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United States guitar player and singer of the blues (born in 1925) (同)B. B. King, Riley B King
United States woman tennis player (born in 1943) (同)Billie Jean King, Billie Jean Moffitt King
United States charismatic civil rights leader and Baptist minister who campaigned against the segregation of Blacks (1929-1968) (同)Martin Luther King, Martin Luther King Jr.
street names for ketamine (同)jet, super acid, special K, honey oil, green, cat valium, super C
the 11th letter of the Roman alphabet (同)k
any of a group of organic substances essential in small quantities to normal metabolism
a mountain peak in the Karakoram Range in northern Kashmir; the 2nd highest peak in the world (28,250 feet high) (同)Godwin Austen, Mount Godwin Austen, Dapsang

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Kelvin / Kindergarten / (チェスの)King / kalium(ラテン語)(=potassium)の化学記号
『ビタミン』,栄養素(身体の喜常な機能を維持するために少量ながら必要な有機化合物)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/26 15:30:50」(JST)

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Vitamin K₂ (the menaquinones) is a group name for a family of related compounds, generally subdivided into short-chain menaquinones (with MK-4 as the most important member) and the long-chain menaquinones, of which MK-7, MK-8 and MK-9 are nutritionally the most recognized.

Description

Vitamin K₂, the main storage form in animals, has several subtypes, which differ in isoprenoid chain length. These vitamin K₂ homologues are called menaquinones, and are characterized by the number of 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 K₂ in animal products since MK-4 is normally synthesized from vitamin K₁ 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 K₂ may have enzyme functions distinct from those of vitamin K₁.

Menaquinone-7 is different from MK-4 in that it is not produced by human tissue. MK-7 may be converted from phylloquinone (K₁) in the colon by E. coli bacteria.^[1] However, bacterially derived menaquinones (MK-7) appear to contribute minimally to overall vitamin K status.^[2]^[3] MK-4 and MK-7 are both found in the United States in dietary supplements for bone health.

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%.^[4] MK-4 (45 mg daily) has been approved by the Ministry of Health in Japan since 1995 for the prevention and treatment of osteoporosis.^[5]

All K vitamins are similar in structure: they share a “quinone” ring, but differ in the length and degree of saturation of the carbon tail and the number of “side chains”.^[6] The number of side chains is indicated in the name of the particular menaquinone (e.g., MK-4 means that four molecular units - called isoprene units - are attached to the carbon tail) and this influences the transport to different target tissues.

Vitamin K structures. MK-4 and MK-7 are both subtypes of K₂.

Mechanism of action

The mechanism of action of vitamin K₂ is similar to vitamin K₁. Traditionally, K vitamins were recognized as the factor required for coagulation, but the functions performed by this vitamin group were revealed to be much more complex. K vitamins play an essential role as cofactor for the enzyme γ-glutamyl carboxylase, which is involved in vitamin K-dependent carboxylation of the gla domain in "Gla proteins" (i.e., in conversion of peptide-bound glutamic acid (Glu) to γ-carboxy glutamic acid (Gla) in these proteins).

Carboxylation reaction - 'Vitamin K cycle'

Carboxylation of these vitamin K-dependent Gla-proteins, besides being essential for the function of the protein, is also an important vitamin recovery mechanism since it serves as a recycling pathway to recover vitamin K from its epoxide metabolite (KO) for reuse in carboxylation.

Several human Gla-containing proteins synthesized in several different types of tissues have been discovered:

Coagulation factors (II, VII, IX, X), as well as anticoagulation proteins (C, S, Z). These Gla-proteins are synthesized in the liver and play an important role in blood homeo-stasis.
Osteocalcin. This non-collagenous protein is secreted by osteoblasts and plays an essential role in the formation of mineral in bone.
Matrix gla protein (MGP). This calcification inhibitory protein is found in numerous body tissues, but its role is most pronounced in cartilage and in arterial vessel walls.
Growth arrest-specific protein 6 (GAS6). GAS6 is secreted by leucocytes and endothelial cells in response to injury and helps in cell survival, proliferation, migration, and adhesion.
Proline-rich Gla-proteins (PRGP), transmembrane Gla-proteins (TMG), Gla-rich protein (GRP) and periostin; whose precise functions are still unexplored.

Health effects

Absorption profile of different K vitamins

Vitamin K is absorbed along with dietary fat from the small intestine and transported by chylomicrons in the circulation. Most of vitamin K₁ is carried by triacylglycerol-rich lipoproteins (TRL) and rapidly cleared by the liver; only a small amount is released into the circulation and carried by LDL and HDL. MK-4 is carried by the same lipoproteins (TRL, LDL, and HDL) and cleared fast as well. The long-chain menaquinones are absorbed in the same way as vitamin K₁ and MK-4, but are efficiently redistributed by the liver in predominantly LDL (VLDL). Since LDL has a long half life in the circulation, these menaquinones can circulate for extended times resulting in higher bioavailability for extra-hepatic tissues as compared to vitamin K₁ and MK-4. Accumulation of vitamin K in extra-hepatic tissues has direct relevance to vitamin K functions not related to hemostasis.^[7]

Dietary sources and adequate intake

In 2012, Canadian health writer Kate Rhéaume-Bleue suggested the Recommended Daily Allowance (RDA) for K vitamins (range of 80-120 µg) might be too low.^[8] Earlier suggestions in the scientific literature, which note that the RDA is based on hepatic (i.e. related to the liver) requirements only, date back as far as 1998.^[9]^[10] This hypothesis is supported by the fact that the majority of the Western population exhibits a substantial fraction of undercarboxylated extra-hepatic proteins. Thus, complete activation of coagulation factors is satisfied, but there doesn’t seem to be enough vitamin K₂ for the carboxylation of osteocalcin in bone and MGP in the vascular system.^[11]^[12] Highest concentrations of vitamin K₁ are found in green leafy vegetables, but significant concentrations are also present in non-leafy green vegetables, several vegetable oils, fruits, grains and dairy. In Europe and the USA 60%, or more, of total vitamin K₁ intake is provided by vegetables, the majority by green leafy vegetables. National surveys reveal that K₁ intakes vary widely. Intakes determined by weighed-dietary Intakes are similar in mainland Britain to the USA with average daily intakes of around 70–80 μg, which is less than the adequate intake for vitamin K. Apart from animal livers, the richest dietary source of long-chain menaquinones are fermented foods (from bacteria not moulds or yeasts) typically represented by cheeses (MK-8, MK-9) in Western diets and natto (MK-7) in Japan. Food frequency questionnaire-derived estimates of relative intakes in the Netherlands suggest that ~90% of total vitamin K intakes are provided by K₁, ~7.5 % by MK-5 through to MK-9 and ~ 2.5% by MK-4. Most food assays measure only fully unsaturated menaquinones; accordingly cheeses have been found to contain MK-8 at 10–20 μg/100g and MK-9 at 35–55 μg/100 g.^[13]

Dietary intake sources

Vitamin K₂ is preferred by the extra-hepatic tissues (bone, cartilage, vasculature) and this may be produced as MK-4 by the animal from K₁, or may be of bacterial origin (MK-7, MK-9, and other MK numbers). The latter may be consumed already prepared by bacteria (see below). Discussion is ongoing as to what extent K₂ produced by intestinal bacteria contributes to daily vitamin K₂ needs. If, however, intestinal bacterial supply was enough to supplement all tissues needing K₂, we would not find high fractions of undercarboxylated Gla-proteins in human studies.^{[citation needed]}

Natural K2 is also found in bacterial fermented foods, like mature cheeses and curd. The MK-4 form of K2 is often found in relatively small quantities in meat and eggs. The richest source of natural K2 is the traditional Japanese dish natto^[14] made of fermented soybeans and Bacillus subtilis, which provides an unusually rich source of K₂ as long-chain MK-7: its consumption in Northern Japan has been linked to significant improvement in K vitamin's status and bone health in many studies. The intense smell and strong taste, however, make this soyfood a less attractive source of K₂ for Westerners' tastes. Supplement food companies sell nattō extract, standardized for K₂ content, in capsules. It is not known whether B. subtilis will produce K2 with other legumes (chickpeas, beans, lentils).

Food sources of vitamin K₂ 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.^[15]

Food 100 grams (3.5 oz) portion	Microgram (μg)	Proportion of vitamin K₂	Food 100 grams (3.5 oz) portion	Microgram (μg)	Proportion of vitamin K₂
Natto, cooked	1,103.4	(90% MK-7, 10% other MK)	Chicken Leg	8.5	(100% MK-4)
Goose liver pâté	369.0	(100% MK-4)	Ground beef (medium fat)	8.1	(100% MK-4)
Hard cheeses (Dutch Gouda style), raw	76.3	(6% MK-4, 94% other MK)	Chicken liver (braised)	6.7	(100% MK-4)
Soft cheeses (French Brie style)	56.5	(6.5% MK-4, 93.5% other MK)	Hot dog	5.7	(100% MK-4)
Egg yolk, (Netherlands)	32.1	(98% MK-4, 2% other MK)	Bacon	5.6	(100% MK-4)
Goose leg	31.0	(100% MK-4)	Calf’s liver (pan-fried)	6.0	(100% MK-4)
Egg yolk (U.S.)	15.5	(100% MK-4)	Sauerkraut	4.8	(100% MK-4)
Butter	15.0	(100% MK-4)	Whole milk	1.0	(100% MK-4)
Chicken liver (raw)	14.1	(100% MK-4)	Salmon (Alaska, Coho, Sockeye, Chum, and King wild (raw))	0.5	(100% MK-4)
Chicken liver (pan-fried)	12.6	(100% MK-4)	Cow’s liver (pan-fried)	0.4	(100% MK-4)
Cheddar cheese (U.S.)	10.2	(6% MK-4, 94% other MK)	Egg white	0.4	(100% MK-4)
Meat franks	9.8	(100% MK-4)	Skim milk	0.0
Chicken breast	8.9	(100% MK-4)
Table from Rhéaume-Bleue, pp. 66–67.

Vitamin K₂ (menaquinone-4) is synthesized by animal tissues and is found in meat, eggs, and dairy products.^[16] Menaquinone-7 is synthesized by bacteria during fermentation and is found in fermented soybeans (natto), and in most fermented cheeses.^[17] In natto, none of the vitamin K is from menaquinone-4, and in cheese only 2–7% is.^[18]

Anticoagulants and K₂ supplementation

Recent studies found a clear association between long-term anticoagulant treatment (OAC) and reduced bone quality due to reduction of active osteocalcin. OAC might lead to an increased incidence of fractures, reduced bone mineral density/bone mineral content, osteopenia, and increased serum levels of undercarboxylated osteocalcin.^[19] Bone mineral density was significantly lower in stroke patients with long-term warfarin treatment compared to untreated patients and osteopenia was probably an effect of warfarin-interference with vitamin K recycling.^[20] Furthermore, OAC is often linked to an undesired soft-tissue calcification in both children and adults.^[21]^[22] This process has been shown to be dependent upon the action of K vitamins. Vitamin K deficiency results in undercarboxylation of MGP. Vascular calcification was shown to appear in warfarin-treated experimental animals within two weeks.^[23] Also in humans on OAC treatment, two-fold more arterial calcification was found as compared to patients not receiving vitamin K antagonists.^[24]^[25] Among consequences of anticoagulant treatment: increased aortic wall stiffness, coronary insufficiency, ischemia, and even heart failure. Arterial calcification might also contribute to systolic hypertension and ventricular hypertrophy.^[26]^[27] Coumarins, by interfering with vitamin K metabolism, might also lead to an excessive calcification of cartilage and tracheobronchial arteries.

Anticoagulant therapy is usually instituted to avoid life-threatening diseases and a high vitamin K intake interferes with the anticoagulant effect. Patients on warfarin (Coumadin) treatment, or treatment with other vitamin K antagonist drugs, are therefore advised not to consume diets rich in K vitamins. However, the latest research proposed to combine vitamins K with OAC to stabilize the INR (International normalized ratio, a laboratory test measure of blood coagulation).

Toxicity

There is no known toxicity associated with high doses of menaquinones (vitamin K₂). A point of concern is however the potential interference of K vitamins with OAC treatment: individuals taking anticoagulant medications, such as warfarin (coumarins), should consult their doctor before taking Vitamin K₂. Unlike the other fat-soluble vitamins, vitamin K is not stored in any significant quantity in the liver; therefore toxic level is not a described problem. All data available at this time demonstrate that vitamin K has no adverse effects in healthy subjects. The recommendations for the daily intake of vitamin K, as issued recently by the Institute of Medicine, also acknowledge the wide safety margin of vitamin K: “A search of the literature revealed no evidence of toxicity associated with the intake of either K₁ or K₂”. Animal models involving rats, if generalizable to humans, show that MK-7 is well-tolerated.^[28]

References

^ Vermeer, C; Braam L (2001). "Role of K vitamins in the regulation of tissue calcification". Journal of bone and mineral metabolism 19 (4): 201–206. doi:10.1007/s007740170021. PMID 11448011.
^ Suttie, JW (1995). "The importance of menaquinones in human nutrition". Annual Review of Nutrition 15: 399–417. doi:10.1146/annurev.nu.15.070195.002151. PMID 8527227.
^ Weber, P (2001). "Vitamin K and bone health". Nutrition 17 (10): 880–887. doi:10.1016/S0899-9007(01)00709-2. PMID 11684396.
^ Sato, Y; Kanoko T; Satoh K; Iwamoto J (2005). "Menatetrenone and vitamin D2 with calcium supplements prevent nonvertebral fracture in elderly women with Alzheimer's disease". Bone 36 (1): 61–8. doi:10.1016/j.bone.2004.09.018. PMID 15664003.
^ Iwamoto, I; Kosha S; Noguchi S-i (1999). "A longitudinal study of the effect of vitamin K₂ on bone mineral density in postmenopausal women a comparative study with vitamin D₃ and estrogen-progestin therapy". Maturitas 31 (2): 161–164. doi:10.1016/S0378-5122(98)00114-5. PMID 10227010.
^ Shearer MJ.2003 in Physiology. Elsevier Sciences LTD. 6039-45.
^ Martin J. Shearer, Paul Newman. Metabolism and cell biology of vitamin K. Thromb Haemost 2008
^ Kate Rhéaume-Bleue, Vitamin K₂ and the Calcium Paradox. Mississaugua: Wiley, 2012, p. 74.
^ Booth SL, Suttie JW. Dietary intake and adequacy of K vitamins. J Nutr. 1998;128(5):785-8.
^ Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. 2002;1570(1):27-32.
^ Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M, Dobnig H. Vascular calcification and osteoporosis--from clinical observation towards molecular understanding. Osteoporos Int. 2007;18(3):251-9.
^ Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD. Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J Bone Miner Res. 1991;6(11):1211-6.
^ Shearer N, Metabolism and cell biology of vitamin K. Thromb Haemost. 2008
^ Kaneki M, Hodges SJ, Hosoi T, Fujiwara S, Lyons A, Crean SJ, Ishida N, Nakagawa M, Takechi M, Sano Y, Mizuno Y, Hoshino S, Miyao M, Inoue S, Horiki K, Shiraki M, Ouchi Y, Orimo H; Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of K vitamins2: possible implications for hip-fracture risk; Nutrition; 2001; 17(4): 315-321.
^ food sources for vitamin K₂. Livestrong.com. Retrieved on 21 April 2013.
^ Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL (2006). "Vitamin k contents of meat, dairy, and fast food in the U.S. Diet". J. Agric. Food Chem. 54 (2): 463–7. doi:10.1021/jf052400h. PMID 16417305.
^ Tsukamoto Y, Ichise H, Kakuda H, Yamaguchi M (2000). "Intake of fermented soybean (natto) increases circulating vitamin K₂ (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals". J. Bone Miner. Metab. 18 (4): 216–22. doi:10.1007/s007740070023. PMID 10874601.
^ "On the Trail of the Elusive X-Factor: Vitamin K₂ Revealed". ^{[verification needed]}
^ Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ 3rd. Changes in bone density after exposure to oral anticoagulants: a meta-analysis.Osteoporos Int. 1999;9(5):441-8.
^ Sato Y, Honda Y, Kunoh H, Oizumi K. Long-term oral anticoagulation reduces bone mass in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Stroke. 1997;28(12):2390-4.
^ Barnes C, Newall F, Ignjatovic V, Wong P, Cameron F, Jones G, Monagle P. Reduced bone density in children on long-term warfarin. Pediatr Res. 2005;57(4):578-81.
^ Hawkins D, Evans J. Minimising the risk of heparin-induced osteoporosis during pregnancy. Expert Opin Drug Saf. 2005;4(3):583-90
^ Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998;18(9):1400-7.
^ Schurgers LJ, Aebert H, Vermeer C, Bültmann B, Janzen J. Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood. 2004 15;104(10):3231-2.
^ Koos R, Mahnken AH, Mühlenbruch G, Brandenburg V, Pflueger B, Wildberger JE, Kühl HP. Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol. 2005;96(6):747-9.
^ Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932-43.
^ Raggi P, Shaw LJ, Berman DS, Callister TQ. Prognostic value of coronary artery calcium screening in subjects with and without diabetes. J Am Coll Cardiol. 2004;43(9):1663-9.
^ Pucaj et al. (Sep 2011) "Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7", Toxicology Mechanisms and Methods Vol.21 No.7 pp.520–532

UpToDate Contents

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1. ビタミンKの概要 overview of vitamin k
2. 閉経後の女性における骨粗鬆症のマネージメントの概要 overview of the management of osteoporosis in postmenopausal women
3. ワルファリン関連出血または高用量INRのマネージメント management of warfarin associated bleeding or supratherapeutic inr
4. 食事中の脂肪 dietary fat
5. INRコントロールに対するワルファリンとモジュレーターの生物学 biology of warfarin and modulators of inr control

English Journal

Vitamin K2 in different bovine muscles and breeds.

Rødbotten R1, Gundersen T2, Vermeer C3, Kirkhus B4.Author information 1Nofima AS, Norwegian Institute of Food, Fisheries and Aquaculture Research, P.O. Box 210, N-1431 Ås, Norway. Electronic address: rune.rodbotten@nofima.no.2AS Vitas, Gaustadalleen 21, N-0349 Oslo, Norway.3VitaK BV, Oxfordlaan 70, 6229 EV Maastricht, The Netherlands.4Nofima AS, Norwegian Institute of Food, Fisheries and Aquaculture Research, P.O. Box 210, N-1431 Ås, Norway.AbstractMeat is a natural source of vitamin K, a vitamin associated with reduced bone loss and prevention of osteoporosis. Whether vitamin K content varies between breeds and muscles in cattle is not known. In the present study, contents of vitamin K1 (phylloquinone) and K2 (menaquinone, MK) were analysed in three different muscles from steers of two different breeds, Norwegian Red and Jersey, respectively. Results showed that MK4 was the most dominant of the vitamin K2 analogues, while only traces were found of MK6 and MK7. Both breeds had higher levels of MK4 in M. biceps femoris (BF) and M. longissimus dorsi (LD) compared to M. psoas major (PM). The results also showed significantly higher MK4 levels in muscles from Jersey compared to Norwegian Red. Furthermore, MK4 was not associated with intramuscular fat, suggesting a physiological role for MK4 in skeletal muscle cells. There were no association between vitamin K content and tenderness.
Meat science.Meat Sci.2014 May;97(1):49-53. doi: 10.1016/j.meatsci.2014.01.005. Epub 2014 Jan 22.
Meat is a natural source of vitamin K, a vitamin associated with reduced bone loss and prevention of osteoporosis. Whether vitamin K content varies between breeds and muscles in cattle is not known. In the present study, contents of vitamin K1 (phylloquinone) and K2 (menaquinone, MK) were analysed i
PMID 24508562

Effects of vitamin K in postmenopausal women: Mini review.

Guralp O1, Erel CT2.Author information 1Obstetrics and Gynecology, Bozova State Hospital, Sanliurfa, Turkey. Electronic address: dronur@hotmail.com.2Istanbul University, Cerrahpasa School of Medicine, Obstetrics and Gynecology, Division of Reproductive Endocrinology, Istanbul, Turkey.AbstractPossible benefits of vitamin K on bone health, fracture risk, markers of bone formation and resorption, cardiovascular health, and cancer risk in postmenopausal women have been investigated for over three decades; yet there is no clear evidence-based universal recommendation for its use. Interventional studies showed that vitamin K1 provided significant improvement in undercarboxylated osteocalcin (ucOC) levels in postmenopausal women with normal bone mineral density (BMD); however, there are inconsistent results in women with low BMD. There is no study showing any improvement in bone-alkaline-phosphatase (BAP), n-telopeptide of type-1 collagen (NTX), 25-hydroxy-vitamin D, and urinary markers. Improvement in BMD could not be shown in the majority of the studies; there is no interventional study evaluating the fracture risk. Studies evaluating the isolated effects of menatetrenone (MK-4) showed significant improvement in osteocalcin (OC); however, there are inconsistent results on BAP, NTX, and urinary markers. BMD was found to be significantly increased in the majority of studies. The fracture risk was assessed in three studies, which showed decreased fracture risk to some extent. Although there are proven beneficial effects on some of the bone formation markers, there is not enough evidence-based data to support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal women receiving vitamin D and calcium supplementation. Interventional studies investigating the isolated role of vitamin K on cardiovascular health are required. Longterm clinical trials are required to evaluate the effect of vitamin K on gynecological cancers. MK-4 seems safe even at doses as high as 45mg/day.
Maturitas.Maturitas.2014 Mar;77(3):294-299. doi: 10.1016/j.maturitas.2013.11.002. Epub 2013 Nov 27.
Possible benefits of vitamin K on bone health, fracture risk, markers of bone formation and resorption, cardiovascular health, and cancer risk in postmenopausal women have been investigated for over three decades; yet there is no clear evidence-based universal recommendation for its use. Interventio
PMID 24342502

Identification of a probiotic bacteria-derived activator of the aryl hydrocarbon receptor that inhibits colitis.

Fukumoto S1, Toshimitsu T2, Matsuoka S3, Maruyama A1, Oh-Oka K1, Takamura T1, Nakamura Y1, Ishimaru K1, Fujii-Kuriyama Y4, Ikegami S2, Itou H2, Nakao A5.Author information 1Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.2Food Science Research Labs, Division of Research and Development, Meiji Co. Ltd, Kanagawa, Japan.3Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.4Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.51] Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan [2] Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.AbstractThe aryl hydrocarbon receptor (AhR) recognizes environmental xenobiotics and is originally thought to be involved in the metabolism (detoxification) of the substances. Recently, AhR is highlighted as an important regulator of inflammation. Notably, accumulating evidence suggests that activation of the AhR suppresses inflammatory bowel diseases (IBDs). Therefore, non-toxic AhR activators become attractive drug candidates for IBD. This study identified 1,4-dihydroxy-2-naphthoic acid (DHNA), a precursor of menaquinone (vitamin K2) abundantly produced by Propionibacterium freudenreichii ET-3 isolated from Swiss-type cheese, as an AhR activator. DHNA activated the AhR pathway in human intestinal epithelial cell line Caco2 cells and in the mouse intestine. Oral treatment of mice with DHNA induced anti-microbial proteins RegIIIβ and γ in the intestine, altered intestinal microbial flora and inhibited dextran sodium sulfate (DSS)-induced colitis, which recapitulated the phenotypes of AhR activation in the gut. As DHNA is commercially available in Japan as a prebiotic supplement without severe adverse effects, DHNA or its derivatives might become a promising drug candidate for IBD via AhR activation. The results also implicate that intestinal AhR might act not only as a sensor for xenobiotics in diet and water but also for commensal bacterial activity because DHNA is a precursor of vitamin K2 produced by vitamin K2-synthesizing commensal bacteria as well as propionic bacteria. Hence, DHNA might be a key bacterial metabolite in the host-microbe interaction to maintain intestinal microbial ecosystem.Immunology and Cell Biology advance online publication, 11 February 2014; doi:10.1038/icb.2014.2.
Immunology and cell biology.Immunol Cell Biol.2014 Feb 11. doi: 10.1038/icb.2014.2. [Epub ahead of print]
The aryl hydrocarbon receptor (AhR) recognizes environmental xenobiotics and is originally thought to be involved in the metabolism (detoxification) of the substances. Recently, AhR is highlighted as an important regulator of inflammation. Notably, accumulating evidence suggests that activation of t
PMID 24518984

Japanese Journal

大豆サポニンとビタミンK₂(メナキノン-7)の構造・吸収・機能 (研究小集会(第11回)大豆部会)

佐藤俊郎,加茂修一
日本食品科学工学会誌 = Journal of the Japanese Society for Food Science and Technology 60(9), 527-533, 2013-09
NAID 40019780737

ビタミンK₂(メナキノン-4)合成酵素の構造と機能解析 (第13回日本骨粗鬆症学会学術奨励賞受賞演題)

中川公恵,廣田佳久,澤田夏美 [他]
オステオポローシスジャパン : 日本骨粗鬆症学会雑誌 20(1), 25-30, 2012
NAID 40019205371

核内受容体SXR (Steroid and Xenobiotic Receptor) のアゴニスト活性を持つ新規ビタミンK誘導体の合成と構造活性相関の検討

須原義智,元吉沙也加,廣田佳久 [他],澤田夏美,中川公恵,常盤広明,岡野登志夫
YAKUGAKU ZASSHI 132(8), 881-886, 2012
… Vitamin K2 is a ligand for a nuclear receptor, steroid and xenobiotic receptor (SXR), that induces the gene expressions of CYP3A4. … We synthesized new vitamin K analogues with the same isoprene side chains symmetrically introduced at the 2 and 3 positions of 1,4-naphthoquinone and vitamin K2 analogues with hydroxyl or phenyl groups at the ω-terminal of the side chain. …
NAID 130001888705