Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p-Nitroaniline is an intermediate in the preparation of several azo dyes used for coloring consumer products. Toxicology and carcinogenicity studies were conducted by administering p-nitroaniline (>99% pure) in corn oil by gavage to groups of male and female B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, mouse Iymphoma cells, and Drosophila melanogaster. 14-DAY STUDIES: Groups of five male and five female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 10, 30, 100, 300, or 1,000 mg/kg body weight 5 days per week for 2 weeks. All mice that received 1,000 mg/kg died from chemical-related toxicity by day 4 of the studies. Final mean body weights of mice receiving 300 mg/kg or less were similar to those of the controls. Hematology results were consistent with chemical-related methemoglobinemia and regenerative anemia. Met hemoglobin concentrations in all groups of dosed mice were significantly higher than those in controls. Hematocrit values in mice that received 300 mg/kg and total erythrocyte counts in mice that received 100 or 300 mg/kg were significantly lower than those in controls. Reticulocyte counts in 300 mg/kg male mice and in 100 or 300 mg/kg females were significantly higher than controls. Heinz bodies were observed in erythrocytes of all 300 mg/kg mice and in two 100 mg/kg male mice. The absolute and relative spleen weights of 100 and 300 mg/kg mice were significantly greater than those of the controls. Hematopoiesis and pigment (hemosiderin) accumulation were observed in the splenic red pulp of males and females receiving 300 mg/kg; pigment (hemosiderin) accumulation in Kupffer cells of the liver was also seen in male mice at this dose level. 13-WEEK STUDIES: Groups of 20 male and 20 female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 1, 3, 10, 30, or 100 mg/kg body weight 5 days per week for up to 13 weeks. Eight or nine mice in each group were evaluated at 7 weeks. There were no deaths associated with exposure to p-nitroaniline, and final mean body weights of dosed mice were similar to those of the controls. Hematologic and pathologic findings at 7 and 13 weeks were similar to those seen in the 14-day studies and occurred primarily in the 30 and 100 mg/kg groups. Met hemoglobin concentrations were increased and hematocrit levels and erythrocyte counts were decreased relative to those of the controls. Heinz bodies were observed in erythrocytes and nucleated erythrocytes and reticulocytes were increased in number. Absolute and relative spleen weights of male and female mice receiving 30 and 100 mg/kg were significantly greater than those of controls at 7 and 13 weeks. Absolute and relative liver weights of female mice necropsied at 7 weeks were significantly greater in the 30 and 100 mg/kg groups; by 13 weeks, both absolute and relative liver weights were similar to control values. The incidence or severity of splenic hematopoiesis and pigmentation (hemosiderin) increased with dose at the 7-week interim evaluations and at the end of the studies. Pigment (hemosiderin) was also present in Kupffer cells of the liver in dosed male mice. 2-YEAR STUDIES: Groups of 70 male and 70 female B6C3F1 mice received p-nitroaniline in corn oil by gavage at doses of 0, 3, 30, or 100 mg/kg body weight for 5 days per week for up to 103 weeks. The dose selection was based on the hematologic and pathologic findings of the 13-week studies. Nine or ten mice from each group were evaluated at 9 and 15 months for the presence of chemical-related lesions. Body Weights, Clinical Findings, Survival, and Hematology: Mean body weights of male and female mice that received p-nitroaniline were similar to those of control mice throughout the 2-year studies. There were no clinical findings associated with chemical exposure, and survival of dosed mice was similar to that of controls. The hematology findings at the 9 and 15-month interim evaluations were similar to those in the 14-day and 13-week s 13-week studies. The methemoglobin concentrations were significantly higher in all 30 or 100 mg/kg mice; sulfhemoglobin concentrations were significantly higher at 9 months in all 30 or 100 mg/kg female mice and at 15 months in 100 mg/kg females. Hematocrit and erythrocyte counts in 100 mg/kg mice were significantly lower than those in controls. By 9 months, reticulocyte counts were significantly higher in all 30 or 100 mg/kg mice. At 15 months, only the 100 mg/kg mice exhibited significantly higher reticulocyte counts. Neoplasms and Nonneoplastic Lesions: Lesions related to the administration of p-nitroaniline occurred in the spleen, liver, and bone marrow, primarily in mice receiving 30 or 100 mg/kg; these were observed at the 9- and 15-month interim evaluations and at the end of the studies. There were increases in the incidence or severity of splenic congestion, hematopoiesis, pigment (hemosiderin) accumulation, Kupffer cell pigmentation in the liver, and bone marrow hypercellularity (hyperplasia). The incidences of hemangiosarcoma of the liver (0 ppm, 0/50; 3 ppm, 1/50; 30 ppm, 2/50; 100 ppm, 4/50) and hemangioma or hemangiosarcoma (combined) at all sites (5/50, 3/50, 4/50, 10/50) were marginally increased in 100 mg/kg male mice. The incidence of hepatocellular adenoma or carcinoma (combined) was significantly decreased (25/50, 26/50, 25/50, 13/50) in 100 mg/kg male mice. GENETIC TOXICOLOGY: p-Nitroaniline is mutagenic in vitro. It was tested in two laboratories for induction of gene mutations in several strains of Salmonella typhimurium. Both studies showed positive results in strain TA98, with and without S9 activation; results were negative for all other strains. p-Nitroaniline was tested in two laboratories for induction of sister cremated exchanges and chromosomal aberrations in Chinese hamster ovary cells. In the sister cremated exchange study, one laboratory reported negative results without S9 and positive results with S9; the second laboratory reported equivocal results without S9 and negative results with S9. In the chromosomal aberrations study, both laboratories found positive results with S9. Without S9, one laboratory reported weakly positive results while the other reported negative results. p-Nitroaniline induced trifluorothymidine resistance in L5178Y mouse Iymphoma cells in the absence of S9; no induction of trifluorothymidine resistance was noted with S9. In contrast to the positive results in the previous tests, p-nitroaniline did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered by feeding or injection to adult males or by feeding to larvae. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was equivocal evidence of carcinogenic activity of p-nitroaniline in male B6C3F1 mice based on the increased incidences of hemangiosarcoma of the liver and hemangioma or hemangiosarcoma (combined) at all sites. There was no evidence of carcinogenic activity of p-nitroaniline in female B6C3F1 mice receiving doses of 3, 30, or 100 mg/kg.
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PMID:NTP Toxicology and Carcinogenesis Studies of p-Nitroaniline (CAS No. 100-01-6) in B6C3F1 Mice (Gavage Studies). 1261 93

Exposure to toxic metals has become an increasingly recognized source of illness worldwide. Both cadmium and arsenic are ubiquitous in the environment, and exposure through food and water as well as occupational sources can contribute to a well-defined spectrum of disease. The symptom picture of arsenic toxicity is characterized by dermal lesions, anemia, and an increased risk for cardiovascular disease, diabetes, and liver damage. Cadmium has a significant effect on renal function, and as a result alters bone metabolism, leading to osteoporosis and osteomalacia. Cadmium-induced genotoxicity also increases risk for several cancers. The mechanisms of arsenic- and cadmium-induced damage include the production of free radicals that alter mitochondrial activity and genetic information. The metabolism and excretion of these heavy metals depend on the presence of antioxidants and thiols that aid arsenic methylation and both arsenic and cadmium metallothionein-binding. S-adenosylmethionine, lipoic acid, glutathione, selenium, zinc, N-acetylcysteine (NAC), methionine, cysteine, alpha-tocopherol, and ascorbic acid have specific roles in the mitigation of heavy metal toxicity. Several antioxidants including NAC, zinc, methionine, and cysteine, when used in conjunction with standard chelating agents, can improve the mobilization and excretion of arsenic and cadmium.
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PMID:Toxic metals and antioxidants: Part II. The role of antioxidants in arsenic and cadmium toxicity. 1277 58

Dietary nutrient interactions are important factors to consider in the study of nutrient status and requirements. Here, the effects of dietary interactions among copper (Cu), iron (Fe), manganese (Mn) and sulfur amino acids (SAA) on blood cell characteristics and enzyme activities were observed. Male rats (n = 8) were used in a 2 x 2 x 2 x 2 factorial design and fed an AIN-93G-based diet containing dietary Cu (<1 and 5 mg/kg), Fe (10 and 35 mg/kg), Mn (10 and 50 mg/kg) and either L-cystine (LCys) or DL-methionine (DLMet). Blood was analyzed by automated hematology cell counting and by flow cytometry. Severe Cu deficiency was verified by reductions in the activities of serum ceruloplasmin (1% of control), RBC superoxide dismutase (SOD1) (14% of control), liver cytochrome c oxidase activity (25% of control) and serum extracellular SOD (SOD3) activity (20% of controls). Because Cu is required for Fe utilization, many physiologic responses that require Fe were affected by both deficiencies, including lowered blood hemoglobin (Hgb), lower RBC volume and Hgb concentration, and an increased number of reticulocytes. Cu and Fe deficiencies together worsened some conditions, i.e., lower Hgb, lower RBC Hgb, increased RBC distribution width, increased number of reticulocytes and nucleated RBC, and a higher platelet count. Increasing dietary Mn had little effect on most variables, except to reduce serum Cu when dietary Cu was adequate but not when it was low, and to reduce RBC SOD1 activity when dietary Fe was low but not when it was adequate. Hgb concentrations were higher (P < 0.002) in Cu-deficient rats fed LCys than in those fed DLMet. There was no effect in Cu-adequate rats. Hgb was higher (P < 0.004) in Fe-adequate rats fed LCys than in those fed DLMet, with no effect in Fe-deficient rats. Although the anemia of Cu deficiency in AIN-93G-fed rats was not as pronounced as that reported in rats fed the AIN-76A-based diet, other manifestations of the deficiency were prominent.
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PMID:Contrasting and cooperative effects of copper and iron deficiencies in male rats fed different concentrations of manganese and different sources of sulfur amino acids in an AIN-93G-based diet. 1474 82

Hookworm infection is a major cause of iron deficiency anemia and malnutrition in developing countries. The Ancylostoma ceylanicum Kunitz-type inhibitor (AceKI) is a 7.9-kDa broad-spectrum inhibitor of trypsin, chymotrypsin, and pancreatic elastase that has previously been isolated from adult hookworms. Site-directed mutagenesis of the predicted P1 inhibitory reactive site amino acid confirmed the role of Met(26) in mediating inhibition of the three target serine proteases. By using reverse transcription-PCR, it was demonstrated that the level of AceKI gene expression increased following activation of third-stage larvae with serum and that the highest level of expression was reached in the adult stage of the parasite. Immunohistochemistry studies performed with polyclonal immunoglobulin G raised against recombinant AceKI showed that the inhibitor localized to the subcuticle of the adult hookworm, suggesting that it has a potential in vivo role in neutralizing intestinal proteases at the surface of the parasite. Immunization with recombinant AceKI was shown to confer partial protection against hookworm-associated growth delay without a measurable effect on anemia. Taken together, the data suggest that AceKI plays a role in the pathogenesis of hookworm-associated malnutrition and growth delay, perhaps through inhibition of nutrient absorption in infected hosts.
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PMID:Molecular characterization of Ancylostoma ceylanicum Kunitz-type serine protease inhibitor: evidence for a role in hookworm-associated growth delay. 1503 45

The cblE type of homocystinuria is a rare autosomal recessive disorder caused by impaired reductive activation of methionine synthase. Although earlier biochemical studies proposed that the methionine synthase enzyme might be activated by two different reducing systems, mutations were reported in only the methionine synthase reductase gene (MTRR) in cblE patients. The pathogenicity of MTRR mutations, however, has not yet been tested functionally. We report on nine patients of European origin affected by the cblE type of homocystinuria. They presented between 2 weeks and 3 years of age (median age 4 weeks) with anemia, which was macrocytic in only three patients, and with neurological involvement in all but two cases. Bone marrow examination performed in seven patients showed megaloblastic changes in all but one of them. All patients exhibited moderate to severe hyperhomocysteinemia (median plasma total homocysteine [Hcy] 92 mumol/L, range 44-169), while clearly reduced methionine was observed only in four cases. Pathogenic mutations were identified in both parental alleles of the MTRR gene in all patients. Five known (c.903+469T>C, c.1361C>T, c.1459G>A, c.1557-4_1557+3del7, and c.1622_1623dupTA) and three novel mutations (c.7A>T, c.1573C>T, and c.1953-6_1953-2del5) were detected. Importantly, transfection of fibroblasts of cblE patients with a wild-type MTRR minigene expression construct resulted in a significant approximately four-fold increase of methionine synthesis, indicating correction of the enzyme defect. Our study shows a link between a milder predominantly hematological presentation and homozygosity for the c.1361C>T mutation, but no other obvious genotype-phenotype correlation. The identification of mutations in the MTRR gene, together with restoration of methionine synthesis following MTRR minigene expression in cblE cells confirms that this disease is caused by defects in the MTRR gene.
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PMID:cblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression. 1571 22

Familial LCAT deficiency (FLD) is a rare genetic disorder associated with corneal opacities, anaemia and proteinuria with renal failure. Here we report detailed analyses on plasma lipids, lipoproteins, and the molecular defect in two siblings from a Polish family presenting classical symptoms of FLD and their family members with newly discovered Val309Met mutation in exon 6 of LCAT gene. Both patients displayed low total (2.19 and 2.94 mmol/l) and HDL-cholesterol concentrations (0.52 and 0.48 mmol/l), low percentage of cholesteryl esters (CE) (11.1 and 12%), and decreased apo AI and apo AII serum levels. Low LDL-cholesterol, apo B and Lp(a) levels, and increased oleate/linoleate ratios in CE could be of importance in the development of atherosclerosis in these patients with low HDL-cholesterol. LCAT activity was 10% of normal, alpha-LCAT activity was 0, and LCAT concentration was undetectable by immunoassay. Plasma CETP activity was at lower limits of normal. PCR and sequence analysis of DNA from the proband and affected brother revealed a novel G-->A mutation in exon 6 of LCAT gene, which resulted in an amino acid substitution of valine for methionine (Val309Met). The proband and affected brother were both homozygous carriers, while the mother, siblings and children of patients were heterozygous carriers of a newly discovered mutation. This is the first LCAT mutation described in the Slavic population.
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PMID:Familial lecithin-cholesterol acyltransferase deficiency: biochemical characteristics and molecular analysis of a new LCAT mutation in a Polish family. 1605 Dec 54

The role of hyperhomocysteinemia (HHcy) as a risk marker for cardiovascular diseases in renal patients is a matter of controversy. The remethylation of homocysteine (Hcy) to methionine in the kidneys is of great importance for Hcy clearance. Hcy remethylation is markedly decreased in patients on hemodialysis, but transsulfuration remains mostly unaffected. Markedly increased concentrations of methylmalonic acid (MMA), as a metabolic marker of vitamin B12 deficiency, have been found in approximately 70% of renal patients. This is in contrast to normal concentrations of vitamin B12 usually reported in such patients. We demonstrated in cell culture experiments that the uptake of vitamin B12 by mononuclear cells from renal patients was lower than that taken up by cells from controls. The lowering of MMA and Hcy concentrations in renal patients after B12 administration may indicate the presence of intracellular pre-treatment deficiency. We administered folic acid (5 mg) plus vitamin B6 (50 mg) and B12 (0.7 mg) three times per week intravenously to hyperhomocysteinemic dialysis patients. Hcy decreased after 4 weeks by 51%. Hcy was normalized in almost all patients, while serum concentrations of MMA and cystathionine were reduced by 28% and 26%, respectively. Cystathionine, an indicator for the transsulfuration pathway, showed a drastic increase in renal disease and was only slightly lowered by B-vitamin treatment. The increased cystathionine/cysteine ratio in renal patients indicates possible impairment of the catabolism of cystathionine by cystathionase. Moreover, renal failure is associated with severe abnormalities in plasma concentrations of S-adenosyl Hcy (SAH) and S-adenosyl methionine (SAM), as well as the SAM/SAH ratio. This ratio is an indicator of the availability of methyl groups from SAM. Therapeutic doses of B-vitamins in dialysis patients led to a limited improvement in the biomarkers of methylation and probably did not have a significant effect on transmethylation potential in the cells. Furthermore, elevated serum levels of asymmetric dimethylarginine (ADMA) in renal patients, which are associated with a poor outcome for such patients, could be lowered, but this effect was confined to patients who had no anemia. Future studies may consider extending the duration of vitamin treatment, as well as agents that may enhance the hydrolysis of SAH and cystathionine.
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PMID:Hyperhomocysteinemia and response of methionine cycle intermediates to vitamin treatment in renal patients. 1619 95

Intravenous iron is commonly used in conjunction with erythropoietic agents to treat anemia in patients with chronic kidney disease. Iron has been proposed to promote oxidative stress and endothelial dysfunction in vascular tissues. We studied the acute effects of intravenous iron sucrose on homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. In all, 40 healthy subjects received intravenous iron sucrose 100 mg or placebo over 30 min immediately before ingestion of 100 mg/kg of oral methionine in a double-blind, randomized study. Flow- and nitroglycerin-mediated dilation in the brachial artery, serum markers of iron stores, and homocysteine and nitrotyrosine levels were measured before and after study drug administration. Intravenous iron significantly increased transferrin saturation and non-transferrin-bound iron (NTBI) when compared with placebo. Flow-mediated dilation significantly decreased from baseline 1 h after administration of iron sucrose when compared with placebo (from 6.66+/-0.47 to 1.93+/-0.35% after iron sucrose vs from 6.00+/-0.40 to 5.61+/-0.46% after placebo, P<0.001), but did not differ between groups at 4 h (1.10+/-0.39 vs 1.33+/-0.51%). Nitroglycerin-mediated vasodilation, and homocysteine and 3-nitrotyrosine levels did not differ after administration of iron sucrose and placebo. Intravenous administration of iron sucrose in the setting of transient hyperhomocysteinemia induced by methionine ingestion significantly increased transferrin saturation and plasma levels of NTBI and significantly attenuated flow-mediated dilation in the brachial artery when compared with placebo. This potential mechanistic link between intravenous iron and endothelial dysfunction warrants further study of cardiovascular effects of intravenous iron in anemic chronic kidney disease populations.
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PMID:Iron sucrose augments homocysteine-induced endothelial dysfunction in normal subjects. 1646 88

The proband was born at 36 weeks, appropriate for gestational age, to nonconsanguineous white parents. There was no evidence of hyperbilirubinemia or intrahepatic cholestasis in the neonatal period, and she had normal newborn screen results. She presented with 3 episodes of life-threatening bleeding and anemia. The diagnostic evaluation for her bleeding diathesis revealed an abnormal clotting profile with no biochemical evidence for hepatocellular damage. She was incidentally noted to have severe growth deceleration that failed to respond to 502 kJ/kg (120 kcal/kg) per day of protein-hydrolyzed formula. An extensive diagnostic workup for failure to thrive, which was otherwise normal, included plasma amino acid analysis that revealed hyperglutaminemia and citrulline levels within the reference range. Testing of a repeat sample revealed isolated hypercitrullinemia. No argininosuccinic acid was detected. Her ammonia level and urine orotic acid were within the reference ranges. Subsequent plasma amino acid analysis exhibited a profile suggestive of neonatal intrahepatic cholestasis caused by citrin deficiency with elevations in citrulline, methionine, and threonine. Western blotting of fibroblasts demonstrated citrin deficiency, and a deletion for exon 3 was found in the patient's coding DNA of the SLC25A13 gene. On the basis of the experience with adults carrying this condition, the patient was given a high-protein, low-carbohydrate diet. The failure to thrive and bleeding diathesis resolved. When compliance with the dietary prescription was relaxed, growth deceleration was again noted, although significant bleeding did not recur. This is the first report of an infant of Northern European descent with citrin deficiency. The later age at presentation with failure to thrive and bleeding diathesis and without obvious evidence of neonatal intrahepatic cholestasis expands the clinical spectrum of citrin deficiency. This case emphasizes the importance of continued dietary control and growth monitoring in children with neonatal intrahepatic cholestasis caused by citrin deficiency and identifies a new metabolic entity responsible for failure to thrive.
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PMID:Citrin deficiency: a novel cause of failure to thrive that responds to a high-protein, low-carbohydrate diet. 1733 92

Methionine (Meth) is an essential amino acid involved in DNA methylation and glutathione biosynthesis. We examined the effect of Meth on the development of steatohepatitis. Rats were fed (five weeks) amino acid-based Meth-choline-sufficient (A-MCS) or total deficient (MCD) diets and gavaged daily (two weeks) with vehicle (B-vehicle/MCD), or Meth replacement (C-Meth/MCD). To assess the effect of short-term deficiency, after three weeks one MCS group was fed a deficient diet (D-MCS/MCD). Animals fed the deficient diet for two weeks lost (29%) weight and after five weeks weighed one third as much as those on the sufficient diet, and also developed anemia (P < 0.01). Hepatic transaminases progressively increased from two to five weeks (P < 0.01), leading to severe hepatic pathology. Meth administration normalized hematocrit, improved weight (P < 0.05), and suppressed abnormal enzymes activities (P < 0.01). Meth administration improved blood and hepatic glutathione (GSH), S-adenosylmethionine (SAMe), and hepatic lesions (P < 0.01). The deficient diet significantly upregulated proinflammatory and fibrotic genes, which was ameliorated by Meth administration. These data support a pivotal role for methionine in the pathogenesis of the dietary model of Meth-choline-deficient (MCD) steatohepatitis (NASH).
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PMID:Methionine deficiency and hepatic injury in a dietary steatohepatitis model. 1771 May 50


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