Vitamin K, vitamin E and the coumarin drugs.
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Adult↗
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Metabolism of vitamin K and vitamin K 2,3-epoxide via interaction with a common disulfide.
The effects of thiols and sulfhydryl blocking reagents on the reduction of vitamin K to vitamin K hydroquinone and vitamin K 2,3-epoxide to vitamin K and vitamin K hydroquinone catalyzed by rat hepatic microsomes were investigated to determine the mechanism(s) for these reactions. Both vitamin K and vitamin K 2,3-epoxide reductions were catalyzed more effectively with dithiols than with monothiols as the reductant. The sulfhydryl reagent N-ethylmaleimide (NEM) inhibited vitamin K and vitamin K 2,3-epoxide reduction much more effectively when microsomes were initially treated with dithiothreitol (prereduced). In prereduced microsomes iodoacetamide was approximately half as effective an inhibitor of vitamin K and vitamin K 2,3-epoxide reduction as NEM, but in microsomes not prereduced it was more effective. Iodoacetic acid was ineffective as an inhibitor. Vitamin K or vitamin K 2,3-epoxide added to prereduced microsomes blocked subsequent inhibition by NEM of vitamin K and vitamin K 2,3-epoxide metabolism, respectively. Vitamin K added to prereduced microsomes also blocked inhibition by NEM of vitamin K 2,3-epoxide metabolism, and vitamin K 2,3-epoxide addition blocked inhibition by NEM of vitamin K metabolism. Vitamin K did not diminish the rate of vitamin K 2,3-epoxide metabolism, however, nor did vitamin K 2,3-epoxide diminish the rate of vitamin K metabolism. These data establish that exogenous thiol compounds promote the reduction of at least one protein disulfide which participates in the metabolism of vitamin K and vitamin K 2,3-epoxide. Presumably, the resultant sulfhydryl groups are reoxidized to the disulfide form during the metabolism of either vitamin which protects them from reaction with NEM.
Animals↗
Reversible metabolism of vitamin K-vitamin K epoxide: modeling considerations and limitations.
Due to the cyclical natural of the vitamin K-vitamin K epoxide system, a two-compartment reversible metabolism model was used to describe this interconversion. In attempting to apply this model to the vitamin K-vitamin K epoxide cycle using literature data from dogs, interconversion and elimination clearances were obtained which are not physiologic. Consequently, the assumptions of the model were reexamined with respect to their validity. One critical assumption of the two-compartment model for interconversion is that it can only be applied in the absence of flow limitations. To determine what effect flow limitations may exert on the vitamin K and vitamin K epoxide apparent blood clearances, a model separating the liver from the blood compartment was proposed assuming the interconversion and metabolism of vitamin K and its epoxide occurred only within the liver. Simulated data suggested that if the reversible metabolic clearance values exceeded the distribution clearance terms, all the apparent clearances calculated using blood concentration-time data were in error. It is suggested that a two-compartment interconversion model might be too simplistic for the vitamin K-vitamin K epoxide cycle where the reversible metabolism is efficient and the distributional clearance may be rate limiting.
Animals↗
Identification of a warfarin-sensitive protein component in a 200S rat liver microsomal fraction catalyzing vitamin K and vitamin K 2,3-epoxide reduction.
A partially purified, 200S submicrosomal fraction exhibiting thiol-dependent vitamin K1 (vitamin K) and epoxide reductase activities has been isolated by partial solubilization of rat hepatic microsomes with sodium cholate and separation by centrifugation at 105 000 g into a discontinuous sucrose gradient. At pH 7.4, the rates of vitamin K and vitamin K 2,3-epoxide reduction per milligram of 200S fraction protein were equivalent and were 2.5-3.0 times faster than in microsomes. Reduction of vitamin K 2,3-epoxide occurred in a tightly coupled, two-step reaction initially to vitamin K and subsequently to vitamin K hydroquinone (vitamin KH2). Incorporation of glycerol or sucrose and of sodium cholate into reaction mixtures equivalently affected the rates of both vitamin K and vitamin K 2,3-epoxide reduction, but in the case of epoxide metabolism, the ratios of vitamin KH2/vitamin K were much lower, suggesting that the second reaction has been partially uncoupled from the first. A 14 000-17 000-dalton warfarin-sensitive protein (WSP) that participates in vitamin K and vitamin K 2,3-epoxide reduction in the 200S fraction was identified by incorporation of N-[3H]ethylmaleimide ([3H]NEM) into the catalytically active reduced form of one or more attached disulfides. Reduction of WSP with dithiothreitol was required for reaction with [3H]NEM, and the substrates vitamin K and vitamin K 2,3-epoxide and the inhibitor warfarin all effectively blocked the reaction. 2-Mercaptoethanol could not substitute for dithiothreitol.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Prophylactic vitamin K for vitamin K deficiency bleeding in neonates.
BACKGROUND: Vitamin K deficiency can cause bleeding in an infant in the first weeks of life. This is known as Hemorrhagic Disease of the Newborn (HDN). HDN is divided into three categories: early, classic and late HDN. Early HDN occurs within 24 hours post partum and falls outside the scope of this review. Classic HDN occurs on days one to seven; common bleeding sites are gastrointestinal, cutaneous, nasal and from a circumcision. Late HDN occurs from week 2-12; the most common bleeding sites are intracranial, cutaneous, and gastrointestinal. Vitamin K is commonly given prophylactically after birth for the prevention of HDN, but the preferred route is uncertain. OBJECTIVES: To review the evidence from randomized trials in order to determine the effectiveness of vitamin K prophylaxis in the prevention of classic and late HDN. Main questions are: Is one dose of vitamin K, given after birth, able to significantly reduce the incidence of classic and late HDN? Is there a significant difference between the oral route and the intramuscular route in preventing classic and late HDN? Are multiple oral doses of vitamin K, given after birth, able to significantly reduce the incidence of classic and late HDN? SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. SELECTION CRITERIA: All trials using random or quasi-random patient allocation, in which methods of vitamin K prophylaxis in infants were compared to each other, placebo or no treatment, were included. DATA COLLECTION AND ANALYSIS: Data were extracted independently by each author and were analysed with the standard methods of the Cochrane Collaboration and its Neonatal Review Group, using relative risk, risk difference and weighted mean difference. MAIN RESULTS: Two eligible randomized trials, each comparing a single dose of intramuscular vitamin K with placebo or nothing, assessed effect on clinical bleeding. One dose of vitamin K reduced clinical bleeding at 1-7 days, including bleeding after circumcision, and improved biochemical indices of coagulation status. Eleven additional eligible randomized trials compared either a single oral dose of vitamin K with placebo or nothing, a single oral with a single intramuscular dose of vitamin K, or three oral doses with a single intramuscular dose. None of these trials assessed clinical bleeding. Oral vitamin K improved biochemical indices of coagulation status at 1-7 days. There was no evidence of a difference between the oral and intramuscular route in effects on biochemical indices of coagulation status. A single oral compared with a single intramuscular dose resulted in lower plasma vitamin K levels at two weeks and one month, whereas a 3-dose oral schedule resulted in higher plasma vitamin K levels at two weeks and at two months than did a single intramuscular dose. REVIEWER'S CONCLUSIONS: A single dose (1.0 mg) of intramuscular vitamin K after birth is effective in the prevention of classic HDN. Either intramuscular or oral (1.0 mg) vitamin K prophylaxis improves biochemical indices of coagulation status at 1-7 days. Neither intramuscular nor oral vitamin K has been tested in randomized trials with respect to effect on late HDN. Oral vitamin K, either single or multiple dose, has not been tested in randomized trials for its effect on either classic or late HDN.
Humans↗
R- and S-Warfarin inhibition of vitamin K and vitamin K 2,3-epoxide reductase activities in the rat.
Reduction of vitamin K 2,3-epoxide and vitamin K catalyzed by hepatic microsomal enzymes is required for normal, postribosomal, gamma-carboxyglutamate formation in the prothrombin complex Factors II, VII, IX, and X. The R- and S-warfarin enantiomers differentially inhibit (S-warfarin is 2 to 5 times more active) vitamin K function by mechanisms which have not been unambiguously determined. As a step toward determining the physiologically relevant site(s) of warfarin-antivitamin K activity we investigated in Wistar rats the effects of R- and S-warfarin on vitamin K 2,3-epoxide and vitamin K reductase activities and correlated them with effects on plasma concentrations of the Factors II, VII, and X. Based on the results of these studies we conclude that: 1) warfarin inhibition of the vitamin K 2,3-epoxide and vitamin K reductases is essentially irreversible; 2) S-warfarin stereoselectively inhibits both reductases in vivo but not in vitro; 3) the vitamin K reductase which utilizes dithiothreitol as cofactor in vitro is primarily responsible for vitamin K reduction to vitamin K hydroquinone under physiological conditions; 4) warfarin initially inhibits gamma-carboxyglutamate formation by inhibiting simultaneously the vitamin K 2,3-epoxide and vitamin K reductases; and 5) following enantiomer administration there is an apparent lack of correlation between the restoration of the reductase activities and the reinitiation of coagulation factor synthesis.
Animals↗
The influence of (R)- and (S)-warfarin, vitamin K and vitamin K epoxide upon warfarin anticoagulation.
The contribution of (R)- and (S)-warfarin enantiomers, vitamin K and vitamin K epoxide and patient factors to inter-individual variability in daily warfarin requirements were examined in a group of 73 patients. Simple correlation analysis showed a significant positive relationship between INR values and plasma (S)-warfarin concentrations (r = 0.25; p = 0.038). Multivariate analysis for relationships with INR demonstrated a highly significant positive relationship between INR and (S)-warfarin (p = 0.004) and plasma vitamin K epoxide concentrations (p = 0.028), and a significant negative relationship between INR and plasma vitamin K concentrations (p = 0.034). Twenty five percent of variation in INR could be explained by these variables (adjusted R2 = 0.25). Correlation analysis of data showed that warfarin dosage was significantly and negatively correlated with patient age (r = -0.42; p <0.0001). Patient age accounted for 25% of variation in warfarin dosage requirements (R2 = 0.25). The combined effects of age and vitamin K appear to account for much of the inter-individual variability in warfarin dosage requirements.
Adult↗
A comprehensive review of vitamin K and vitamin K antagonists.
For more than 60 years, vitamin K-dependent proteins have been known to play an important role in regulating blood coagulation. During recent years it has become clear, however, that vitamin K is also involved in other physiologic processes, including bone metabolism and vascular biology. Because the vitamin K requirement of bone and vessel wall is higher than that of the liver (where the clotting factors are produced) recommended daily allowance (RDA) values for K vitamins must be redefined. According to the new definition, a substantial part of the population is mildly deficient in vitamin K, and at later ages this deficiency may contribute to increased bone fracture risk, arterial calcification, and cardiovascular disease.
Blood Coagulation↗
Comparative effects of vitamin K and vitamin D supplementation on calcium balance in young rats fed normal or low calcium diets.
We examined the effect of vitamin K and vitamin D supplementation on calcium balance in young rats fed a normal or low calcium diet. Eighty female Sprague-Dawley rats, 6 wk of age, were randomized by the stratified weight method into eight groups with 10 rats in each group: 0.5% (normal) or 0.1% (low) calcium diet, 0.5% or 0.1% calcium diet+vitamin K (vitamin K2, menatetrenone, 30 mg/100 g, food intake), 0.5% or 0.1% calcium diet+vitamin D (25 microg/100 g, food intake), and 0.5% or 0.1% calcium diet+vitamin K+vitamin D. The duration of the study was 10 wk. Vitamin K supplementation promoted the reduction in urinary calcium excretion and retarded the abnormal elevation of serum PTH level in rats fed a low calcium diet, and stimulated intestinal calcium absorption in rats fed a normal calcium diet. Vitamin D supplementation stimulated intestinal calcium absorption with prevention of the abnormal elevation of serum PTH levels and prevented hypocalcemia in rats fed a low calcium diet, and stimulated intestinal calcium absorption in rats fed a normal calcium diet. The stimulation of intestinal calcium absorption was associated with increased serum 1,25-dihydroxyvitamin D levels. An additive effect of vitamin K and vitamin D on intestinal calcium absorption was found only in rats fed a normal calcium diet. This study shows the differential effects of vitamin K and vitamin D supplementation on calcium balance in young rats fed a normal or low calcium diet.
Animals↗
Relationship of dithiothreitol-dependent microsomal vitamin K quinone and vitamin K epoxide reductases inhibition of epoxide reduction by vitamin K quinone.
Vitamin K quinone was shown to be an effective inhibitor of vitamin K epoxide reduction by whole rat liver microsomes. Observation of inhibition was dependent upon the mode of addition of the substrate and inhibitor suggesting segregation of the compounds into different microsomal vesicles under certain conditions. The result is consistent with reduction of both vitamin K quinone and vitamin K epoxide by a single enzyme or a multisite enzyme complex.
Animals↗
Current concepts and controversies in the use of vitamin K.
Vitamin K is a fat-soluble vitamin crucial to the production of many proteins involved with the coagulation process. It is integral in the synthesis of coagulants (factors II, VII, IX and X) and anticoagulants (proteins C and S). It is generally recognised that routine administration of vitamin K (phytomenadione) shortly after birth will prevent major neonatal morbidity and mortality related to haemorrhage. Vitamin K supplementation during pregnancy is also recommended if mothers are on anticonvulsant therapy or prolonged treatment with certain antibiotics. These medications, if ingested by pregnant women, predispose the neonate to a bleeding tendency caused by vitamin K deficiency. Vitamin K treatment of pregnant mothers before premature delivery has also been suggested to reduce the incidence of severe intracranial haemorrhage (ICH) in premature neonates. Although further studies are pending, the data to date do not support using antenatal vitamin K for preventing ICH.
Anticonvulsants↗
Inhibition by warfarin enantiomers of prothrombin synthesis, protein carboxylation, and the regeneration of vitamin K from vitamin K epoxide.
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Animals↗
The mechanism of action of vitamin K.
Vitamin K is the blood-clotting vitamin. The mechanism of action of vitamin K is discussed in terms of a new carbanion model that mimics the proton abstraction from the gamma position of protein-bound glutamate. This is the essential step leading to carboxylation and activation of the blood-clotting proteins. The model comprises an oxygenation that is coupled to carbon-carbon bond formation, as is the oxygenation of vitamin K hydroquinone to vitamin K oxide. The model hypothesis is also supported by the mechanism of inhibition of the carboxylase by HCN, which acts as an acid-base inhibitor rather than a metal-complexing inhibitor. The new model postulates a dioxetane intermediate that explains the presence of a second atom of 18O (from 18O2) incorporated into vitamin K oxide in the course of the enzymatic carboxylation. Finally, the chemistry developed here has been used to define the active site of vitamin K hydroquinone as the carbon-carbon bond adjacent to the methyl group.
Animals↗
Why we need a clinical trial for vitamin K.
Vitamin K is given to many babies born in the United Kingdom, but we still do not know if it has substantial hazards. Because the population exposed to vitamin K is very large even quite small hazards would involve many adverse events. It is therefore important to be able to put reasonably close bounds on the potential damage that vitamin K prophylaxis could cause. Past research has not allowed us to do this but a large randomised controlled clinical trial of vitamin K against no vitamin K, enrolling only infants at low risk of haemorrhagic disease, would do so. There is no question that vitamin K is a useful treatment in babies at highest risk of haemorrhagic disease: the question is whether the trend towards use of vitamin K in lower risk babies should be encouraged.
Adolescent↗
[Vitamin K].
Vitamin K has several biological functions in which the major role is a cofactor for gamma-carboxylation of glutamate residues in Gla proteins, such as, several coagulant and anticoagulant proteins for blood clotting. This enzymatic process can be wholly dissolved. If adequate amounts of vitamin K are absent or anticoagulant drugs are administered, this process will be incomplete and abnormal proteins will appear in the blood. Recently, it was found that this carboxylation is blocked by the antibiotics having the N-methyltetrazolethiol group. These antibiotics inhibit vitamin K epoxide reductase, stop the recycling of vitamin K and cause vitamin K deficiency. Vitamin K is also necessary for biosynthesis of osteocalcin, which is a important protein in the normal function of the bone.
Animals↗
Differential effect of vitamin K and vitamin D supplementation on bone mass in young rats fed normal or low calcium diet.
The purpose of this study was to clarify the differential effect of vitamin K and vitamin D supplementation on bone mass in young rats fed a normal or low calcium diet. Ninety female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into nine groups with 10 rats in each group: baseline control, and 0.5% (normal) or 0.1% (low) calcium diet, either alone, or with vitamin K (30 mg/100g, food intake), vitamin D (25 micro g/100 g, food intake), or vitamin K + vitamin D. After 10 weeks of feeding, bone histomorphometric analyses were performed on cortical bone of the tibial shaft and cancellous bone of the proximal tibia. Vitamin K supplementation increased the maturation-related cancellous bone gain and retarded the reduction in the maturation-related cortical bone gain in rats fed a low calcium diet, and increased the maturation-related cortical bone gain in rats fed a normal calcium diet. Vitamin D supplementation reduced the maturation-related cancellous bone gain, prevented the reduction in periosteal bone gain, and enhanced the enlargement of the marrow cavity, with no significant effect on the reduction in the maturation-related cortical bone gain in rats fed a low calcium diet, and increased the maturation- related cancellous and cortical bone gains with increased periosteal bone gain in rats fed a normal calcium diet. An additive effect of vitamin K and vitamin D on the maturation- related cortical bone gain was found in rats fed a normal calcium diet. This study shows the differential effects of vitamin K and vitamin D supplementation on cancellous and cortical bone mass in young rats fed a normal or low calcium diet, as well as the additive effect on cortical bone under calcium sufficient condition.
Age Factors↗
Management of osteoporosis: is there a role for vitamin K?
Vitamin K is required for the biological activity of several coagulation factors, which is considered as the classical function of vitamin K. Recent research, however, suggests a role of vitamin K in bone metabolism. The metabolic role of vitamin K is to facilitate the carboxylation of glutamyl to gamma-carboxyglutamyl residues. Besides the hepatic tissue, in which the clotting factors are produced gamma-carboxyglutamyl-containing proteins are also abundantly available in bone tissue. Osteocalcin accounts for up to 80% of the total gamma-carboxyglutamyl content of mature bone. Human carboxylated osteocalcin contains 3 gamma-carboxyglutamyl residues which confer a highly specific affinity to the calcium ion of the hydroxyapatite molecule. Besides the gamma-carboxylation of osteocalcin vitamin K may also affect other parameters of bone metabolism, such as calcium hemostasis, and prostaglandin E2 and interleukin 6 production. Evidence from observational studies and first intervention trials indicate that vitamin K intakes much higher than the current recommendations improved biochemical markers of bone formation as well as bone density. In conclusion, the mechanistic data as well as the observational data and the results of the first controlled clinical trials in humans point to a beneficial effect of additional intakes of vitamin K in bone health.
Bone Density↗
[Effect of certain active vitamin K and vitamin K antagonistic substances on growth of wheat].
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Antifibrinolytic Agents↗