the groups at either intervention period. Thus, the additional intake of MK-4 might be beneficial in the maintenance of bone health in postmenopausal Japanese women.
Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma.
Yoshiji H, Noguchi R, Toyohara M, Ikenaka Y, Kitade M, Kaji K, Yamazaki M, Yamao J, Mitoro A, Sawai M, Yoshida M, Fujimoto M, Tsujimoto T, Kawaratani H, Uemura M, Fukui H.
J Hepatol. 2009 Aug;51(2):315-21. Epub 2009 May 15.
PMID: 19501932
CONCLUSIONS: The combination treatment of VK and ACE-I may suppress the cumulative recurrence of HCC after the curative therapy, at least partly through suppression of the VEGF-mediated neovascularization.
[Vitamin K and Bone Update. In vivo Metabolism of Vitamin K. - In relation to the conversion of vitamin K(1) to MK-4 -]
Okano T, Nakagawa K, Kamao M.
Clin Calcium. 2009 Dec;19(12):1779-87. Japanese.
PMID: 19949269
Phylloquinone is a major form (>90%) of dietary vitamin K, but the form of vitamin K that exists at the highest concentrations in tissues of animals and humans is menaquinone-4 (MK-4) . Despite this great difference, the origin of tissue MK-4 had not been clarified until recently. We demonstrated that deuterium-labeled phylloquinone was converted into deuterium-labeled MK-4 in mice and this conversion occurred following an oral or enteral administration, but not parenteral administration. By the oral route, the phylloquinone with the deuterium-labeled side chain (phytyl side-chain) was clearly converted into menaquinone-4 with a non-deuterium-labeled side chain (geranylgeranyl side-chain) , implying that phylloquinone was converted into menaquinone-4 via integral side-chain removal. Our results suggest that cerebral menaquinone-4 originates from phylloquinone intake and the release of menadione from phylloquinone in the intestine followed by the prenylation of menadione into menaquinone-4 in the intestine or tissues
Vitamin K content of foods and dietary vitamin K intake in Japanese young women.
Kamao M, Suhara Y, Tsugawa N, Uwano M, Yamaguchi N, Uenishi K, Ishida H, Sasaki S, Okano T.
J Nutr Sci Vitaminol (Tokyo). 2007 Dec;53(6):464-70.
PMID: 18202532
Several reports indicate an important role for vitamin K in bone health as well as blood coagulation. However, the current Adequate Intakes (AI) might not be sufficient for the maintenance of bone health. To obtain a closer estimate of dietary intake of phylloquinone (PK) and menaquinones (MKs), PK, MK-4 and MK-7 contents in food samples (58 food items) were determined by an improved high-performance liquid chromatography method. Next, we assessed dietary vitamin K intake in young women living in eastern Japan using vitamin K contents measured here and the Standard Tables of Food Composition in Japan. PK was widely distributed in green vegetables and algae, and high amounts were found in spinach and broccoli (raw, 498 and 307 microg/100 g wet weight, respectively). Although MK-4 was widely distributed in animal products, overall MK-4 content was lower than PK. MK-7 was observed characteristically in fermented soybean products such as natto (939 microg/100 g). The mean total vitamin K intake of all subjects (using data from this study and Japanese food composition tables) was about 230 microg/d and 94% of participants met the AI of vitamin K for women aged 18-29 y in Japan, 60 microg/d. The contributions of PK, MK-4 and MK-7 to total vitamin K intake were 67.7, 7.3 and 24.9%, respectively. PK from vegetables and algae and MK-7 from pulses (including fermented soybean foods) were the major contributors to the total vitamin K intake of young women living in eastern Japan
"As far as I can tell, MK-4 is capable of performing all the functions of vitamin K. MK-4 can even activate blood clotting factors, which is a role traditionally ascribed to vitamin K1. Babies are often born clotting deficient, which is why we give newborns vitamin K1 injections in the U.S. to prevent hemorrhaging. In Japan, they give children MK-4 to prevent hemorrhage, an intervention that is very effective. Could that have to do with the fact that Japan has half the infant mortality rate of the U.S.?
Today, I found another difference between MK-4 and MK-7. I was reading a paper about SXR-independent effects of vitamin K2 on gene expression. The investigators found that MK-4 strongly activates transcription of two specific genes in osteoblast cells. Osteoblasts are cells that create bone tissue. The genes are GDF15 and STC2 and they're involved in bone and cartilage formation. They tested K1 and MK-7, and in contrast to MK-4, they did not activate transcription of the genes in the slightest. This shows that MK-4 has effects on gene expression in bone tissue that MK-7 doesn't have.
That being said, MK-7 may still have a place in a healthy diet. Just because it can't do everything MK-4 can, doesn't mean it has no role. It may be able to fill in for MK-4 in some functions, or reduce the dietary need for MK-4. But no one really knows at this point. Hunter-gatherers would have had a source of longer menaquinones, including MK-7, from livers. So it's possible that we're adapted to a modest MK-7 intake on top of MK-4. "
Effect of vitamin K2 (menaquinone-7) in fermented soybean (natto) on bone loss in ovariectomized rats.
Yamaguchi M, Taguchi H, Gao YH, Igarashi A, Tsukamoto Y.
J Bone Miner Metab. 1999;17(1):23-9.
PMID: 10084398
This study demonstrates that the intake of dietary MK-7 has a preventive effect on bone loss caused by OVX. This effect may be partly caused by MK-4, which is formed by degradation of MK-7.
"[Vitamin K and Bone Update. The biological effects of vitamin K(2) on bone quality.]
Amizuka N, Li M, Guo Y, Liu Z, Suzuki R, Yamamoto T.
Clin Calcium. 2009 Dec;19(12):1788-96. Japanese.
PMID: 19949270
Post-transcriptional maturation with the presence of vitamin K(2) promotesgamma-carboxylation of osteocalcin, enabling further binding to hydroxyapatite, from which one could infer that vitamin K(2) increased the quality of bone matrix. For instance, vitamin K(2) rescued the impaired collagen mineralization caused by Mg insufficiency, by promoting a re-association of the process of collagen mineralization with mineralized nodules. Sodium warfarin, which antagonizes the function of vitamin K(2), reduced the binding of osteocalcin to bone matrices, and consequently resulted in crystalline particles being dispersed throughout the osteoid without forming mineralized nodules. Therefore,gamma-carboxylated Gla proteins mediated by vitamin K(2) appear to play a pivotal role in normal mineralization in bone."