Differential lipoprotein transport pathways of K-vitamins in healthy subjects (original) (raw)
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Age and Dietary Form of Vitamin K Affect Menaquinone4 Concentrations in Male
Phylloquinone, the primary dietary form of vitamin K, is converted to menaquinone-4 (MK-4) in certain tissues. MK-4 may have tissue-specific roles independent of those traditionally identified with vitamin K. Fischer 344 male rats of different ages (2, 12, and 24 mo, n ¼ 20 per age group) were used to compare the conversion of phylloquinone to MK-4 with an equivalent dose of another dietary form of vitamin K, 2#,3#-dihydrophylloquinone. Rats were age-and diet-group pair-fed phylloquinone (198 6 9.0 mg/kg diet) or dihydrophylloquinone (172 6 13.0 mg/kg diet) for 28 d. MK-4 was the primary form of vitamin K in serum, spleen, kidney, testes, bone marrow, and brain myelin fractions, regardless of age group. MK-4 concentrations were significantly lower in kidney, heart, testes, cortex (myelin), and striatum (myelin) in the dihydrophylloquinone diet group compared with the phylloquinone diet group (P , 0.05). The MK-4 concentrations in 2-mo-old rats were lower in liver, spleen, kidney, heart, and cortex (myelin) but higher in testes compared with 24-mo-old rats (P , 0.05).
Biochemical Pharmacology, 1995
AbstractRa1.s were made vitamin K-deficient by feeding them a diet devoid of vitamin K and by rigorously preventing coprophagy. After one week, circulating prothrombin concentrations were between 5 and 10% of initial values, and various amounts of phylloquinone, menaquinone-4, and menaquinone-9 were given in a single dose either subcutaneously, orally, or colorectally. The relative 'vitamin K activities' of these compounds were assessed by comparing their ability to support prothrombin synthesis after subcutaneous injection. Intestinal and colonic absorption were deduced from the difference between subcutaneous and either oral or colorectal administration of the vitamers. It is concluded that the colonic absorption of all three forms of vitamin K is extremely poor. suggesting that physiological menaquinones in the colon do not contribute substantially to vitamin K status in rats. Furthermore, the stimulation of prothrombin synthesis by menaquinone-9 lasted much longer than that by the two other K-vitamers, resulting in a substantially higher 'vitamin K activity' of menaquinone-9.
Molecular Nutrition & Food Research, 2012
Scope: The mechanism for increased bleeding and decreased vitamin K status accompanying vitamin E supplementation is unknown. We hypothesized that elevated hepatic ␣-tocopherol (␣-T) concentrations may stimulate vitamin K metabolism and excretion. Furthermore, ␣-T may interfere with the side chain removal of phylloquinone (PK) to form menadione (MN) as an intermediate for synthesis of tissue-specific menaquinone-4 (MK-4). Methods and results: In order to investigate these hypotheses, rats were fed phylloquinone (PK) or menadione (MN) containing diets (2 mol/kg) for 2.5 weeks. From day 10, rats were given daily subcutaneous injections of either ␣-T (100 mg/kg) or vehicle and were sacrificed 24 h after the seventh injection. Irrespective of diet, ␣-T injections decreased MK-4 concentrations in brain, lung, kidney, and heart; and PK in lung. These decreases were not accompanied by increased excretion of urinary 5C-or 7C-aglycone vitamin K metabolites, however, the urinary ␣-T metabolite (␣-CEHC) increased ≥100-fold. Moreover, ␣-T increases were accompanied by downregulation of hepatic cytochrome P450 expression and modified expression of tissue ATP-binding cassette transporters. Conclusion: Thus, in rats, high tissue ␣-T depleted tissue MK-4 without significantly increasing urinary vitamin K metabolite excretion. Changes in tissue MK-4 and PK levels may be a result of altered regulation of transporters.
Menadione is a metabolite of oral vitamin K
British Journal of Nutrition, 2006
Phylloquinone is converted into menaquinone-4 and accumulates in extrahepatic tissues. Neither the route nor the function of the conversion is known. One possible metabolic route might be the release of menadione from phylloquinone by catabolic activity. In the present study we explored the presence of menadione in urine and the effect of vitamin K intake on its excretion. Menadione in urine was analysed by HPLC assay with fluorescence detection. Urine from healthy male volunteers was collected before and after administration of a single dose of K vitamins. Basal menadione excretion in non-supplemented subjects (n 6) was 5·4 (SD 3·2) mg/d. Urinary menadione excretion increased greatly after oral intake of the K vitamins, phylloquinone and menaquinone-4 and -7. This effect was apparent within 1 -2 h and peaked at about 3 h after intake. Amounts of menadione excreted in 24 h after vitamin K intake ranged, on a molar basis, from 1 to 5 % of the administered dose, indicating that about 5-25 % of the ingested K vitamins had been catabolized to menadione. Menadione excretion was not enhanced by phylloquinone administered subcutaneously or by 2 0 ,3 0 -dihydrophylloquinone administered orally. In archived samples from a depletion/repletion study Am J Clin Nutr 74, 783 -790), urinary menadione excretion mirrored dietary phylloquinone intake. The present study shows that menadione is a catabolic product of K vitamins formed after oral intake. The rapid appearance in urine after oral but not subcutaneous administration suggests that catabolism occurs during intestinal absorption. The observations make it likely that part of the menaquinone-4 in tissues results from uptake and prenylation of circulating menadione.
Blood, 2007
Vitamin K is a cofactor in the production of blood coagulation factors (in the liver), osteocalcin (in bone), and matrix Gla protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health, relatively high intakes of vitamin K are required. The synthetic short-chain vitamin K 1 is commonly used in food supplements, but recently the natural long-chain menaquinone-7 (MK-7) has also become available as an over-the-counter (OTC) supple-ment. The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K 1 and MK-7. Serum vitamin K species were used as a marker for absorption and osteocalcin carboxylation as a marker for activity. Both K 1 and MK-7 were absorbed well, with peak serum concentrations at 4 hours after intake. A major difference between the 2 vitamin K species is the very long half-life time of MK-7, resulting in much more stable serum levels, and accumulation of MK-7 to higher levels (7-to 8-fold) during prolonged intake. MK-7 induced more complete carboxylation of osteocalcin, and hematologists should be aware that preparations supplying 50 g/d or more of MK-7 may interfere with oral anticoagulant treatment in a clinically relevant way. (Blood. 2007;109:3279-3283)
Age and dietary form of vitamin K affect menaquinone-4 concentrations in male Fischer 344 rats
The Journal of nutrition, 2008
Phylloquinone, the primary dietary form of vitamin K, is converted to menaquinone-4 (MK-4) in certain tissues. MK-4 may have tissue-specific roles independent of those traditionally identified with vitamin K. Fischer 344 male rats of different ages (2, 12, and 24 mo, n = 20 per age group) were used to compare the conversion of phylloquinone to MK-4 with an equivalent dose of another dietary form of vitamin K, 2',3'-dihydrophylloquinone. Rats were age- and diet-group pair-fed phylloquinone (198 +/- 9.0 microg/kg diet) or dihydrophylloquinone (172 +/- 13.0 microg/kg diet) for 28 d. MK-4 was the primary form of vitamin K in serum, spleen, kidney, testes, bone marrow, and brain myelin fractions, regardless of age group. MK-4 concentrations were significantly lower in kidney, heart, testes, cortex (myelin), and striatum (myelin) in the dihydrophylloquinone diet group compared with the phylloquinone diet group (P < 0.05). The MK-4 concentrations in 2-mo-old rats were lower in l...
British Journal of Nutrition, 2012
Vitamin K is required for the carboxylation of Gla-proteins in the liver (coagulation factors) and extra-hepatic tissues, such as bone (osteocalcin, OC), and arterial wall (matrix Gla-protein, MGP). Although the coagulation factors are essentially fully carboxylated under normal conditions, 10-40 % of OC and MGP remains undercarboxylated. We were therefore interested to study the dose -response effects of extra intake of menaquinones on the carboxylation of the extra-hepatic Gla-proteins. A total of forty-two healthy Dutch men and women aged between 18 and 45 years were randomised into seven groups to receive: placebo capsules or menaquinone-7 (MK-7) capsules at a daily dose of 10, 20, 45, 90, 180 or 360 mg. Circulating uncarboxylated OC (ucOC), carboxylated OC (cOC) and desphospho-uncarboxylated MGP were measured by ELISA. The ucOC:cOC ratio was calculated from circulating ucOC and cOC values. Endogenous thrombin potential and peak height were determined by calibrated automated thrombography. To increase the statistical power, we collapsed the treatment groups into three dosage groups: placebo, low-dose supplementation (doses below RDA, Commission Directive 2008/100/EC), and highdose supplementation (doses around RDA, Commission Directive 2008/100/EC). MK-7 supplementation at doses in the order of the RDA (Commission Directive 2008/100/EC) increased the carboxylation of circulating OC and MGP. No adverse effects on thrombin generation were observed. Extra MK-7 intake at nutritional doses around the RDA (Commission Directive 2008/100/EC) improved the carboxylation of the extra-hepatic vitamin K-dependent proteins. Whether this improvement contributes to public health, i.e. increasing the protection against age-related diseases needs further investigation in specifically designed intervention trials.
Vitamin K plasma levels determination in human health
Clinical Chemistry and Laboratory Medicine (CCLM), 2016
Vitamin K (phylloquinone or vitamin K 1 and menaquinones or vitamin K 2) plays an important role as a cofactor in the synthesis of hepatic blood coagulation proteins, but recently has also aroused an increasing interest for its action in extra-hepatic tissues, in particular in the regulation of bone and vascular metabolism. The accurate measurement of vitamin K status in humans is still a critical issue. Along with indirect assays, such as the undercarboxylated fractions of vitamin K-dependent proteins [prothrombin, osteocalcin (OC), and matrix gla protein], the direct analysis of blood levels of phylloquinone and menaquinones forms might be considered a more informative and direct method for assessing vitamin K status. Different methods for direct quantification of vitamin K serum levels are available. High-performance liquid chromatography (HPLC) methods coupled with post-column reduction procedures and fluorimetric or electrochemical detection are commonly used for food and blood analysis of phylloquinone, but they show some limitations when applied to the analysis of serum menaquinones because of interferences from triglycerides. Recent advancements include liquid chromatography tandem mass spectrometry (LCMS/MS) detection, which assures higher specificity. The optimization and standardization of these methods requires specialized laboratories. The variability of results observed in the available studies suggests the need for further investigations to obtain more accurate analytical results.
Extrahepatic tissue concentrations of vitamin K are lower in rats fed a high vitamin E diet
Nutrition & metabolism, 2006
An adverse hematological interaction between vitamins E and K has been reported, primarily in patients on anticoagulants. However, little is known regarding circulating levels or tissue concentrations of vitamin K in response to vitamin E supplementation. The purpose of this study was to examine the effect of different levels of dietary alpha-tocopherol on phylloquinone and menaquinone-4 concentrations, while maintaining a constant intake of phylloquinone, in rat tissues. Male 4-wk old Fischer 344 rats (n = 33) were fed one of 3 diets for 12 wk: control (n = 13) with 30 mg all-rac-alpha-tocopherol acetate/kg diet; vitamin E-supplemented (n = 10) with 100 mg all-rac-alpha-tocopherol acetate/kg diet; and vitamin E-restricted (n = 10) with <10 mg total tocopherols/kg diet. All 3 diets contained 470 +/- 80 microg phylloquinone/kg diet. Phylloquinone concentrations were lower (P < or = 0.05) in the vitamin E-supplemented compared to the vitamin E-restricted group (mean +/- SD splee...