Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002878 (hemolytic anemia)
 7,530 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and metabolic studies were performed in four members of a Spanish family with partial (50%) 6 phosphogluconate dehydrogenase (6PGD) deficiency. In all cases the activities of 6 phosphogluconolactone (6PGL) and glutathione reductase (GR) were normal, and the molecular characterization performed in the partially purified 6PGD from the propositus showed normal kinetic and electrophoretic patterns. Two females (the propositus and her sister) suffered from a well-compensated chronic nonspherocytic hemolytic anemia (CNSHA) and exhibited decreased RBC glutathione (GSH) stability with increased oxidative susceptibility, defined by enhanced malonyldialdehyde (MDA) generation "in vitro." The other two members of the family (the propositus's mother and brother) were clinically asymptomatic. In the propositus and her sister, RBC metabolism exhibited a markedly abnormal concentration of glycolytic intermediates, mainly characterized by striking increases in fructose 1,6 bisphosphate (50-fold), dihydroxiacetone-phosphate (20-fold) and glyceraldehyde 3-phosphate (tenfold). Although the precise mechanism of the hemolysis in the two patients is unknown, the enhanced oxidative threat observed in their RBCs may interfere in some way with the glycolytic pathway function, leading to a marked increase in certain metabolic intermediates located before the glyceraldehyde 3 phosphate dehydrogenase (GA3PD) step. Since it seems that GA3PD half-life is modulated by fluctuations of the cytosolic redox status, an "in situ" approach was simulated by using permeabilized RBCs. In these conditions, GA3PD activity was significantly lower in the propositus and her sister than in the asymptomatic members of the family and the simultaneous normal control.
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PMID:Congenital 6-phosphogluconate dehydrogenase (6PGD) deficiency associated with chronic hemolytic anemia in a Spanish family. 894 58

Hydroxylamine is a direct-acting hematotoxic agent leading to hemolytic anemia in animals and man. The effect of hydroxylamine on the morphology, sulfhydryl status and membrane skeletal proteins of human erythrocytes were studied. Loss of reduced glutathione (GSH) from the red blood cells was directly proportional to the hydroxylamine concentration used. This loss of GSH was larger than the sum of the increase in the amounts of extracellular glutathione and intracellular oxidized glutathione (GSSG). The extracellular glutathione is mainly present as GSSG, which is in agreement with the fact that only GSSG is exported from the erythrocytes by membrane bound ATPases. Lack of GSSG export was not limited by decreased ATP levels in the erythrocytes and we concluded that the GSH that disappeared did not become available as intracellular GSSG. After reduction of the erythrocyte incubates the lost GSH was almost completely recovered indicating that the lost GSH is present in the cell as protein-glutathione mixed disulfides. Glutathione thus stored within the cell can be quickly recovered by combined thioltransferase and glutathione reductase activity when conditions become more favorable again. SDS-polyacrylamide gel electrophoresis of membrane ghosts from human red cells revealed changes in skeletal proteins with a smearing of bands 1, 2 and 3 to the higher molecular weight end of the gel and the appearance of new monomeric and dimeric hemoglobin bands at about 16 and 30 kD. The observed alterations are probably a consequence of disulfide bridge formation between cellular proteins (mainly hemoglobin) and skeletal proteins as well as between hemoglobin monomers. Exposure of hydroxylamine to erythrocytes caused severe Heinz body formation but the outside morphology of the cells was only marginally altered. The described changes in sulfhydryl status of the red blood cells are likely to play a major role in the premature splenic sequestration of hydroxylamine-damaged erythrocytes.
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PMID:Hydroxylamine treatment increases glutathione-protein and protein-protein binding in human erythrocytes. 939 34

A child of Italian origin with a congenital haemolytic anaemia had spectrophotometrically undetectable erythrocyte adenylate kinase (AK) activity. Her parents and brother had approximately 50% normal AK activity, and AK electrophoresis of red blood cell (RBC) crude extract on cellulose acetate strips showed the presence of the normal allele AK1-1. No AK band was detected in the AK electrophoresis of the proband, in whom the erythrocyte 2,3-diphosphoglycerate (2,3DPG) and glutathione (GSH) concentrations were normal whereas adenosine triphosphate (ATP) concentration, pyruvate kinase (PK) and glucose-6P-dehydrogenase (G6PD) activities were increased, reflecting the high reticulocyte count (6.9%). No other evident enzymatic defect was detected by standard procedures. Analysis of AK gene exons, based on polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP), clearly showed an abnormality in the fragment containing exon 6. The subsequent sequence analysis of this abnormal fragment revealed homozygous and heterozygous A-->G substitutions in the proband and in the parents and brother respectively at codon 164, corresponding to a tyrosine-->cysteine substitution in the AK protein.
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PMID:Severe erythrocyte adenylate kinase deficiency due to homozygous A-->G substitution at codon 164 of human AK1 gene associated with chronic haemolytic anaemia. 943 20

In the gamma-glutamyl cycle, hereditary defects have been described in four of the six enzymes namely: gamma-GC synthetase; GSH synthetase; gamma-glutamyl transpeptidase and 5-oxoprolinase. Mutants are still to be found in gamma-glutamyl cyclotransferase and in the dipeptidase. Deficiency of GSH synthatase or gamma-GC synthetases results in low levels of GSH. In gamma-GC synthetase deficiency hemolytic anemia is the most prominent symptom, with or without hepatosplenomegaly. In generalized GSH synthetase deficiency 5-oxoproline is overproduced due to lack of feedback inhibition of gamma-GC synthetase. These patients have metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and about 50% of them also have progressive neurological symptoms. Treatment includes acidosis correction, high doses of vitamin E and C and avoidance of drugs precipitating hemolytic crises in G6PD deficiency. Therapeutic trials with GSH analogues, N-acetylcysteine and GSH esters have been carried out. Glutathione synthetase deficiency restricted to erythrocytes results in hemolytic anemia but no 5-oxoprolinuria. gamma-Glutamyl transpeptidase deficiency is associated with GSH-emia and GSH-uria whereas 5-oxoprolinase deficiency is associated with 5-oxoprolinuria. In diagnostic work it must be emphasized that erythrocytes contain an incomplete gamma-glutamyl cycle; they lack both gamma-glutamyl transpeptidase and 5-oxoprolinase and these enzyme activities must therefore be analyzed in other types of cells such as leukocytes and fibroblasts. It is also important to investigate other patients with inherited defects in the gamma-glutamyl cycle to learn more about the biological role of GSH in man.
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PMID:Patients with genetic defects in the gamma-glutamyl cycle. 967 48

Glucose 6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy of human beings and is the most common cause of jaundice and acute hemolytic anemia in South East Asia. The deficiency causes acute hemolytic anemia following ingestion of 6-amino quinoline antimalarials, phenacetin, and other substances. The rapid identification of infants or patients with this deficiency would help to prevent their exposure to these substances and subsequent risk to health. The assay is relatively simple. A 3mm punch from a dried blood spot sample is placed in a well of a black fluorescent microtiter plate containing calibrators and controls in duplicate. 100 microl of reagent is added and the sample is allowed to react for 30 minutes at ambient temperature after which 200 microl of stop reagent is added. The plate may be read immediately or up to one hour in a fluorescent reader (ex 355 nm: em 460 nm). Glutathione. ascorbate and bilirubin do not affect the assay. hemoglobin does quench the fluorescence by about 1.1 fluorescence units/g/dHb. This would not cause any false negatives and deficients would not be missed. G6PD activity in whole blood normal samples was examined at -20, 6 and 37 degrees C over 14 days. The samples lost about 20% activity after 48 hours and 31% by the end of 14 days. The samples stored at -20 degrees C and 6 degrees C remained relatively stable over this period. In a preliminary study eight diagnosed G6PD deficient samples had a mean value of 2.0 U/gHb (range 0.8 to 4.4) and fell within 3 SD units of the mean. Forty one normal samples had a mean of 6.6 micromol/min/gHb. Only one sample with a low hemoglobin level fell outside of 3 SD units of the mean. The Wallac assay was compared to the Sigma G6PD assay and although the values appeared lower at normal levels, the deficient samples compared well.
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PMID:A simple, rapid fluorometric assay for the determination of glucose 6-phosphate dehydrogenase activity in dried blood spot specimens. 1140 Jul 94

The antitumor agent sulofenur (LY186641), which has shown promising activity against a wide range of cancers, causes hemolytic anemia and methemoglobinemia at dose-limiting toxicities. The antitumor and toxicological mechanism(s) of action of the drug is (are) not well understood, but unlike other antineoplastic agents, sulofenur does not interfere with DNA, RNA, or protein synthesis, or with polynucleotide function. In the present study, we evaluated the hypothesis that sulofenur undergoes bioactivation in vivo to generate p-chlorophenyl isocyanate (CPIC), which could carbamoylate biological macromolecules directly or form a conjugate with glutathione (GSH) which would serve as a latent form of CPIC. The objectives of this study, therefore, were to determine if the GSH and N-acetylcysteine conjugates of CPIC were excreted into bile and urine, respectively, after an i.p. dose of sulofenur to rats. In addition, the chemical stability and thiol exchange properties of these S-linked conjugates were determined. The results of this study indicate that sulofenur does undergo metabolism in vivo to yield the GSH conjugate of CPIC, and that this conjugation reaction is reversible and subject to thiol exchange in buffered aqueous solution (pH 7.4, 37 degrees C). In contrast, sulofenur itself was stable under these same conditions, even in the presence of GSH and glutathione-S-transferase (GST), thus raising the possibility that bioactivation of sulofenur is necessary for liberation of CPIC. These findings suggest that the generation of this isocyanate in vivo and subsequent carbamoylation of biological macromolecules may play a role in the toxicity and/or antitumor activity of sulofenur and related diarylsulfonylureas.
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PMID:Glutathione-dependent metabolism of the antitumor agent sulofenur. Evidence for the formation of p-chlorophenyl isocyanate as a reactive intermediate. 1184 51

An 8-month-old, spayed female Shetland sheepdog presented 48 hours after ingesting acetaminophen (1 gm/kg body weight). On presentation, the dog was laterally recumbent and hypovolemic. The dog had brown mucous membranes, severe Heinz-body hemolytic anemia, bleeding tendencies, and a red blood cell (RBC) glutathione (GSH) concentration that was 10% of reference values, despite a regenerative erythroid response. Treatment with s-adenosyl-l-methionine (SAMe) as a GSH donor successfully rescued this dog, despite the animal's late presentation after drug ingestion. A loading dose (40 mg/kg body weight) of a stable SAMe salt per os was followed by a maintenance dose (20 mg/kg body weight) sid for 7 days. Additional therapeutic interventions included an intravenous (i.v.) infusion of one unit of packed RBCs (on admission), i.v. fluid support (3 days), and famotidine (7 days) to reduce gastric acidity. Sequential assessment of RBC GSH concentrations and RBC morphology documented response to antidote administration within 72 hours. This case suggests that SAMe may provide a therapeutic option for treatment of acetaminophen toxicosis in dogs capable of retaining an orally administered antidote and maintaining adequate hepatic function for metabolism of SAMe to its thiol substrates.
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PMID:S-adenosyl-L-methionine (SAMe) for the treatment of acetaminophen toxicity in a dog. 1202 11

Primaquine is an important antimalarial drug that is often dose-limited in therapy by the onset of hemolytic anemia. We have shown recently that an N-hydroxy metabolite of primaquine, 6-methoxy-8-hydroxylaminoquinoline (MAQ-NOH), is a direct-acting hemolytic agent in rat red cells and that the hemolytic activity of this metabolite is associated with GSH oxidation and oxidative damage to both membrane lipids and skeletal proteins. To determine whether the formation of free radicals may be involved in this process, rat red cells (40% suspensions) were incubated with hemolytic concentrations of MAQ-NOH (150-750 microM) and examined by EPR spectroscopy using 2-ethoxycarbonyl-2-methyl-3,4-dihydro-2H-pyrrole-1-oxide (EMPO) as a spin trap. Addition of MAQ-NOH to red cell suspensions containing 10 mM EMPO gave rise to an EPR spectrum with hyperfine constants consistent with those of an EMPO-hydroxyl radical adduct standard. Of interest, formation of EMPO-OH was constant for up to 20 min and dependent on the presence of erythrocytic GSH. Although no other radical adduct signals were detected in the cells by EPR, spectrophotometric analysis revealed the presence of ferrylhemoglobin, which indicates that hydrogen peroxide is generated under these experimental conditions. The data support the hypothesis that oxygen-derived and possibly other free radicals are involved in the mechanism underlying MAQ-NOH-induced hemolytic anemia.
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PMID:Primaquine-induced hemolytic anemia: formation of free radicals in rat erythrocytes exposed to 6-methoxy-8-hydroxylaminoquinoline. 1243 35

Gamma-glutamylcysteine synthetase (gamma-GCS) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis: the adenosine triphosphate (ATP)-dependent ligation of glutamate and cysteine. gamma-GCS consists of a catalytic (gamma-GCSH) and modifier (gamma-GCSL) subunit. Hereditary deficiency of gamma-GCS has been reported in a small number of patients and is associated with low erythrocyte levels of gamma-GCS and GSH leading to hemolytic anemia. Here we report a novel gamma-GCSH mutation, isolated from the cDNA of 2 related patients diagnosed with gamma-GCS deficiency. Each was found to be homozygous for a C>T missense mutation at nucleotide 379, encoding for a predicted Arg127Cys amino acid change. Computerized structure modeling identified that the mutated amino acid lies within a cleft on the protein surface of gamma-GCSH, and the border of this cleft was shown to contain Cys249, an evolutionarily conserved residue that has been proven to lie near the binding site of gamma-GCSH. Transfection studies showed that the mutation is associated with decreased GSH production, and binding studies using purified recombinant protein showed that the mutant protein has markedly decreased enzymatic activity compared to wild type.
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PMID:A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production. 1266 48

Epidemiological evidence indicates that a high dietary intake of plants of the Allium family, such as garlic and onions, decreases the risk of cancer in humans. It has been suggested that this effect is due to the ability of the aliphatic mono-, di-, tri-, and tetrasulfides derived from these vegetables to increase tissue activities of Phase 2 detoxification enzymes. In contrast, toxic effects have been recorded in domestic and farm animals after the consumption of garlic or onions, involving oxidative damage to erythrocytes and consequent hemolytic anemia. This effect again has been attributed to the aliphatic sulfides. In the present study, the ability of sulfides derived from garlic and onions to generate "active oxygen" species and cause oxidative damage to erythrocytes in vitro has been compared, together with their ability to cause hemolytic anemia and increase the activity of the Phase 2 enzymes quinone reductase (QR) and glutathione S-transferase (GST) in rats. Monosulfides were without significant effect on any parameter. Di-, tri-, and tetrasulfides generated hydrogen peroxide in the presence of GSH and hemoglobin and caused oxidative damage to erythrocytes in vitro. The activity decreased in the order of tetra- > tri- > disulfide, with the allyl compounds being more potent than the propyl. In vivo, both allyl and propyl tri- and tetrasulfides were powerful hemolytic agents. In contrast, only the allyl sulfides increased the activities of QR and GST; the propyl derivatives were completely without effect. Allyl and propyl tri- and tetrasulfides, thus, may contribute to the toxic effects of Allium vegetables, while only the allyl derivatives are effective in increasing tissue activities of cancer-protective enzymes.
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PMID:Comparative effects of mono-, di-, tri-, and tetrasulfides derived from plants of the Allium family: redox cycling in vitro and hemolytic activity and Phase 2 enzyme induction in vivo. 1270


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