vitamin-k-semiquinone-radical and Metabolism--Inborn-Errors

Topics: Anti-Bacterial Agents; Antifibrinolytic Agents; Communication; Erythromycin; Hearing Tests; Hepatitis B Vaccines; Humans; Infant, Newborn; Injections, Intramuscular; Metabolism, Inborn Errors; Neonatal Screening; Nurseries, Hospital; Ointments; Ophthalmia Neonatorum; Parents; Primary Prevention; Professional-Family Relations; Treatment Refusal; Vaccination Refusal; Vitamin K

Warfarin resistance is a phenomenon that patients need to take much higher than normally prescribed dosage of warfarin to maintain the target therapeutic international normalized ratio (INR) range, or even fail to reach the target INR. Warfarin resistance can be categorized in etiologic terms as hereditary vs acquired, or in pharmacologic terms as pharmacokinetic vs pharmacodynamic. Once warfarin resistance is diagnosed, the type of resistance should be determined as soon as possible so that treatment could be oriented toward the causes. Poor compliance, genetic mutations, concurrent medications that could decrease the absorption or increase the clearance of warfarin, and consumption of diet rich in vitamin K are the major reasons for warfarin resistance. Educating patients, increasing warfarin dosage and switching to other anticoagulants would be effective for warfarin resistance.

Topics: Anticoagulants; Drug Monitoring; Female; Humans; International Normalized Ratio; Male; Metabolism, Inborn Errors; Vitamin K; Vitamin K Epoxide Reductases

We report a child with an isolated complex III respiratory chain deficiency and global developmental delay who had severe pruritus with elevated plasma bile acid levels. A liver biopsy showed micronodular cirrhosis, and enzymologic evaluation demonstrated an isolated complex III deficiency in both liver and muscle. His pruritus improved and serum bile acid levels decreased after treatment with menadione and vitamin C.

Topics: Anemia, Iron-Deficiency; Ascorbic Acid; Bile Acids and Salts; Child, Preschool; Developmental Disabilities; Drug Therapy, Combination; Electron Transport; Electron Transport Complex III; Humans; Male; Metabolism, Inborn Errors; Pruritus; Vitamin K

Topics: Avitaminosis; Chemical Phenomena; Chemistry; Humans; Metabolism, Inborn Errors; Nutritional Requirements; Vitamin A; Vitamin A Deficiency; Vitamin D; Vitamin D Deficiency; Vitamin E; Vitamin E Deficiency; Vitamin K; Vitamin K Deficiency; Vitamins

Warfarin is a rodenticide commonly used worldwide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. Recently, warfarin-resistant brown rats (Rattus norvegicus) were found around the Aomori area of Japan. There is no significant difference in the metabolic activity of warfarin in sensitive and resistant brown rats. To clarify the mechanism underlying warfarin resistance, we cloned the VKORC1 gene from rats and identified a novel substitution of arginine to proline at position 33 of the VKORC1 amino acid sequence. Then, we determined the differences in kinetics of VKOR activity between warfarin-resistant and sensitive rats. Hepatic microsomal VKOR-dependent activity was measured over a range of vitamin K epoxide concentrations from 6.25 to 150 µM. The Vmax values of resistant rats (0.0029 ± 0.020 nmol/min/mg) were about one tenth of those of sensitive rats (0.29 ± 0.12 nmol/min/mg). The Km values of resistant rats (47 ± 32 µM) were similar to those of sensitive rats (59 ± 18 µM). Warfarin-sensitive rats exhibited enzyme efficiencies (Vmax/Km) which were ten-fold greater than those observed in resistant rats. It may mean that VKOR activity of warfarin-resistant Aomori rats is almost lost, because their enzymatic efficiencies are very low even without warfarin. Further studies are needed to clarify how these rats can survive with a markedly reduced VKOR activity and how they simultaneously exhibit warfarin resistance.

Topics: Animals; Female; Gene Expression Regulation, Enzymologic; Japan; Male; Metabolism, Inborn Errors; Mixed Function Oxygenases; Mutation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rodenticides; Vitamin K; Vitamin K 1; Vitamin K Epoxide Reductases; Warfarin

Topics: Biomarkers; Child, Preschool; Consanguinity; Humans; Lactates; Liver; Male; Metabolism, Inborn Errors; Muscles; NAD(P)H Dehydrogenase (Quinone); Quinone Reductases; Vitamin K

Topics: Bone and Bones; Cartilage; Child; Chondrodysplasia Punctata; Female; Humans; Metabolism, Inborn Errors; Mixed Function Oxygenases; Nose; Pregnancy; Teratogens; Vitamin K; Vitamin K Epoxide Reductases; Warfarin

The bioenergetic capacity of skeletal muscle in a 17-year-old patient with a severe defect in complex III of the electron transport chain has been examined by 31P NMR measurements of the molar ratio of phosphocreatine to inorganic phosphate (PCr/Pi). Resting ratios were 1.3-2.5, which can be compared with roughly 8.6 for a young, normal female control at rest. Quantitative evaluation of the activity of oxidative metabolism was afforded by the rate of recovery of PCr/Pi from exercise and was found to be 2.5% of normal. After administration of menadione and ascorbate, we found a 21-fold increase of the recovery rate relative to the pretherapy value, to within 56% of the recovery rate of the young female control. Thus, NMR examinations of skeletal muscle at rest and in recovery from activity document marked improvement to specific drug therapy in the electron transport capabilities and the ATP synthesis rate of a patient with a deficiency in a cytochrome b-containing complex III. Improvements in functional ability, although not as dramatic as biochemical changes, are also apparent.

Topics: Adenosine Triphosphate; Ascorbic Acid; Electron Transport; Humans; Magnetic Resonance Spectroscopy; Metabolism, Inborn Errors; Mitochondria, Muscle; Oxidative Phosphorylation; Phosphocreatine; Vitamin K

Topics: Ascorbic Acid; Birth Weight; Breast Feeding; Gastroenteritis; Humans; Hypernatremia; Infant Food; Infant Nutrition Disorders; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Newborn, Diseases; Metabolism, Inborn Errors; Respiratory Tract Infections; Tetany; Vitamin A; Vitamin D; Vitamin K; Vomiting

Topics: Adult; Age Factors; Alkaline Phosphatase; Body Height; Child; Child, Preschool; Cholestasis; Consanguinity; Edema; Fats; Feces; Female; Hemorrhage; Heterozygote; Humans; Hyperbilirubinemia; Hyperlipidemias; Infant; Infant, Newborn; Liver; Malabsorption Syndromes; Male; Metabolism, Inborn Errors; Pedigree; Pruritus; Tooth Discoloration; Transaminases; Vitamin K

Topics: Ascorbic Acid; Dihydrolipoamide Dehydrogenase; Drug Therapy; Erythrocytes; Humans; Metabolism, Inborn Errors; Methemoglobin; Methemoglobinemia; Methylene Blue; NAD; Sulfites; Vitamin K; Vitamin K 3