Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver microsomes contain a specific warfarin binding site that is related to the target enzyme vitamin KO reductase [Thijssen HHW and Baars LGM, Biochem Pharmacol 38: 1115-1120, 1989]. In this study the distribution of the warfarin binder in the rat was investigated. Rats were given tracer doses of [14C]warfarin and tissue distribution was estimated after a time period. The selectivity of the distribution was verified by the ability of unlabeled warfarin to displace in vivo the tissue accumulated [14C]warfarin. The relation to the target enzyme vitamin KO reductase was verified by comparing the results with distribution behavior in the Scottish warfarin-resistant rat strain. The results show that in addition to liver various non-hepatic tissues accumulate warfarin. Among the tissues having a high accumulation ratio and a high rate of exchange by unlabeled warfarin are liver, pancreas, kidney, and salivary gland. Also arteria (aorta), bone, lung and spleen show exchangable [14C]warfarin accumulation. In HS rats the [14C]warfarin distribution was affected similarly for all tissues; lower levels of accumulation and higher rates of exchange by unlabeled warfarin. The tissue-bound warfarin was recovered predominantly in the microsomal fraction. Its release could only be accomplished in the presence of dithiothreitol and appeared to be stereoselective. The in vivo distribution pattern correlated with the number of warfarin binding sites in the tissue microsomes. The microsomal vitamin KO reductase activity did not always correlate to the binding capacity. The distribution was not affected by vitamin K deficiency. Warfarin-treated rats showed vitamin K epoxide accumulation in most of the organs having the warfarin binder.
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PMID:Tissue distribution of selective warfarin binding sites in the rat. 195 36

In three patients treated with cephalosporins (one patient with latamoxef, two patients with cefazedone) vitamin K1 was injected to investigate whether this was followed by an increase in vitamin K1 2,3-epoxide plasma concentrations as compared to controls. Such a rise in K1-epoxide concentrations in the plasma can be demonstrated following treatment with coumarins. This reflects an inhibition of the vitamin K1-epoxide reductase in the liver. Coumarins are thought to induce hypoprothrombinaemia by such a mechanism. In all three patients we found a considerable increase in the vitamin K1-epoxide plasma concentrations following injection of 10 mg vitamin K1, whereas in normal subjects only traces of K1-epoxide could be detected (less than 0.030 micrograms/ml). The K1-epoxide concentrations found in our three patients treated with cephalosporins were 0.12, 0.16 and 0.19 micrograms/ml, respectively. This indicates that latamoxef or cefazedone might reduce clotting factor synthesis by a coumarin-like mechanism of action in these patients. Although the effect of cephalosporins in enhancing vitamin K1-epoxide plasma concentrations is less than that of coumarins, it might cause severe hypoprothrombinaemia in the presence of latent vitamin K deficiency.
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PMID:Possible coumarin-like mechanism of action for cephalosporins. 649 97

Three unrelated infants presented with radiographic punctate calcifications, nasal hypoplasia, and abnormalities of the spine. Additional anomalies included cupped ears in 2 patients and one each with Dandy-Walker malformation with hydrocephaly, congenital cataracts, and peripheral pulmonary artery stenosis. The mothers of these 3 patients had chronic conditions associated with intestinal malabsorption requiring total parenteral nutrition for varying periods of time. The underlying causes of malabsorption were celiac disease, short bowel syndrome secondary to surgical resection, and jejuno-ileal bypass, respectively. Bleeding diathesis occurred in one mother requiring vitamin K supplementation during the second and third trimesters of pregnancy. We speculate that the chondrodysplasia punctata and other abnormalities in these children were caused by an acquired maternal vitamin K deficiency manifested during early pregnancy. However, the involvement of other vitamin deficiencies cannot be excluded. Thus, vitamin K deficiency of the embryo secondary to maternal malabsorption appears to be a third vitamin K-related mechanism leading to chondrodysplasia punctata in addition to warfarin embryopathy and epoxide reductase deficiency (pseudo-warfarin embryopathy).
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PMID:Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. 938 32

Newborns are susceptible to hemorrhages (hemorrhagic disease of the newborn or HDN) due to vitamin K deficiency. Induction of cytochrome P450 in the fetal liver by maternal anticonvulsant therapy such as phenobarbital or phenytoin is considered to be a major cause. An observed increase in late hemorrhagic disease (LHD) in breast fed neonates gave rise to the hypothesis that PCBs and dioxins, P450-inducing contaminants present in human milk, might effect vitamin K-dependent blood coagulation. This hypothesis was studied in rats. Administration of a single oral dose of 0.003, 0.03, 0.3, 3 or 30 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) per kg bodyweight or 0.75, 4, 20, 100 or 500 micromol 2,2',4,4',5,5'-hexachlorobiphenyl/kg bw (HxCB) to female and male rats resulted in dose-related reductions of the vitamin K-dependent coagulation factor VII. The highest factor VII reduction in female rats was 44%, observed after TCDD exposure. The Lowest Observed Adverse Effect Level (LOAEL) of TCDD on female factor VII levels was 0.3 nmol/kg bw (96 ng/kg). There was a significant inverse correlation between Factor VII levels and induction of hepatic ethoxyresorufin O-deethylating (EROD) activity, reflecting CYP1A1, and total P450 content. HxCB had no effect on female coagulation factors. In contrast, in male rats only exposure to HxCB, which induces mainly CYP2B1 and 2B2, decreased both coagulation factors dramatically up to 88%. The LOAEL of HxCB on factor VII in male rats was 100 micromol/kg bw (36 mg/kg). In general, effects on coagulation factors in male rats exceeded those in females. In addition, sex-dependent differences of TCDD and HxCB were observed on the hepatic vitamin K cycle enzyme activities in female and male rats. Vitamin K-dependent (gamma-glutamyl carboxylase activity was mainly induced in female rats; 2.3-fold in the highest dose group of TCDD. In male rats only vitamin K 2,3-epoxide reductase (KO-reductase) activity was induced 1.7-fold by the highest dose of HxCB. KO-reductase activity in female rats was also increased by TCDD, however, less pronounced than the carboxylase activity. Concluding, the hepatic vitamin K cycle still functions and is not blocked by TCDD or HxCB, thus explaining the observed reduction in factor VII. Finally, the possible role of P450 in vitamin K deficiency is discussed. Based on these results it is suggested to investigate the possible role of PCBs and dioxin-like compounds in LHD in more detail.
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PMID:Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,2',4,4',5,5'-hexachlorobiphenyl on vitamin K-dependent blood coagulation in male and female WAG/Rij-rats. 1090 69

Our objective was to characterize the etiologic factors and outcome for stroke in children. We retrospectively reviewed the charts of patients between the ages of 40 days and 94 months (36.5 +/- 23.7 months) with stroke seen at Istanbul Medical Faculty, Department of Pediatrics between January 1995 and December 2003. We found 79 cases of stroke: 57 ischemic and 22 hemorrhagic strokes. Seventeen children had vitamin K deficiency dependent hemorrhage. In 14 children stroke occurred as a complication of cardiac disease, 7 had moyamoya disease, 3 had protein C deficiency, 2 had thalassemia, 2 had hyperhomocysteinemia (methylene tetrahydrofolate reductase gene mutation), 2 were heterozygote for factor V Leiden, 3 had Down's syndrome, 1 was diagnosed with antiphospholipid syndrome, 1 had glycogen storage disease, and in 28 children no underlying cause could be found. Multiple risk factors were found in 4 children. The outcome in all 79 stroke patients was as follows: asymptomatic 60%; symptomatic epilepsy or persistent neurologic deficit 37%; death 3%; and recurrent stroke 5%. Thus, an underlying cause for stroke was identified in 65% of the children in the study group; 40% of the children either died or suffered motor and/or cognitive sequelae.
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PMID:Stroke in childhood: experience in Istanbul, Turkey. 1663 11

Relatively little is known about the vitamin K status and requirements in term and preterm infants, though hemorrhagic disease of the newborn infant continues to be a worldwide problem. This brief review of vitamin K metabolism, vitamin K dependent proteins, and the vitamin K cycle covers some new thoughts about the importance of vitamin K to human health including the preterm infant. A review of perinatal vitamin K metabolism concludes that little vitamin K actually crosses the placenta from mother to infant. The neonatal sources of vitamin K are generally limited to the vitamin K prophylaxis given at the time of birth, dietary sources, and questionable amounts from vitamin K present in the intestinal tract synthesized from bacteria. Preterm infants receive large quantities of vitamin K from prophylaxis, TPN solutions, infant formula and breast milk fortifiers. Thus, vitamin serum concentration in preterm infants is up to one hundred times higher than those found in adults and 10-20 times those found in term formula-fed infants. Though no toxicity has been reported, the elevation of epoxide reductase (VKOR) from the vitamin K cycle found in the serum of preterm infants is worthy of additional study. PIVKA-II (abnormal prothrombin) is not a reliable indicator of vitamin K deficiency in preterm or term infants.
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PMID:Vitamin K the basics--what's new? 2011 43

Atherosclerosis is the main cause of morbidity and mortality in the general population, and premature death in patients with chronic kidney disease (CKD) especially dialysis ones. Besides the typical cardiovascular risk factors there is a considerable vascular calcification of intima media in these patients. Vitamin K - dependent proteins play an essential role in the pathogenesis of mineral and bone disorders related to CKD, including vascular calcification. Vitamin K is a family of vitamins, varying in the number of isoprenoid groups (saturated or unsaturated) connected into 2-methyl-1,4-naphthoquinone ring in C3 position. Vitamin K-dependent proteins require carboxylation (VKDPs) for biological activation. The coagulant factors are the most well-known VKDPs, but the role of the other proteins, like Matrix Gla Protein (MGP), Growth Arrest Specific Gene 6 (Gas-6) and osteocalcin has been recently discovered. MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Carboxylation of osteocalcin promotes bone formation. Additionally vitamin K increases proliferation of osteoblasts and apoptosis of osteoclasts, influencing on bone remodeling. There is few studies indicating for decreased consumption of vitamin K in the general population. The restrictive diet recommended for dialysis patients additionally diminishes its daily supply, increasing the chance for vitamin K deficiency in this population. Clinical consequences of inhibition of epoxide reductase by generally used anticoagulants, that inhibiting vitamin K cycle and preventing gamma-carboxylation of Gla proteins, in the peripheral tissue is hardly known. This paper summaries the state of the art knowledge focused on the role of vitamin K in mineral and bone metabolism disorders in CKD patients.
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PMID:[Vitamin K, bone metabolism and vascular calcification in chronic kidney disease]. 2233 14