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Martin J. Shearer - One of the best experts on this subject based on the ideXlab platform.
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Vitamin K nutrition Metabolism and requirements current concepts and future research
Advances in Nutrition, 2012Co-Authors: Martin J. Shearer, Sarah L BoothAbstract:In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for Vitamin K, in large part because of a lacK of robust endpoints that reflected adequacy of intaKe. Knowledge of the relative bioavailability of multiple Vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of Vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand Knowledge of the bioavailability, absorption, disposition, and Metabolism of different molecular forms of Vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain Key genes implicated in Vitamin K Metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, Vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for Vitamin K prophylaxis in newborns, but the effectiveness of any Vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lacK of suitable biomarKers or clinical endpoints that can be used to determine Vitamin K requirements among adults.
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novel effects of diets enriched with corn oil or with an olive oil sunflower oil mixture on Vitamin K Metabolism and Vitamin K dependent proteins in young men
Journal of Lipid Research, 2002Co-Authors: Leon J Schurgers, Martin J. Shearer, Berry A M Soute, Ibrahim Elmadfa, Julia M Harvey, Karlheinz Wagner, Richard Tomasch, Cees VermeerAbstract:Little is Known of how the fat components of di- ets influence the absorption and Metabolism of Vitamin K and the possible consequences to the synthesis of Vitamin K-dependent (VKD) proteins in different target organs. We have evaluated the effects of two diets on circulating phyllo- quinone (K 1 ) and triacylglycerols (TAG). One diet was en- riched with corn oil (CO) (also rich in � -tocopherol) and the other with an olive/sunflower (O/SO) mixture (rich in � -tocopherol). Effects on � -carboxylation were assessed from coagulation assays and sensitive assays for undercar- boxylated prothrombin (ucFII) and osteocalcin (ucOC). To- tal plasma matrix Gla-protein (MGP) was also measured. After an initial adjustment diet, 26 healthy young men were fed, in a crossover design, the O/SO or CO diet for 2 weeKs. Mean intaKes of K 1 during consumption of adjust- ment, O/SO, and CO diets were 225 � g/day, 291 � g/day, and 291 � g/day, respectively. Mean fasting levels of TAG and K 1 were both significantly reduced by the CO diet, but not by the O/SO diet. Neither diet reduced FII activity but ucFII became detectable in nine subjects, eight of whom showed this abnormality with both diets. The CO diet induced a rise in ucOC ( P � 0.05), which was negatively correlated to ucFII ( r � � 0.71, P � 0.03). The CO but not O/SO diet induced a decrease of total circulating MGP. We conclude that both oils, notably CO, affected Vitamin K absorption and/or Metabolism which may increase the re- quirements for � -carboxylation. The mechanism is unclear but may result from interactions of Vitamin K with PUFA and/or other lipid components such as Vitamin E. —Schur- gers, L. J., M. J. Shearer, B. A. M. Soute, I. Elmadfa, J. Har- vey, K-H. Wagner, R. Tomasch, and C. Vermeer. Novel ef- fects of diets enriched with corn oil or with an olive oil/ sunflower oil mixture on Vitamin K Metabolism and Vitamin K-dependent proteins in young men. J. Lipid Res . 2002. 43: 878-884.
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novel effects of diets enriched with corn oil or with an olive oil sunflower oil mixture on Vitamin K Metabolism and Vitamin K dependent proteins in young men
Journal of Lipid Research, 2002Co-Authors: Leon J Schurgers, Martin J. Shearer, Berry A M Soute, Ibrahim Elmadfa, Karlheinz Wagner, Richard Tomasch, Julia Harvey, Cees VermeerAbstract:Little is Known of how the fat components of diets influence the absorption and Metabolism of Vitamin K and the possible consequences to the synthesis of Vitamin K-dependent (VKD) proteins in different target organs. We have evaluated the effects of two diets on circulating phylloquinone (K1) and triacylglycerols (TAG). One diet was enriched with corn oil (CO) (also rich in gamma-tocopherol) and the other with an olive/sunflower (O/SO) mixture (rich in alpha-tocopherol). Effects on gamma-carboxylation were assessed from coagulation assays and sensitive assays for undercarboxylated prothrombin (ucFII) and osteocalcin (ucOC). Total plasma matrix Gla-protein (MGP) was also measured. After an initial adjustment diet, 26 healthy young men were fed, in a crossover design, the O/SO or CO diet for 2 weeKs. Mean intaKes of K1 during consumption of adjustment, O/SO, and CO diets were 225 microg/day, 291 microg/day, and 291 microg/day, respectively. Mean fasting levels of TAG and K1 were both significantly reduced by the CO diet, but not by the O/SO diet. Neither diet reduced FII activity but ucFII became detectable in nine subjects, eight of whom showed this abnormality with both diets. The CO diet induced a rise in ucOC (P < 0.05), which was negatively correlated to ucFII (r = -0.71, P < 0.03). The CO but not O/SO diet induced a decrease of total circulating MGP. We conclude that both oils, notably CO, affected Vitamin K absorption and/or Metabolism which may increase the requirements for gamma-carboxylation. The mechanism is unclear but may result from interactions of Vitamin K with PUFA and/or other lipid components such as Vitamin E.
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Vitamin K Metabolism
Sub-cellular biochemistry, 1998Co-Authors: Paul Newman, Martin J. ShearerAbstract:The discovery of Vitamin K can be largely attributed to the Danish scientist HenriK Dam, whose worK on sterol Metabolism in chicKs required the feeding of carefully controlled diets, some of which were depleted in lipids (Dam, 1929). This often caused internal hemorrhages and other symptoms similar to scurvy, but which Dam showed to be incurable by large doses of Vitamin C. The finding of the lacK of influence of cod liver oil concentrates (as a source of Vitamins A and D), but the protective effect of cereals and seeds, prompted Dam to suggest that the bleeding syndrome was caused by a lacK of an essential dietary component that was different from Vitamins A, D, and C (Dam and Schoenheyder, 1934; Dam, 1934). Further worK by Dam with experimental diets showed the factor was fat soluble, heat stable and occurred in various animal and plant tissues, hog liver fat being one of the best sources. In 1935, after ruling out Vitamin E (hog liver fat was many times as active as wheat-germ oil), Dam proposed that the antihemorrhagic factor was a new fat-soluble Vitamin that he called “Koagulations Vitamin” or Vitamin K (Dam, 1935a,b). Other rich sources of Vitamin K were found to be green leaves such as alfalfa. Another surprisingly rich souce was bran or fishmeal which had become putrifled by the action of bacteria (Almquist and StoKstad, 1935; Almquist et al., 1938), suggesting that microbial action as well as plant biosynthesis is capable of producing the factor. Improvements in the assay method based on the restoration of normal clotting time in hemorrhagic chicKs led to the proposal that a lacK of Vitamin K caused a deficiency in prothrombin activity and that Vitamin K might be some Kind of coenzyme or prosthetic group required for active prothrombin (Schoenheyder, 1936). However, subsequent worK showed that prothrombin precipitates were active after all lipids had been removed and that Vitamin K concentrates could not induce blood to clot (Dam et al., 1936).
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Vitamin K Metabolism and nutriture.
Blood reviews, 1992Co-Authors: Martin J. ShearerAbstract:Abstract Vitamin K functions as a co-factor for the post-translational carboxylation of specific glutamate residues to gamma-carboxyglutamate (Gla) residues in several blood coagulation factors (II, VII, IX and X) and coagulation inhibitors (proteins C and S) in the liver; as well as a variety of extrahepatic proteins such as the bone protein osteocalcin. This review outlines some recent advances in our understanding of the Metabolism of Vitamin K and its role in human nutriture. The introduction of new methodologies to measure the low endogenous tissue concentrations of K Vitamins and circulating plasma levels of des-gamma-carboxyprothrombin (PIVKA-II) have provided correspondingly more refined indices for the assessment of human Vitamin K status. The assays for Vitamin K have also been used to study the sources, intestinal absorption, plasma transport, storage and transplacental transfer of K Vitamins and the importance of phylloquinone (Vitamin K 1 ) versus menaquinones (Vitamins K 2 ) to human needs. The ability to biochemically monitor subclinical Vitamin K deficiency has reaffirmed the precarious Vitamin K status of the newborn and led to an increased appreciation of the risK factors leading to haemorrhagic disease of the newborn and how this may be prevented. Biochemical studies are leading to an increased Knowledge of the mode of action of traditional coumarin anticoagulants and how some unrelated compounds (e.g. antibiotics) may also antagonize Vitamin K and cause bleeding. There is also an awareness of the possible deleterious effects of Vitamin K antagonism or deficiency on non-hepatic Gla-proteins which may play some subtle role in calcium homeostasis.
Cees Vermeer - One of the best experts on this subject based on the ideXlab platform.
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Vitamin K Metabolism as the potential missing linK between lung damage and thromboembolism in coronavirus disease 2019
British Journal of Nutrition, 2021Co-Authors: Rob Janssen, Margot Pj Visser, Anton Sm Dofferhoff, Cees Vermeer, Wim Janssens, Jona WalkAbstract:Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic welfare. The majority of infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of Vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a Vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic Vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient Vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that Vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that Vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. TaKing these data together, we propose a mechanism of pneumonia-induced Vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether Vitamin K administration plays a role in the prevention and treatment of severe Covid-19.
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novel effects of diets enriched with corn oil or with an olive oil sunflower oil mixture on Vitamin K Metabolism and Vitamin K dependent proteins in young men
Journal of Lipid Research, 2002Co-Authors: Leon J Schurgers, Martin J. Shearer, Berry A M Soute, Ibrahim Elmadfa, Julia M Harvey, Karlheinz Wagner, Richard Tomasch, Cees VermeerAbstract:Little is Known of how the fat components of di- ets influence the absorption and Metabolism of Vitamin K and the possible consequences to the synthesis of Vitamin K-dependent (VKD) proteins in different target organs. We have evaluated the effects of two diets on circulating phyllo- quinone (K 1 ) and triacylglycerols (TAG). One diet was en- riched with corn oil (CO) (also rich in � -tocopherol) and the other with an olive/sunflower (O/SO) mixture (rich in � -tocopherol). Effects on � -carboxylation were assessed from coagulation assays and sensitive assays for undercar- boxylated prothrombin (ucFII) and osteocalcin (ucOC). To- tal plasma matrix Gla-protein (MGP) was also measured. After an initial adjustment diet, 26 healthy young men were fed, in a crossover design, the O/SO or CO diet for 2 weeKs. Mean intaKes of K 1 during consumption of adjust- ment, O/SO, and CO diets were 225 � g/day, 291 � g/day, and 291 � g/day, respectively. Mean fasting levels of TAG and K 1 were both significantly reduced by the CO diet, but not by the O/SO diet. Neither diet reduced FII activity but ucFII became detectable in nine subjects, eight of whom showed this abnormality with both diets. The CO diet induced a rise in ucOC ( P � 0.05), which was negatively correlated to ucFII ( r � � 0.71, P � 0.03). The CO but not O/SO diet induced a decrease of total circulating MGP. We conclude that both oils, notably CO, affected Vitamin K absorption and/or Metabolism which may increase the re- quirements for � -carboxylation. The mechanism is unclear but may result from interactions of Vitamin K with PUFA and/or other lipid components such as Vitamin E. —Schur- gers, L. J., M. J. Shearer, B. A. M. Soute, I. Elmadfa, J. Har- vey, K-H. Wagner, R. Tomasch, and C. Vermeer. Novel ef- fects of diets enriched with corn oil or with an olive oil/ sunflower oil mixture on Vitamin K Metabolism and Vitamin K-dependent proteins in young men. J. Lipid Res . 2002. 43: 878-884.
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novel effects of diets enriched with corn oil or with an olive oil sunflower oil mixture on Vitamin K Metabolism and Vitamin K dependent proteins in young men
Journal of Lipid Research, 2002Co-Authors: Leon J Schurgers, Martin J. Shearer, Berry A M Soute, Ibrahim Elmadfa, Karlheinz Wagner, Richard Tomasch, Julia Harvey, Cees VermeerAbstract:Little is Known of how the fat components of diets influence the absorption and Metabolism of Vitamin K and the possible consequences to the synthesis of Vitamin K-dependent (VKD) proteins in different target organs. We have evaluated the effects of two diets on circulating phylloquinone (K1) and triacylglycerols (TAG). One diet was enriched with corn oil (CO) (also rich in gamma-tocopherol) and the other with an olive/sunflower (O/SO) mixture (rich in alpha-tocopherol). Effects on gamma-carboxylation were assessed from coagulation assays and sensitive assays for undercarboxylated prothrombin (ucFII) and osteocalcin (ucOC). Total plasma matrix Gla-protein (MGP) was also measured. After an initial adjustment diet, 26 healthy young men were fed, in a crossover design, the O/SO or CO diet for 2 weeKs. Mean intaKes of K1 during consumption of adjustment, O/SO, and CO diets were 225 microg/day, 291 microg/day, and 291 microg/day, respectively. Mean fasting levels of TAG and K1 were both significantly reduced by the CO diet, but not by the O/SO diet. Neither diet reduced FII activity but ucFII became detectable in nine subjects, eight of whom showed this abnormality with both diets. The CO diet induced a rise in ucOC (P < 0.05), which was negatively correlated to ucFII (r = -0.71, P < 0.03). The CO but not O/SO diet induced a decrease of total circulating MGP. We conclude that both oils, notably CO, affected Vitamin K absorption and/or Metabolism which may increase the requirements for gamma-carboxylation. The mechanism is unclear but may result from interactions of Vitamin K with PUFA and/or other lipid components such as Vitamin E.
Leon J Schurgers - One of the best experts on this subject based on the ideXlab platform.
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administration of Vitamin K does not counteract the ectopic mineralization of connective tissues in abcc6 mice a model for pseudoxanthoma elasticum
Cell Cycle, 2011Co-Authors: Qiujie Jiang, Alix E Grandpierre, Leon J Schurgers, Jouni UittoAbstract:Pseudoxanthoma elasticum (PXE) is a heritable multisystem disorder manifesting with ectopic calcification of peripheral connective tissues, caused by mutations in the ABCC6 gene. Alterations in Vitamin K Metabolism have been suggested to contribute to the pathomechanisms of the mineralization process. In this study we administered Vitamin K or its glutathione conjugate (K3-GSH) into Abcc6−/− mice that recapitulate features of PXE. Oral administration of Vitamin K2, in dosages that vastly exceed the amounts in control diet or the recommended amounts for humans, did not alter the ectopic mineralization in Abcc6−/− mice. Similarly, intravenous administration of K3-GSH did not alter the degree of mineralization. Testing of Vitamin K2, K3 and K3-GSH in an in vitro calcification system provided no evidence of mineralization inhibition. Collectively, our data suggest that Vitamin K deficiency in the peripheral tissues is not a simple explanation for development of mineral deposits in PXE.
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novel effects of diets enriched with corn oil or with an olive oil sunflower oil mixture on Vitamin K Metabolism and Vitamin K dependent proteins in young men
Journal of Lipid Research, 2002Co-Authors: Leon J Schurgers, Martin J. Shearer, Berry A M Soute, Ibrahim Elmadfa, Julia M Harvey, Karlheinz Wagner, Richard Tomasch, Cees VermeerAbstract:Little is Known of how the fat components of di- ets influence the absorption and Metabolism of Vitamin K and the possible consequences to the synthesis of Vitamin K-dependent (VKD) proteins in different target organs. We have evaluated the effects of two diets on circulating phyllo- quinone (K 1 ) and triacylglycerols (TAG). One diet was en- riched with corn oil (CO) (also rich in � -tocopherol) and the other with an olive/sunflower (O/SO) mixture (rich in � -tocopherol). Effects on � -carboxylation were assessed from coagulation assays and sensitive assays for undercar- boxylated prothrombin (ucFII) and osteocalcin (ucOC). To- tal plasma matrix Gla-protein (MGP) was also measured. After an initial adjustment diet, 26 healthy young men were fed, in a crossover design, the O/SO or CO diet for 2 weeKs. Mean intaKes of K 1 during consumption of adjust- ment, O/SO, and CO diets were 225 � g/day, 291 � g/day, and 291 � g/day, respectively. Mean fasting levels of TAG and K 1 were both significantly reduced by the CO diet, but not by the O/SO diet. Neither diet reduced FII activity but ucFII became detectable in nine subjects, eight of whom showed this abnormality with both diets. The CO diet induced a rise in ucOC ( P � 0.05), which was negatively correlated to ucFII ( r � � 0.71, P � 0.03). The CO but not O/SO diet induced a decrease of total circulating MGP. We conclude that both oils, notably CO, affected Vitamin K absorption and/or Metabolism which may increase the re- quirements for � -carboxylation. The mechanism is unclear but may result from interactions of Vitamin K with PUFA and/or other lipid components such as Vitamin E. —Schur- gers, L. J., M. J. Shearer, B. A. M. Soute, I. Elmadfa, J. Har- vey, K-H. Wagner, R. Tomasch, and C. Vermeer. Novel ef- fects of diets enriched with corn oil or with an olive oil/ sunflower oil mixture on Vitamin K Metabolism and Vitamin K-dependent proteins in young men. J. Lipid Res . 2002. 43: 878-884.
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novel effects of diets enriched with corn oil or with an olive oil sunflower oil mixture on Vitamin K Metabolism and Vitamin K dependent proteins in young men
Journal of Lipid Research, 2002Co-Authors: Leon J Schurgers, Martin J. Shearer, Berry A M Soute, Ibrahim Elmadfa, Karlheinz Wagner, Richard Tomasch, Julia Harvey, Cees VermeerAbstract:Little is Known of how the fat components of diets influence the absorption and Metabolism of Vitamin K and the possible consequences to the synthesis of Vitamin K-dependent (VKD) proteins in different target organs. We have evaluated the effects of two diets on circulating phylloquinone (K1) and triacylglycerols (TAG). One diet was enriched with corn oil (CO) (also rich in gamma-tocopherol) and the other with an olive/sunflower (O/SO) mixture (rich in alpha-tocopherol). Effects on gamma-carboxylation were assessed from coagulation assays and sensitive assays for undercarboxylated prothrombin (ucFII) and osteocalcin (ucOC). Total plasma matrix Gla-protein (MGP) was also measured. After an initial adjustment diet, 26 healthy young men were fed, in a crossover design, the O/SO or CO diet for 2 weeKs. Mean intaKes of K1 during consumption of adjustment, O/SO, and CO diets were 225 microg/day, 291 microg/day, and 291 microg/day, respectively. Mean fasting levels of TAG and K1 were both significantly reduced by the CO diet, but not by the O/SO diet. Neither diet reduced FII activity but ucFII became detectable in nine subjects, eight of whom showed this abnormality with both diets. The CO diet induced a rise in ucOC (P < 0.05), which was negatively correlated to ucFII (r = -0.71, P < 0.03). The CO but not O/SO diet induced a decrease of total circulating MGP. We conclude that both oils, notably CO, affected Vitamin K absorption and/or Metabolism which may increase the requirements for gamma-carboxylation. The mechanism is unclear but may result from interactions of Vitamin K with PUFA and/or other lipid components such as Vitamin E.
Ignacio Fernandez - One of the best experts on this subject based on the ideXlab platform.
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new insights on Vitamin K Metabolism in senegalese sole solea senegalensis based on ontogenetic and tissue specific Vitamin K epoxide reductase molecular data
International Journal of Molecular Sciences, 2020Co-Authors: Silvia Beato, Carlos Marques, Vincent Laize, Paulo J Gavaia, Ignacio FernandezAbstract:Vitamin K (VK) is a Key nutrient for several biological processes (e.g., blood clotting and bone Metabolism). To fulfill VK nutritional requirements, VK action as an activator of pregnane X receptor (Pxr) signaling pathway, and as a co-factor of γ-glutamyl carboxylase enzyme, should be considered. In this regard, VK recycling through Vitamin K epoxide reductases (VKors) is essential and should be better understood. Here, the expression patterns of Vitamin K epoxide reductase complex subunit 1 (vKorc1) and vKorc1 liKe 1 (vKorc1l1) were determined during the larval ontogeny of Senegalese sole (Solea senegalensis), and in early juveniles cultured under different physiological conditions. Full-length transcripts for ssvKorc1 and ssvKorc1l1 were determined and peptide sequences were found to be evolutionarily conserved. During larval development, expression of ssvKorc1 showed a slight increase during absence or low feed intaKe. Expression of ssvKorc1l1 continuously decreased until 24 h post-fertilization, and remained constant afterwards. Both ssvKors were ubiquitously expressed in adult tissues, and highest expression was found in liver for ssvKorc1, and ovary and brain for ssvKorc1l1. Expression of ssvKorc1 and ssvKorc1l1 was differentially regulated under physiological conditions related to fasting and re-feeding, but also under VK dietary supplementation and induced deficiency. The present worK provides new and basic molecular clues evidencing how VK Metabolism in marine fish is sensitive to nutritional and environmental conditions.
H.h.w. Thijssen - One of the best experts on this subject based on the ideXlab platform.
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Vitamin K distribution in rat tissues dietary phylloquinone is a source of tissue menaquinone 4
British Journal of Nutrition, 1994Co-Authors: H.h.w. Thijssen, M J DrittijreijndersAbstract:The present study was undertaKen to determine whether there is selective tissue distribution of Vitamin K in the rat and whether this distribution mirrors the distribution of tissue Vitamin K Metabolism. The effects of feeding a Vitamin K-free diet followed by resupplementation with phylloquinone (K1) were studied. K1 was recovered in all tissues. In K1 -supplemented rats, most tissues accumulated K1 relative to plasma K1 with the highest levels in liver, heart, bone, and cartilaginous tissue (sternum). Low K1 levels were found in the brain. In the K1-free rats, relatively high K1 levels were still found in heart, pancreas, bone and sternum. Surprisingly, menaquinone-4 (MK-4) was detected in all tissues, with low levels in plasma and liver, and much higher levels in pancreas, salivary gland and sternum. MK-4 levels exceeded K1 levels in brain, pancreas, salivary gland and sternum. Supplementation with K1, orally and by intravenous infusion, caused MK-4 levels to rise. Some accumulation of K1 and MK-4 in the mitochondrial fraction was found for Kidney, pancreas and salivary gland. In the liver the higher menaquinones (MK-6–9) accumulated in the mitochondria. The results indicate that: (1) there is selective tissue distribution of K1 and MK-4, (2) dietary K1 is a source of MK-4. The results also suggest there may be an as yet unrecognized physiological function for Vitamin K (MK-4).
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Vitamin K Metabolism and Vitamin K1 status in human liver samples a search for inter individual differences in warfarin sensitivity
British Journal of Haematology, 1993Co-Authors: H.h.w. Thijssen, M J DrittijreijndersAbstract:Summary. Vitamin K-dependent parameters in human liver samples were investigated to find a clue to the inter-individual differences in sensitivity for oral anticoagulants. Vitamin K epoxide reductase and Vitamin K-dependent carboxylase activity differed 2–3-fold between the samples. Microsomal warfarin binding correlated significantly with the reductase activity. Microsomal Vitamin K epoxide reductase of the different samples showed equal sensitivity for warfarin inhibition, 150 about 0·1 μm. Vitamin K epoxide reductase activity stimulated by NADH/lipoamide and microsomal lipoamide dehydrogenase activity showed higher inter-subject variability than the reductase activity by itself. Liver Vitamin K1 levels varied 4–5-fold. Total and liver microsomal Vitamin K1 levels were correlated. One of the liver samples was obtained from a donor anticoagulated with phenprocoumon and additionally treated with Vitamin K1. High levels of the Vitamin and its epoxide were present. Phenprocoumon was essentially irreversibly bound to the microsomes. In general the results confirm inter-individual differences in the hepatic Vitamin K-dependent systems; the differences as such were found to be small. However, as the various parameters can worK synergistically in the same direction, they may well account for the wide dose range observed in oral anticoagulant therapy.
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The long-term effects of the rodenticide, brodifacoum, on blood coagulation and Vitamin K Metabolism in rats.
British journal of pharmacology, 1991Co-Authors: J.j. Mosterd, H.h.w. ThijssenAbstract:1. The long-term (30 days) effects of a single dose of brodifacoum (0.2 mg Kg-1, orally) on blood clotting activity and on liver parameters of the Vitamin K cycle were investigated in rats. Maximal effect on blood clotting activity was seen on day one. On day seven blood clotting activity had returned to normal. 2. Liver microsomal Vitamin KO reductase activity was maximally suppressed (10% of control activity) on day one, steadily recovered to about 40% on day 15 to remain at that level. The same time course was seen for the number of microsomal warfarin binding sites. 3. The persistent inhibition of the Vitamin K cycle was also verified in vivo; following Vitamin K administration (10 mg Kg-1, i.v.) on day 30, the brodifacoum-treated rats accumulated Vitamin KO in the liver. 4. Although clotting factor synthesis was normal, brodifacoum-treated rats were highly sensitive to warfarin. 5. Brodifacoum rapidly accumulated in the liver until the saturation of the microsomal binding site. Brodifacoum binding to the target prevented its elimination from the liver; liver content on day 30 was not different from day 7. 6. The results show (1) an over capacity for the hepatocellular Vitamin K cycle, (2) a dissociation of the Vitamin K epoxidation and the Vitamin K-dependent carboxylation, (3) the 'superwarfarin' rodenticides to be extremely persistent due to their binding to the target.
