vitamin-k-1 and coumarin

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.

Topics: Animals; Blood Coagulation; Calcium; Carbon-Carbon Ligases; Coumarins; Homeostasis; Humans; Mixed Function Oxygenases; Osteoporosis; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamin K Epoxide Reductases

Dicumarinic oral anticoagulants have a narrow therapeutic range and a great individual variability in response, which makes calculation of the correct dose difficult and critical. Genetic factors involved in this variability include polymorphisms of genes that encode the metabolic enzyme CYP2C9 and the target enzyme vitamin K epoxide reductase complex 1 (VKORC1); these polymorphisms can be associated with reduced enzymatic expression. We examined the frequency of the most relevant variants encoding CYP2C9 (alleles *1, *2 and *3) and VKORC1 (SNP -1639A>G) in the Argentinian population. Molecular typing was performed by PCR-RFLP on a randomly selected sample of 101 healthy volunteers from the Hospital Italiano de Buenos Aires gene bank. Fifty-seven subjects were identified as homozygous for CYP2C9*1 and 14 for *2, while 24 and 5 were heterozygous for *2 and *3 alleles; one individual was a composite heterozygote (*2/*3). When we examined VKORC1, 21 subjects were AA homozygous, 60 were AG heterozygotes and 20 were GG homozygotes. This is the first analysis of genotypic frequencies for CYP2C9 and VKORC1 performed in an Argentinian population. These allele prevalences are similar to what is known for Caucasian population, reflecting the European ancestor of our patient population, coming mostly from Buenos Aires city and surroundings. Knowledge of this prevalence information is instrumental for cost-effective pharmacogenomic testing in patients undergoing oral anticoagulation treatment.

Topics: Adult; Aged; Anticoagulants; Argentina; Aryl Hydrocarbon Hydroxylases; Coumarins; Cytochrome P-450 CYP2C9; Drug Administration Schedule; Female; Gene Frequency; Genetic Variation; Genotype; Humans; Male; Middle Aged; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Single Nucleotide; Vitamin K 1; Vitamin K Epoxide Reductases; Warfarin; Young Adult

Coumarin and homologous compounds are the most widely used anticoagulant drugs worldwide. They function as antagonists of vitamin K, an essential cofactor for the posttranslational gamma-glutamyl carboxylation of the so-called vitamin K-dependent proteins. As vitamin K hydroquinone is converted to vitamin K epoxide (VKO) in every carboxylation step, the epoxide has to be recycled to the reduced form by the vitamin K epoxide reductase complex (VKOR). Recently, a single coumarin-sensitive protein of the putative VKOR enzyme complex was identified in humans (vitamin K epoxide reductase complex subunit 1, VKORC1). Mutations in VKORC1 result in two different phenotypes: warfarin resistance (WR) and multiple coagulation factor deficiency type 2 (VKCFD2). Here,we report on the expression of site-directed VKORC1 mutants, addressing possible structural and functional roles of all seven cysteine residues (Cys16, Cys43, Cys51, Cys85, Cys96, Cys132, Cys135), the highly conserved residue Ser/Thr57, and Arg98, known to cause VKCFD2 in humans. Our results support the hypothesis that the C132-X-X-C135 motif in VKORC1 comprises part of the redox active site that catalyzes VKO reduction and also suggest a crucial role for the hydrophobic Thr-Tyr-Ala motif in coumarin binding. Furthermore, our results support the concept that different structural components of VKORC1 define the binding sites for vitamin K epoxide and coumarin.

Topics: Amino Acid Sequence; Anticoagulants; Binding Sites; Cell Line; Coumarins; Disulfides; Drug Resistance; Humans; Hydrophobic and Hydrophilic Interactions; Kidney; Mixed Function Oxygenases; Molecular Sequence Data; Mutagenesis, Site-Directed; Vitamin K 1; Vitamin K Epoxide Reductases

Topics: Administration, Oral; Anticoagulants; Coumarins; Female; Follow-Up Studies; Humans; Male; Prospective Studies; Risk; Thrombosis; Time Factors; Vitamin K 1; Warfarin

Clinical use of antibiotics containing a N-methyl-thiotetrazole (NMTT) side chain has been reported to be associated with an increased incidence of a vitamin K-responsive hypoprothrombinemia. Administration of NMTT to rats decreased the activity of the liver microsomal vitamin K epoxide reductase, increased the liver ratio of vitamin K epoxide to vitamin K, and decreased the rate of metabolism of injected vitamin K epoxide. These responses are the same as those observed following the administration of coumarin anticoagulants. In contrast to the effect of coumarin anticoagulants, NMTT did not inhibit the vitamin K epoxide reductase in vitro. These data suggest that the hypoprothrombinemia which has been observed following use of these antibiotics results from the inactivation of the liver vitamin K epoxide reductase by NMTT or a NMTT metabolite.

Topics: Animals; Azoles; Coumarins; Cytosol; Dithiothreitol; Hypoprothrombinemias; Male; Microsomes, Liver; Mixed Function Oxygenases; Rats; Tetrazoles; Vitamin K; Vitamin K 1; Vitamin K Epoxide Reductases; Warfarin

Topics: Coumarins; Drug Resistance; Food, Formulated; Humans; Netherlands; Vitamin K 1

Topics: Anticoagulants; Coumarins; Humans; Male; Metabolism; Pharmacology; Prothrombin Time; Vitamin K 1; Warfarin

Topics: Anticoagulants; Coumarins; Humans; Inorganic Chemicals; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Heparin Antagonists; Humans; Hypoprothrombinemias; Naphthoquinones; Prothrombin; Retinoids; Vitamin K; Vitamin K 1

Topics: Accidents; Anticoagulants; Antifibrinolytic Agents; Coumarins; Hemorrhage; Humans; Thrombosis; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Humans; Thromboplastin; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Antidotes; Coumarins; Female; Genital Diseases, Female; Hemorrhage; Humans; Thrombophlebitis; Vitamin K; Vitamin K 1

Topics: Administration, Intravenous; Anticoagulants; Antidotes; Coumarins; Dicumarol; Hemorrhagic Disorders; Hypoprothrombinemias; Prothrombin; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Hemorrhage; Humans; Naphthoquinones; Phenprocoumon; Retinoids; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Coumarins; Female; Genitalia; Genitalia, Female; Gynecology; Humans; Thromboembolism; Vitamin K; Vitamin K 1

Topics: 4-Hydroxycoumarins; Anticoagulants; Antidotes; Antifibrinolytic Agents; Coumarins; Dicumarol; Hemostatics; Vitamin K; Vitamin K 1

Topics: 4-Hydroxycoumarins; Anticoagulants; Antidotes; Coumarins; Female; Hemostatics; Humans; Phenprocoumon; Prothrombin Time; Thrombophlebitis; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Ethyl Biscoumacetate; Heparin Antagonists; Naphthoquinones; Phenindione; Thromboembolism; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Hemorrhage; Naphthoquinones; Poisoning; Retinoids; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Antidotes; Blood Coagulation; Coumarins; Dicumarol; Hemostatics; Humans; Prothrombin Time; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Antifibrinolytic Agents; Coumarins; Female; Genitalia; Genitalia, Female; Humans; Hypoprothrombinemias; Phenprocoumon; Postpartum Period; Prothrombin; Thrombophlebitis; Vitamin K; Vitamin K 1

Topics: Antidotes; Antifibrinolytic Agents; Coumarins; Heparin Antagonists; Naphthoquinones; Retinoids; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Ethyl Biscoumacetate; Hemostatics; Humans; Hypoprothrombinemias; Injections, Intravenous; Retinoids; Vitamin K; Vitamin K 1

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Hemorrhagic Disorders; Heparin Antagonists; Hypoprothrombinemias; Naphthoquinones; Vitamin K; Vitamin K 1; Vitamin K 3

Topics: Anticoagulants; Capillaries; Cardiovascular System; Coumarins; Phenprocoumon; Prothrombin Time; Vitamin K 1

Topics: Coumarins; Fibrinolytic Agents; Humans; Vitamin K; Vitamin K 1

Topics: Antidotes; Coumarins; Dicumarol; Female; Hemostatics; Humans; Vitamin K; Vitamin K 1

Topics: Anticoagulants; Coumarins; Dicumarol; Ethyl Biscoumacetate; Hemostatics; Humans; Hypoprothrombinemias; Phenindione; Prothrombin; Vitamin K; Vitamin K 1; Vitamin K 3

Topics: Antifibrinolytic Agents; Coumarins; Dicumarol; Hemostatics; Humans; Hypoprothrombinemias; Naphthoquinones; Prothrombin; Retinoids; Vitamin K; Vitamin K 1; Vitamin K 2

Topics: Animals; Antifibrinolytic Agents; Blood Coagulation; Cats; Coumarins; Dicumarol; Hypoprothrombinemias; Liver; Rabbits; Vitamin K; Vitamin K 1

Topics: Administration, Intravenous; Antifibrinolytic Agents; Coumarins; Dicumarol; Emergencies; Emulsions; Naphthoquinones; Prothrombin; Vitamin K; Vitamin K 1