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Medical research on konakion
J Pharm Pharmacol. 2008 Jul; 60(7): 889-93
Tirapelli CR, Resstel LB, de Oliveira AM, Corrêa FM
Phylloquinone (vitamin K(1), VK(1)) is widely used therapeutically and intravenous administration of this quinone can induce hypotension. We aimed to investigate the mechanisms underlying the effects induced by VK(1) on arterial blood pressure. With this purpose a catheter was inserted into the abdominal aorta of male Wistar rats for blood pressure and heart rate recording. Bolus intravenous injection of VK(1) (0.5-20 mgkg(-1)) produced a transient increase in blood pressure followed by a fall. Both the pressor and depressor response induced by VK(1) were dose-dependent. On the other hand, intravenous injection of VK(1) did not alter heart rate. The nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 10 and 20 mgkg(-1)) reduced both the increase and decrease in blood pressure induced by VK(1) (5 mgkg(-1)). On the other hand, indometacin (10 mg kg(-1)), a non-selective cyclooxygenase inhibitor, did not alter the increase in mean arterial pressure (MAP) induced by VK(1). However, VK(1)-induced fall in MAP was significantly attenuated by indometacin. We concluded that VK(1) induces a dose-dependent effect on blood pressure that consists of an acute increase followed by a more sustained decrease in MAP. The hypotension induced by VK(1) involves the activation of the nitric oxide (NO) pathway and the release of vasodilator prostanoid(s).
Uptake of postprandial lipoproteins into bone in vivo: Impact on osteoblast function.
Bone. 2008 Apr 10;
Niemeier A, Niedzielska D, Secer R, Schilling A, Merkel M, Enrich C, Rensen PC, Heeren J
Dietary lipids and lipophilic vitamins are transported by postprandial lipoproteins and are required for bone metabolism. Despite that, it remains unknown whether bone cells are involved in the uptake of circulating postprandial lipoproteins in vivo. The current study was performed to investigate a putative participation of bone in the systemic postprandial lipoprotein metabolism in mice, to identify potentially involved cell type populations and to analyze whether lipoprotein uptake affects bone function in vivo. As a model for the postprandial state, chylomicron remnants (CR) were injected intravenously into mice. Next to the liver and compared to other organs, bone appeared to be the second most important organ for the clearance of radiolabeled CR particles from the circulation in vivo. In addition, uptake of radiolabeled CR by primary murine osteoblasts and hepatocytes was quantified to be in a similar range in vitro. A complementary approach with fluorescently labeled CR and immunohistochemical staining for apoE proved that intact CR particles were taken up into bone and liver. Electron microscopy localization studies of bone sections revealed CR uptake into sinusoidal endothelial cells, macrophages and osteoblasts. The relative amount of radiolabeled CR uptake into femoral cortical bone, representing predominantly osteoblasts, and bone marrow, representing predominantly non-osteoblast cells, was within the same range. Most importantly, the injection of vitamin K(1)-enriched CR resulted in an increase of the degree of osteocalcin carboxylation in vivo while total osteocalcin concentrations remained unaffected, giving functional proof that osteoblasts process CR in vivo. In conclusion, here we demonstrate that bone is involved in the postprandial lipoprotein metabolism in mice. Osteoblasts participate in CR clearance from the circulation, which has a direct impact on the secretory function of osteoblasts.
Efficacy of high dose phylloquinone in correcting vitamin K deficiency in cystic fibrosis.
J Cyst Fibros. 2008 May 27;
Drury D, Grey VL, Ferland G, Gundberg C, Lands LC
BACKGROUND: Subclinical deficiencies of vitamin K are universally present in unsupplemented cystic fibrosis (CF) patients. The dose required to prevent deficiencies cannot be estimated from the existing literature. The aim of this study is determine if a supplemental dose of 1 mg/day or 5 mg/day vitamin K(1) per day would normalize vitamin K status in a population of children with cystic fibrosis. METHODS: Fourteen pancreatic insufficient CF children, between the ages of 8 to 18 years old, were randomized to receive either 1 mg/day or 5 mg/day vitamin K(1) per day, for one month. Fasting blood tests were done at baseline and after one month of the intervention. The degree of undercarboxylation of osteocalcin (%Glu-OC), and serum vitamin K(1), were evaluated by descriptive statistics and nonparametric Wilcoxon matched-pair test and Mann-Whitney U test. RESULTS: Of the 50% of subjects who were below the optimal serum vitamin K(1) at baseline, all rose into the normal range with supplementation. Supplementation also significantly reduced the overall %Glu-OC from a median of 46.8 to 29.1% (p
Am J Clin Nutr. 2008 May; 87(5): 1513-20
Macdonald HM, McGuigan FE, Lanham-New SA, Fraser WD, Ralston SH, Reid DM
BACKGROUND: Polymorphisms in the apolipoprotein E (APOE) gene are associated with fracture risk, and a potential mechanism is through vitamin K transport. OBJECTIVE: We investigated the relation between dietary vitamin K(1) intake, APOE polymorphisms, and markers of bone health. DESIGN: We measured bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) in a cohort of Scottish women aged 49-54 y in 1990-1994 (baseline) and in 1997-2000 (visit 2). At visit 2, bone markers (urinary pyridinoline crosslinks and serum N-terminal propeptide of type 1 collagen) were measured, 3199 women completed a food-frequency questionnaire, and 2721 women were genotyped for APOE. RESULTS: Compared with quartile 3 (Q3) of energy-adjusted vitamin K(1) intake (mean: 116 microg/d), women in the lowest quartile (mean: 59 microg/d) had lower BMD (analysis of variance; FN, Q1: 0.831 +/- 0.122 g/cm(2); Q3: 0.850 +/- 0.126 g/cm(2); P < 0.001; LS, Q1: 1.000 +/- 0.170 g/cm(2); Q3: 1.020 +/- 0.172 g/cm(2); P = 0.009), remaining significant at the FN after adjustment for age, weight, height, menopausal status or use of hormone replacement therapy, socioeconomic status, and physical activity (P = 0.04). Vitamin K(1) intake was associated with reduced concentrations of pyridinoline crosslinks (Q1: 5.4 +/- 2.0 nmol/mmol; Q4: 5.1 +/- 1.9 nmol/mmol; P = 0.003). Carriers of the E2 allele had greater LS BMD at visit 2 and lost less BMD than did carriers of the E4 allele (E2: -0.50 +/- 1.22%/y; E4: -0.71 +/- 1.17%/y; P = 0.05). After adjustment for confounders, the P value for BMD loss (0.03 for LS and 0.04 for FN) did not reach the level of significance required for multiple testing (P = 0.012). No interaction was observed between dietary vitamin K and APOE on BMD. CONCLUSIONS: Vitamin K(1) intake was associated with markers of bone health, but no interaction was observed with APOE alleles on BMD or markers of bone turnover.
Am J Clin Nutr. 2008 Apr; 87(4): 985-92
Nimptsch K, Rohrmann S, Linseisen J
BACKGROUND: Anticarcinogenic activities of vitamin K have been observed in various cancer cell lines, including prostate cancer cells. Epidemiologic studies linking dietary intake of vitamin K with the development of prostate cancer have not yet been conducted. OBJECTIVE: We evaluated the association between dietary intake of phylloquinone (vitamin K1) and menaquinones (vitamin K2) and total and advanced prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition. DESIGN: At baseline, habitual dietary intake was assessed by means of a food-frequency questionnaire. Dietary intake of phylloquinone and menaquinones (MK-4-14) was estimated by using previously published HPLC-based food-content data. Multivariate-adjusted relative risks of total and advanced prostate cancer in relation to intakes of phylloquinone and menaquinones were calculated in 11 319 men by means of Cox proportional hazards regression. RESULTS: During a mean follow-up time of 8.6 y, 268 incident cases of prostate cancer, including 113 advanced cases, were identified. We observed a nonsignificant inverse association between total prostate cancer and total menaquinone intake [multivariate relative risk (highest compared with lowest quartile): 0.65; 95% CI: 0.39, 1.06]. The association was stronger for advanced prostate cancer (0.37; 0.16, 0.88; P for trend = 0.03). Menaquinones from dairy products had a stronger inverse association with advanced prostate cancer than did menaquinones from meat. Phylloquinone intake was unrelated to prostate cancer incidence (1.02; 0.70, 1.48). CONCLUSIONS: Our results suggest an inverse association between the intake of menaquinones, but not that of phylloquinone, and prostate cancer. Further studies of dietary vitamin K and prostate cancer are warranted.
Vitamin K and bone health in adult humans.
Vitam Horm. 2008; 78: 393-416
Bügel S
Vitamin K is receiving more attention in relation to its role in bone metabolism. Vitamin K is a coenzyme for glutamate carboxylase, which mediates the conversion of glutamate to gamma-carboxyglutamate (Gla). The gamma-carboxylation of the Gla proteins is essential for the proteins to attract Ca2+ and to incorporate these into hydroxyapatite crystals. The best known of the three known bone-related Gla proteins is osteocalcin (OC). Even though the exact role of OC is not known, a number of studies have shown that vitamin K insufficiency or high levels of undercarboxylated osteocalcin (ucOC) is associated with an increase in the concentration of circulating ucOC. Furthermore, several studies have demonstrated that vitamin K insufficiency is associated with low bone mineral density (BMD) and increased fractures. Vitamin K supplementation, on the other hand, has been shown to improve the bone turnover profile and decrease the level of circulating ucOC. Dietary recommendations are based on saturation of the coagulation system, and in most countries the dietary intake is sufficient to obtain the amount recommended. In relation to bone, requirements might be higher. The aim of this chapter is to give an overview of the importance of vitamin K in relation to bone health in adult humans and thereby in the prevention of osteoporosis. Furthermore, I will shortly discuss the interaction with vitamin D and the paradox in relation to warfarin treatment.
Vitamin K-dependent carboxylation.
Vitam Horm. 2008; 78: 131-56
Berkner KL
Vitamin K-dependent (VKD) protein carboxylation uses vitamin K epoxidation to convert Glus to carboxylated Glus (Glas), rendering VKD proteins active in physiologies that include hemostasis, apoptosis, bone mineralization, calcium homeostasis, growth control, and signal transduction. Clusters of Glus are modified by a processive carboxylase, generating a calcium-binding module that allows binding to either hydroxyapatite in the extracellular matrices or cell surfaces where anionic phospholipids become exposed, for example, during apoptosis or cell activation. Naturally occurring carboxylase mutations have been informative for function and are associated with bleeding complications and, surprisingly, a pseudoxanthoma elasticum (PXE)-like phenotype. A major advance in defining carboxylase function is the identification of the base that initiates carboxylation, which raises interesting possibilities for how vitamin K epoxidation is regulated by Glu substrate and carboxylase membrane topology. Vitamin K oxidoreductase (VKOR), the target of warfarin, generates the reduced vitamin K cofactor used by the carboxylase. Oxidation of active site thiols during vitamin K reduction inactivates VKOR, and activity is regenerated by an unknown reductase. The amounts of reduced vitamin K limit the capacity for carboxylation in cells, and overexpression of VKOR, but not carboxylase, improves carboxylation. However, the effect of VKOR overexpression is small, possibly because the reductase that regenerates VKOR activity is saturated. The review discusses these advances, as well as the potential impact of secretory components on carboxylation, which occurs during VKD protein secretion. Also discussed is the role of the carboxylase in mammals and lower organisms, including the bacterial pathogen Leptospira interrogans that has acquired a VKD carboxylase by horizontal transfer.
Structure and function of vitamin K epoxide reductase.
Vitam Horm. 2008; 78: 103-30
Tie JK, Stafford DW
Vitamin K epoxide reductase (VKOR) is an integral membrane protein that catalyzes the reduction of vitamin K 2,3-epoxide and vitamin K to vitamin K hydroquinone, a cofactor required for the gamma-glutamyl carboxylation reaction. VKOR is highly sensitive to inhibition by warfarin, the most commonly prescribed oral anticoagulant. Warfarin inhibition of VKOR decreases the concentration of reduced vitamin K, which reduces the rate of vitamin K-dependent carboxylation and leads to under-carboxylated, inactive vitamin K-dependent proteins. It is proposed that an active site disulfide needs to be reduced for the enzyme to be active. VKOR uses two sulfhydryl groups for the catalytic reaction and these two sulfhydryl groups are oxidized back to a disulfide bond during each catalytic cycle. The recent identification of the gene encoding VKOR allows us to study its structure and function relationship at the molecular level. The membrane topology model shows that VKOR spans the endoplasmic reticulum membrane three times with its amino-terminus residing in the lumen and the carboxyl-terminus residing in the cytoplasm. Both the active site (cysteines 132 and 135) and the proposed warfarin binding site (tyrosine 139) reside in the third transmembrane helix. VKOR is made at high levels in insect cells and is relatively easily purified. This should allow the determination of its three-dimensional structure. A detailed mechanism has been published and the purified enzyme should allow the testing of this mechanism. A major unanswered question is the physiological reductant of VKOR.
Vitam Horm. 2008; 78: 35-62
Oldenburg J, Marinova M, Müller-Reible C, Watzka M
Vitamin K is a collective term for lipid-like naphthoquinone derivatives synthesized only in eubacteria and plants and functioning as electron carriers in energy transduction pathways and as free radical scavengers maintaining intracellular redox homeostasis. Paradoxically, vitamin K is a required micronutrient in animals for protein posttranslational modification of some glutamate side chains to gamma-carboxyglutamate. The majority of gamma-carboxylated proteins function in blood coagulation. Vitamin K shuttles reducing equivalents as electrons between two enzymes: VKORC1, which is itself reduced by an unknown ER lumenal reductant in order to reduce vitamin K epoxide (K>O) to the quinone form (KH2); and gamma-glutamyl carboxylase, which catalyzes posttranslational gamma-carboxylation and oxidizes KH2 to K>O. This article reviews vitamin K synthesis and the vitamin K cycle, outlines physiological roles of various vitamin K-dependent, gamma-carboxylated proteins, and summarizes the current understanding of clinical phenotypes caused by genetic mutations affecting both enzymes of the vitamin K cycle.
The vibrational spectrum of the secondary electron acceptor, A1, in photosystem I.
J Phys Chem B. 2008 Mar 27; 112(12): 3844-52
Bender SL, Keough JM, Boesch SE, Wheeler RA, Barry BA
Photosystem I (PSI) is a multisubunit protein complex which carries out light-induced, transmembrane charge separation in oxygenic photosynthesis. In PSI, the electron-transfer pathway consists of chlorophyll and phylloquinone molecules, as well as iron-sulfur clusters. There are two phylloquinone molecules, which are located in structurally symmetric positions in the reaction center. It has been proposed that both phylloquinone molecules are active as the A1 secondary electron acceptor in bidirectional electron-transfer reactions. The PSI A1 acceptors are of interest because they have the lowest reduction potential of any quinone found in nature. In this work using light-induced FT-IR spectroscopy, isotope-edited spectra are presented, which attribute vibrational bands to the carbonyl stretching vibrations of A1 and A1- and the quinoid ring stretching vibration of A1. Bands are assigned by comparison with hybrid Hartee-Fock density functional calculations, which predict vibrational frequencies, amplitudes, and isotope shifts for the phylloquinone singlet and radical anion states. The results are consistent with an environmental interaction increasing the frequency of the singlet CO vibration and decreasing the frequency of the anion radical CO vibration, relative to model compounds. This environmental interaction may be the asymmetric hydrogen bond to A1/A1-, electrostatic interactions with charged amino acid side chains, or a pi-pi interaction with the indole ring of a nearby tryptophan. Such differential effects on the structure of A1 and A1- may be associated with a destabilization of the anion radical. These studies give novel information concerning the effect of the protein matrix on the PSI electron-transfer cofactor.