Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of iron-overload on both hepatic lipid peroxidation and chemiluminescence was studied in early stages after iron-dextran injection. Total hepatic iron content was markedly elevated over control values 2-6 h after iron dose. A 4-fold increase in light emission was detected after 4-6 h after iron injection. Plasma GOT, GPT and LDH activities were not affected by the treatment suggesting that cell permeability was not affected by necrosis. Increases in the generation of thiobarbituric acid reactive substances (TBARS) and chemiluminescence in liver homogenates, were determined as a function of time after iron administration, in the presence of NADPH as cofactor. Under the same experimental conditions, microsomal cytochrome P-450 content was decreased by 40%, 2 h after iron treatment. To evaluate liver antioxidant defenses, catalase, superoxide dismutase and glutathione peroxidase activities were determined. Glutathione peroxidase activity in the homogenate was not affected by the treatment. Catalase and superoxide dismutase activities declined by 25 and 36%, respectively, compared with control values 4 h after the iron dose. Our data suggest that lipid peroxidation occurs after mild iron overload even though the liver remains functional.
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PMID:Hepatic chemiluminescence and lipid peroxidation in mild iron overload. 147 93

In patients with thalassemia intermedia in whom hyperabsorption of iron may result in serious organ dysfunction, an orally effective iron-chelating drug would have major therapeutic advantages, especially for the many patients with thalassemia intermedia in the Third World. We report reduction in tissue iron stores and normalization of serum ferritin concentration after 9-month therapy with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in a 29-year-old man with thalassemia intermedia and clinically significant iron overload (SF 2,174 micrograms/L, transferrin saturation 100%; elevated AST and ALT, abnormal cardiac radionuclide angiogram) who was enrolled in the study with L1 75 mg/kg/day after he refused deferoxamine therapy. L1-Induced 24-hour urinary iron excretion during the first 6 months of therapy was (mean +/- SD, range) 53 +/- 30 (11 to 109) mg (0.77 mg/kg), declining during the last 3 months of L1 to 24 +/- 14 (13-40) mg (0.36 mg/kg), as serum ferritin decreased steadily to normal range (present value, 251 micrograms/L). Dramatic improvement in signal intensity of the liver and mild improvement in that of the heart was shown by comparison of T1-weighted spin echo magnetic resonance imaging with images obtained immediately before L1 administration was observed after 9 months of L1 therapy. Hepatic iron concentration decreased from 14.6 mg/g dry weight of liver before L1 therapy to 1.9 mg/g liver after 9 months of therapy. This constitutes the first report of normalization of serum ferritin concentration in parallel with demonstrated reduction in tissue iron stores as a result of treatment with L1. Use of L1 as a therapeutic option in patients with thalassemia intermedia and iron overload appears warranted.
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PMID:Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia. 158 21

This study of hepatocellular carcinoma in a homogeneous rural Transkeian population at high risk consisted of: evaluation of liver biopsies of 246 patients with hepatocellular carcinoma using routine histology and immunoperoxidase for HBV stains; collection of reliable data on alcohol consumption, blood HBsAg and ALT status in asymptomatic controls from an adequate population sample; assessment of maize intended for human consumption for contamination by carcinogenic fungi. Tumour histology of rural Blacks did not differ from those described in other studies. Cirrhotic livers were present in 45.1% and iron overload in 68% of cases. Tissue HBsAg was detected in 57% (45% of non-cirrhotic and 59% of cirrhotic livers). Asymptomatic controls showed 9.5% of HBsAg positivity, 3.5% had elevated ALT and 41.3% admitted to alcohol abuse. Maize had insignificant contamination by Aspergillus flavus and very frequent contamination by Fusarium moniloforme. This study suggests a multifactorial aetiology of hepatocellular carcinoma, with viral infection being of the most importance.
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PMID:Hepatocellular carcinoma in a rural population at risk. 166 22

Treatment of rats with 100 mg kg-1 t-butyl hydroperoxide led to an enhanced ethane exhalation as a marker of in vivo lipid peroxidation, as well as a moderate hepatoxicity as evidenced by a rise in plasma activities of liver-specific enzymes (glutamate-pyruvate transaminase and sorbitol dehydrogenase) and an increase in hepatic calcium content. Furthermore, a depletion of hepatic glutathione by 17% was observed. Apart from the loss of glutathione, all these effects were antagonized by pretreatment of rats with the potent iron chelator deferrioxamine and potentiated by pretreatment with low concentrations of FeSO4 having no pro-oxidant activity per se; this was also the case in rats under conditions of iron overload (experimental haemochromatosis). These data indicate a close relationship between t-butyl hydroperoxide-induced lipid peroxidation and its hepatotoxicity, and point out the importance of iron in catalysing reinitiation (propagation) reactions of lipid peroxidation in vivo.
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PMID:The role of iron in t-butyl hydroperoxide-induced lipid peroxidation and hepatotoxicity in rats. 225 81

Iron overload is found clinically in such conditions as hemochromatosis and sideroblastic anemia, and after long term repeated transfusion in aplastic anemia. An animal model of iron overload was successfully developed in rats and rabbits by repeated intraperitoneal injections of ferric nitrilotriacetate (Fe3+-NTA). This procedure induced a diabetic state with hyperglycemia, ketonemia, glycosuria and ketonuria. Blood venesection on these rats reduced the iron load in the liver and pancreas, and ameliorated the general diabetic symptoms. A single injection of Fe3+-NTA in rats induced a temporary elevation in plasma iron concentration, lipid peroxidation in the perfused liver homogenate expressed by malondialdehyde (MDA) formation, blood GOT, GPT, ALP and gamma-GTP sequentially. Fe3+-NTA uptake in the liver caused membrane lipid peroxidation, and subsequently produced a transit liberation of liver cell enzymes, although the incorporated liver Fe3+-NTA was only 1% of the injected dosage (7.5 mg iron/kg BW) at 3 hr after injection. The direct toxic effect of Fe3+-NTA to living cells was examined using cultured normal rat liver parenchymal cells (RL-34). Marked cytolysis was found in cells exposed to more than 25 micrograms of iron through Fe3+-NTA/ml. At 50 micrograms iron of Fe3+-NTA/ml, most cells were lethally injured and the remaining cells were piled up and aggregated at 15 days. They grew on soft agar culture, and when inoculated subcutaneously to five newly born rats a subcutaneous tumor developed in all animals within three weeks. Lung metastases were found in three of five inoculated rats. A spin trapping technique with electron spin resonance (ESR) on Fe3+-NTA employing 5, 5-dimethyl-l-pyrroline-N-oxide (DMPO) yielded a spin adduct with three doublets (DMPO-Z) which corresponded to singlet oxygen. By ESR in the presence of H2O2, the Fe3+-NTA solution strongly generated hydroxyl radical. The production of active oxygen species by Fe3+-NTA solution may explain the toxicity and carcinogenicity of Fe3+-NTA. The majority of stainable iron in the iron overloaded tissue was hemosiderin (Hs). We tried to purify the Hs from multi-transfused human spleen by the method of Weir et al. The purified Hs did not show a DMPO-OH adducts in the presence of H2O2 and DMPO on ESR measurement. The Hs iron was solubilized with several biological ligands in an acidic state in the presence of a reducing reagent like glutathione. Solubilized Hs iron produced iron chelate complexes which resulted in OH radicals production in the presence of H2O2 in acidic conditions below pH 5.5.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Pathogenesis and mechanism of iron overload: ferric nitrilotriacetate, hemosiderin, active oxygen, and carcinogenesis]. 268 76

Porphyria was induced in C57BL/10 mice with iron overload by a single oral dose (100 mg/kg) of hexachlorobenzene (HCB). Within 2 weeks hepatic uroporphyrinogen decarboxylase (EC 4.1.1.37) was inhibited, reaching a maximum (greater than 95%) at 6-8 weeks. There was no recovery by 14 weeks, despite a fall in liver HCB concentrations to only 6% of the day-3 value. The major rise in hepatic porphyrin levels occurred after 4 weeks and secondary inhibition of uroporphyrinogen synthase (EC 4.2.1.75) was inferred from the progressively greater proportion of uroporphyrin I present relative to the III isomer. Plasma alanine aminotransferase (EC 2.6.1.2) activity was also elevated. Although, in further studies, total microsomal cytochrome P-450 content and ethoxyphenoxazone de-ethylase activity reached a peak a few days after dosing and had declined significantly at the time of maximum inhibition of the decarboxylase, additional treatment of HCB-dosed mice with a cytochrome P1-450 inducer, beta-naphthoflavone, enhanced the inhibition, whereas piperonyl butoxide, an inhibitor of cytochrome P-450, partially protected. Uroporphyrinogen decarboxylase was not radiolabelled in vivo by [14C]HCB. There was no major difference in the ability to hydroxylate HCB between hepatic microsomes from induced C57BL/10 mice and those from the insensitive DBA/2 strain. By contrast, lipid peroxidation, in the presence of NADPH, was 8-fold greater in control C57BL/10 microsomes than in DBA/2 microsomes and was stimulated by iron treatment (although not by HCB). The results suggest that the inhibition of hepatic uroporphyrinogen decarboxylase is unlikely to be due to a direct effect of a metabolite of HCB but to another process requiring a specific cytochrome P-450 isoenzyme and an unknown iron species.
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PMID:Mechanistic studies of the inhibition of hepatic uroporphyrinogen decarboxylase in C57BL/10 mice by iron-hexachlorobenzene synergism. 380 Sep 66

The aims of this study were to determine whether chronic ethanol consumption potentiates mitochondrial lipid peroxidation or impairment of mitochondrial oxidative metabolism in rats with chronic iron overload. Experimental iron overload was induced by feeding rats a chow diet supplemented with 2.5% carbonyl iron. After 8 to 12 weeks, half of the iron-loaded and control animals were changed to a liquid diet containing ethanol for 4 to 5 weeks. The remaining animals were fed an isocaloric amount of diet containing dextrin-maltose instead of ethanol for 4 to 5 weeks. Iron-supplemented animals had a 20-fold increase in hepatic iron concentration as compared with controls. Iron and ethanol independently increased plasma alanine aminotransferase (ALT) levels (p < 0.05) while the combination resulted in an additive increase in ALT levels (p < 0.01). Although iron overload increased the levels of mitochondrial conjugated dienes and significantly reduced the mitochondrial respiratory control ratio, ethanol administration did not affect these parameters in animals with or without iron overload. Livers from iron-loaded rats that received ethanol showed mild to moderate steatosis with scattered necroinflammatory foci. There was no significant increase in necroinflammatory foci in the livers of the iron plus ethanol group as compared with the iron group. In conclusion, we have demonstrated an additive increase in hepatocellular injury when ethanol is fed to iron-loaded rats, as evidenced by an increase in plasma ALT level. However, there were no additive or synergistic effects of iron and ethanol on either mitochondrial lipid peroxidation or mitochondrial oxidative metabolism.
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PMID:Hepatic mitochondrial oxidative metabolism and lipid peroxidation in iron-loaded rats fed ethanol. 749 May 19

The protective effect of the hydroxypyridin-4-ones (CP20 and CP94) was studied on iron-loaded rat and human hepatocytes; desferrioxamine B was used as a chelator reference. Iron load was achieved by addition of 5 up to 50 microM iron citrate to the culture medium. One day after iron treatment, an increase in lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and malondialdehyde extracellular concentrations was measured in rat and human hepatocyte cultures. This enzyme release and the increase in free extracellular malondialdehyde were observed with 5 microM iron and high levels were obtained with 50 microM. The bidentate chelators CP20 and CP94 (150 microM) appeared to be as effective as the hexadentate chelator desferrioxamine (50 microM) in the protection of rat and human hepatocytes against the toxic effect of iron load achieved by culturing the cells for 1 day in the presence of 50 microM iron citrate. In rat and human hepatocytes cultured for 1 day in the presence of 1 microM 55Fe-50 microM iron citrate plus CP20, CP94 or desferrioxamine B, a decrease of iron uptake by the cells was observed. When the hepatocytes were cultured for 1 day in the presence of 1 microM 55Fe-50 microM iron citrate and then for a further day in the presence of CP20, CP94 or desferrioxamine B but not iron, the chelators decreased the intracellular iron level, indicating their iron releasing effect from the loaded cells. The observed effects of the hydroxypyridin-4-ones CP20 and CP94 were as potent as the effect of desferrioxamine B. This study presents new data favoring the potential clinical interest of this new class of chelating agents in the treatment of human iron overload.
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PMID:Inhibition of iron toxicity in rat and human hepatocyte cultures by the hydroxypyridin-4-ones CP20 and CP94. 749 88

1. Hepatotoxicity is the most common finding in patients with iron overload since the liver is the major recipient of iron excess, even though the kidney could be a target of iron toxicity. The effect of iron overload was studied in the early stages after iron-dextran injection in rats, as a model for secondary hemocromatosis. 2. Total hepatic and kidney iron content was markedly elevated over control values 20 h after the iron administration. Plasma GOT, GPT and LDH activities were not affected, suggesting that liver cell permeability was not affected by necrosis. 3. Spontaneous liver chemiluminescence was measured as an indicator of oxidative stress and lipid peroxidation. Light emission was increased four-fold 6 h after iron supplementation. 4. Increases in the generation of thiobarbituric acid reactive substances (TBARS in liver and kidney homogenates were detected after iron administration. 5. The activities of catalase, SOD and glutathione peroxidase were determined. Enzymatic activities declined in liver homogenates by 25, 36 and 32%, respectively, 20 h after iron injection. These activities were not affected in kidney as compared to control values, except for SOD activity that was decreased by 26%. 6. The content of alpha-tocopherol was decreased by 31% in whole kidney homogenates and by 40% in plasma. 7. Our data indicate that lipid peroxidation occurs after mild iron overload both in liver and kidney. Enzymatic antioxidants are consumed significantly in liver and alpha-tocopherol content decreases in kidney, suggesting an organ-specific antioxidant effect.
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PMID:Effect of mild iron overload on liver and kidney lipid peroxidation. 764 Jun 23

Pulmonary microthromboembolism is one of the serious complications found in patients with thalassemia. The pathogenesis is undetermined. The thrombotic risk in 44 patients (26 males, 18 females) with beta-thalassemia/hemoglobin E disease and without clinical symptoms of thrombosis were studied. The age ranged from 3-19 yr (X +/- SD = 10 +/- 4). Neither of them had chronic hepatitis B infection. They were divided into three groups according to clinical manifestations as follows: (1) Mild form (n = 12). They did not require blood transfusion. The mean +/- SD of hematocrit was 23.3 per cent +/- 2.3; (2) Severe form (n = 19). They required frequent blood transfusion. The mean +/- SD of hematocrit was 17.7 per cent +/- 1.5; (3) Severe form with splenectomy (n = 13). They seldom required blood transfusion. The mean +/- SD of hematocrit was 21.8 per cent +/- 3.5. Most of the patients had delayed growth. They had high serum ferritin reflecting iron overload status which was prominent in the severe groups (group 2 & 3). The prothrombin time and serum albumin were slightly decreased, and the serum alanine transaminase were slightly increased; all of which reflected mild alteration of liver function. The plasma AT III, PC and PS antigen in the three groups were similar. The mean +/- SD of AT III antigen was 106.7 per cent +/- 22.2 which is normal. The mean +/- SD of PC antigen was 44.2 per cent +/- 14.2 and PS antigen level was 77.2 per cent +/- 17.8.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombotic risk of children with thalassemia. 782 10


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