Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT02288 (NADH)
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Report on a further hemoglobin M variant, discovered in a boy with congenital cyanosis. Chemical analysis of hemoglobin structure revealed indentity with HbM Saskatoon (= beta63 His leads to Tyr). The abnormal hemoglobin is characterized by normal oxygen transport function. The observed slight constant hemolysis is thought to be due to increased instability of the abnormal hemoglobin molecule. In addition to the hemoglobin anomaly, the activity of NADH-methemoglobin reductase was reduced by approximately 40% of normal. None of the parents presented with an abnormal hemoglobin, indicating that the occurrence of hemoglobin M Erlangen is most likely the result of a new mutation.
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PMID:[HbM Erlangen: alpha2beta263(e7) tyr. New mutation with haemolysis and NADH-methaemoglobin reductase deficiency (author's transl)]. 116 74

Two cases of the congenital methemoglobinemia in children due to the deficiency of NADH-dependent methemoglobin reductase in erythrocytes. These children were referred to the Cardiological Ward at the Child Health Centre with suspected cyanotic heart defect. Cardiological examinations excluded heart defect but an increased blood methemoglobin level and decreased activity of NADH-dependent methemoglobin reductase were found, that caused methemoglobinemia. Methylene blue and vitamin C diminished cyanosis. These cases advocate inclusion of methemoglobinemia into differential diagnosis of cyanotic disorders especially if there is no evident pathology in cardio-vascular system.
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PMID:[Cyanosis in children caused by inherited methemoglobinemia due to deficiency of NADH-dependent methemoglobin reductase in erythrocytes]. 281 7

Methaemoglobin is haemoglobin with the iron oxidised to the ferric (Fe ) state from the normal (or reduced) ferrous (Fe++) state. Methaemoglobinaemia refers to the presence of greater than the normal physiological concentration of 1 to 2% methaemoglobin in erythrocytes. Methaemoglobin is incapable of transporting oxygen. It has an intense dark blue colour; thus, clinical cyanosis becomes apparent at a concentration of about 15%. The symptoms are manifestations of hypoxaemia with increasing concentrations of methaemoglobin. Concentrations in excess of 70% are rare, but are associated with a high incidence of mortality. Methaemoglobinaemia may be congenital but is most often acquired. Congenital methaemoglobinaemia is of two types. The first is haemoglobin M disease (several variants) which is due to the presence of amino acid substitutions in either the alpha or beta chains. The second type is due to a deficiency of the NADH-dependent methaemoglobin reductase enzyme. This deficiency has an autosomal dominant transmission, and both homozygous and heterozygous forms have been reported. The heterozygous form is not normally associated with clinical cyanosis, but such individuals are more susceptible to form methaemoglobin when exposed to inducing agents. A wide variety of chemicals including several drugs, e.g. the antimalarials chloroquine and primaquine, local anaesthetics such as lignocaine, benzocaine and prilocaine, glyceryl trinitrate, sulphonamides and phenacetin, have been reported to induce methaemoglobinaemia. An intense 'chocolate brown' coloured blood and central cyanosis unresponsive to the administration of 100% oxygen suggests the diagnosis. A simple bedside test using a drop of the patient's blood on filter paper helps to confirm the clinical suspicion. Methaemoglobin can be quantitated rapidly by a spectrophotometric method.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Drug- and chemical-induced methaemoglobinaemia. Clinical features and management. 353 20

Oxygen transport, the major function of hemoglobin, is dependent upon reduced heme iron. In the red cell, the heme iron is maintained in the reduced form by the methemoglobin reduction system. When the balance between oxidation and reduction of heme iron is perturbed due to the presence of excessive oxidants, decreased reducing capacity or the presence of abnormal hemoglobin, methemoglobinemia ensues. In most cases methemoglobinemia is transitory and of no major clinical consequence. Occasionally, however, it can be life threatening and must be rapidly diagnosed and treated. When methemoglobinemia is of hereditary nature, either due to deficiency of red cell NADH-methemoglobin reductase or due to the presence of M hemoglobin, it is a lifelong problem. Since most of these patients do not have major disabling symptoms, the treatment is aimed at correction of cyanosis.
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PMID:Methemoglobinemia. 400 27

A case of NADH-methaemoglobin-reductase deficiency in a 64 year old man with marked cyanosis and without evidence of cardiac or pulmonary diseases is reported. The level of methaemoglobin was 36% and reached 25% after treatment with ascorbic acid. Erythrocyte NADH-methaemoglobin-reductase activity was only 5% of normal value. Some erythrocyte biochemical and enzymatic characteristics have been evaluated. A family study has also been carried out. Our patient has been considered homozygous for NADH-methaemoglobin-reductase deficiency.
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PMID:[Methemoglobinemia; a description of a case of NADH methemoglobulin reductase deficiency]. 725 39

The ferrous iron of hemoglobin is exposed continuously to high concentrations of oxygen and, thereby, is oxidized slowly to methemoglobin, a protein unable to carry oxygen. To restore hemoglobin function, methemoglobin (ferrihemoglobin) must be reduced to hemoglobin (ferrohemoglobin). Under physiological conditions, methemoglobin reduction is accomplished mainly by red cell NADH-cytochrome b5 reductase (NADH-methemoglobin reductase) so efficiently that there is insignificant amounts of methemoglobin in the circulating blood. However, should methemoglobin formation be increased--e.g., due to the presence of oxidant drugs, or an abnormal methemoglobin not amenable to reduction (hemoglobin M), or a deficiency in red cell cytochrome b5 reductase--methemoglobinemia will result. Most methemoglobinemias have no adverse clinical consequences and need not be treated. Under certain conditions, such as exposure to large amounts of oxidant or in young infants, rapid treatment is necessary. In hereditary cytochrome b5 deficiency, treatment is often directed at improving the poor cosmetic effect of persistent cyanosis with the minimum amount of drugs to give satisfactory clinical results.
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PMID:Concise review: methemoglobinemia. 841 1

In normal erythrocytes, small quantities of methaemoglobin are formed constantly and are continuously reduced, almost entirely by the reduced nicotine adenine dinucleotide (NADH) diaphorase system, rather than the reduced nicotine adenine dinucleotide phosphate (NADPH) diaphorase system. Methaemoglobinaemias are usually the result of xenobiotics, either those that may directly oxidise haemoglobin or those that require metabolic activation to an oxidising species. The most clinically relevant direct methaemoglobin formers include local anaesthetics (such as benzocaine and, to a much lesser extent, prilocaine) as well as amyl nitrite and isobutyl nitrite, which have become drugs of abuse. Indirect, or metabolically activated, methaemoglobin formation by dapsone and primaquine may cause adverse reactions. The clinical consequences of methaemoglobinaemia are related to the blood level of methaemoglobin; dyspnoea, nausea and tachycardia occur at methaemoglobin levels of > or = 30%, while lethargy, stupor and deteriorating consciousness occur as methaemoglobin levels approach 55%. Higher levels may cause cardiac arrhythmias, circulatory failure and neurological depression, while levels of 70% are usually fatal. Cyanosis accompanied by a lack of responsiveness to 100% oxygen indicates a diagnosis of methaemoglobinaemia, which should be confirmed using a CO-oximeter. Pulse oximeters do not detect methaemoglobin and may give a misleading impression of patient oxygenation. Methaemoglobinaemia is treated with intravenous methylene blue (methyl-thioninium chloride; ;1 to 2 mg/kg of a 1% solution). If the patient does not respond, perhaps because of glucose-6-phosphate dehydrogenase (G6PD) deficiency or continued presence of toxin, admission to an intensive care unit and exchange transfusion may be required. Dapsone-mediated chronic methaemoglobin formation can be reduced by coadministration of cimetidine to aid patient tolerance. Increasing knowledge and awareness of drug-mediated acute methaemoglobinaemia among physicians should lead to prompt diagnosis and treatment of this potentially life-threatening condition.
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PMID:Drug-induced methaemoglobinaemia. Treatment issues. 882 17

A human pediatric cardiomyocyte cell culture model of chronic cyanosis was used to assess the effects of low oxygen tension on mitochondrial enzyme activity to address the postoperative increase in lactate and decreased ATP in the myocardium and the high incidence of low-output failure with restoration of normal oxygen tension, after technically successful corrective cardiac surgery. Chronically hypoxic cells (PO2 = 40 mmHg for 7 days) exhibited significantly reduced activities for pyruvate dehydrogenase, cytochrome-c oxidase, succinate cytochrome c reductase, succinate dehydrogenase, and citrate synthase. The activity of NADH-cytochrome c reductase was unaffected. Lactate production and the lactate-to-pyruvate ratio were significantly greater in hypoxic cardiomyocytes. Western and Northern analysis demonstrated a decrease in the levels of various mRNA and corresponding polypeptides in hypoxic cells. Thus hypoxia influences mitochondrial metabolism through acute and chronic adaptive mechanisms, reflecting allosteric (posttranscriptional) and transcriptional modulation. Transcriptional downregulation of key mitochondrial enzyme systems can explain the insufficient myocardial aerobic metabolism and low-output failure in children with cyanotic heart disease after cardiac surgery.
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PMID:Myocardial aerobic metabolism is impaired in a cell culture model of cyanotic heart disease. 981 75

Cytochrome b(5) reductase (b5R) deficiency manifests itself in 2 distinct ways. In methemoglobinemia type I, the patients only suffer from cyanosis, whereas in type II, the patients suffer in addition from severe mental retardation and neurologic impairment. Biochemical data indicate that this may be due to a difference in mutations, causing enzyme instability in type I and complete enzyme deficiency or enzyme inactivation in type II. We have investigated 7 families with methemoglobulinemia type I and found 7 novel mutations in the b5R gene. Six of these mutations predicted amino acid substitutions at sites not involved in reduced nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FAD) binding, as deduced from a 3-dimensional model of human b5R. This model was constructed from comparison with the known 3-dimensional structure of pig b5R. The seventh mutation was a splice site mutation leading to skipping of exon 5 in messenger RNA, present in heterozygous form in a patient together with a missense mutation on the other allele. Eight other amino acid substitutions, previously described to cause methemoglobinemia type I, were also situated in nonessential regions of the enzyme. In contrast, 2 other substitutions, known to cause the type II form of the disease, were found to directly affect the consensus FAD-binding site or indirectly influence NADH binding. Thus, these data support the idea that enzyme inactivation is a cause of the type II disease, whereas enzyme instability may lead to the type I form.
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PMID:Seven new mutations in the nicotinamide adenine dinucleotide reduced-cytochrome b(5) reductase gene leading to methemoglobinemia type I. 1115 44

Congenital methemoglobinemia is a relatively rare clinical disorder characterized by life-long cyanosis, caused by either an inherited mutant hemoglobin (Hb-M) or deficiency of physiologically active NADH-dependent methemoglobin reductase (NADH-MR). NADH-MR deficiency leads to two different types of recessive congenital methemoglobinemia. In type I, cyanosis is the only major symptom and NADH-MR deficiency is restricted only to the red blood cells. In type II, cyanosis is associated with severe mental retardation and neurological impairment. The objective of this study is to establish the cause of cyanosis in our cases of congenital methaemoglobinemia. Erythrocyte NADH-MR activity was assayed spectrophotometrically. Spectral analysis of the hemolysate treated with potassium ferricyanide was recorded between 400-700 nm and Hb electrophoresis on starch gel at pH 7.0 was done to rule out the presence of Hb-M. NADH-MR deficiency was detected in 3 families. There was a history of consanguinity in one of these cases. The three propositi presented with breathlessness, fever and peripheral cyanosis. There was no history of cardiac illness or exposure to drugs and chemicals. There were no signs and symptoms of mental retardation. The presence of Hb-M was ruled out. Hb-A2, Hb-F, G6PD activity and reduced glutathione levels were normal. NADH-MR activity in all the cases ranged from 4.1 to 9.2 IU/g Hb (normal range 7.0-24.0 IU/g Hb). We describe NADH-MR deficiency in three unrelated cases (age 4 months to 6 years) where the activity of the enzyme was 30-40% of normal. These three cases of congenital methemoglobinemia are due to type-I NADH-MR deficiency without mental retardation.
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PMID:Congenital methemoglobinemia due to NADH-methemoglobin reductase deficiency in three Indian families. 1280 31


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