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[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

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.

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 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

[Vitamin K2] Ishida Y. Clin Calcium. 2008 Oct;18(10):1476-82. Review. Japanese. PMID: 18830045 "Vitamin K2 has been approved for the treatment of osteoporosis in Japan since 1995. Vitamin K2 treatment in osteoporosis has been shown to inhibit the occurrence of new bone fractures and to maintain BMD. The uniqueness of the prevention of bone fractures by vitamin K2 is that there has been no direct evidence of the relationship between increase of BMD and a decrease in the occurrence of bone fractures. A recent systematic review of seven Japanese randomized controlled trials by Cockayne has also shown that supplementation with phytonadione (Vitamin K1) and menaquinone (Vitamin K2) , particularly menaquinone-4, is associated with increased BMD and reduced fracture incidence. To confirm these results, a larger well design RCT using fractures as the primary endpoint is clearly needed."

High dietary menaquinone intake is associated with reduced coronary calcification.\nBeulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT.\nAtherosclerosis. 2008 Jul 19. [Epub ahead of print]\nPMID: 18722618 \ndoi:10.1016/j.atherosclerosis.2008.07.010 \n

Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.\nSchurgers LJ, Teunissen KJ, Hamulyák K, Knapen MH, Vik H, Vermeer C.\nBlood. 2007 Apr 15;109(8):3279-83. Epub 2006 Dec 7.\nPMID: 17158229 \nDOI 10.1182/blood-2006-08-040709\n

Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study.\nGeleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC.\nJ Nutr. 2004 Nov;134(11):3100-5.\nPMID: 15514282

Vitamin K has been known as the coagulation vitamin, because of its role in the blood-clotting process. However, research over the last few decades has shown that the role of K Vitamins - and natural Vitamin K2, the menaquinones, in particular - has been greatly expanded. Of note, K Vitamins activity outside the liver is required for calcium utilization, the key factor in maintaining both bone and cardiovascular health.\n\nVitamin K2 helps to activate vitamin K-dependent proteins responsible for healthy tissues. In bone, it activates osteocalcin, a protein required to bind calcium to the mineral matrix, thus strengthening the skeleton. In circulation, Vitamin K2 participates in carboxylation of Matrix Gla Protein (MGP), the most potent inhibitor of arterial calcification known, lowering the risk of vascular damage.

A high menaquinone reduces the incidence of coronary heart disease in women.\nGast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM, Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT.\nNutr Metab Cardiovasc Dis. 2009 Jan 27. [Epub ahead of print]\nPMID: 19179058 \ndoi: 10.1016/j.numecd.2008.10.004\n

Determination of Phylloquinone and Menaquinones in Foods by HPLC\n\nTerhi Koivu-Tikkanen\n\nAcademic Dissertation, January 2001. \nUniversity of Helsinki, Faculty of Agriculture and Forestry, \nDepartment of Applied Chemistry and Microbiology

Menaquinone-4 concentration is correlated with sphingolipid concentrations in rat brain. Carrié I, Portoukalian J, Vicaretti R, Rochford J, Potvin S, Ferland G. J Nutr. 2004 Jan;134(1):167-72. PMID: 14704312

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 the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ. Arch Intern Med. 2006 Jun 26;166(12):1256-61. Review. PMID: 16801507 Conclusions This systematic review suggests that supplementation with phytonadione and menaquinone-4 reduces bone loss. In the case of the latter, there is a strong effect on incident fractures among Japanese patients.

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. "

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).\nNimptsch K, Rohrmann S, Linseisen J.\nAm J Clin Nutr. 2008 Apr;87(4):985-92.\nPMID: 18400723

Increased intakes of vitamin K2, but not vitamin K1, may decrease the risk of coronary heart disease in postmenopausal women, says a new study.\nFor every 10 microgram increase in the amount of vitamin K2 consumed, researchers from the Netherlands report a 9 per cent reduction in the risk of developing coronary heart disease (CHD).

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.