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:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate the onset of toxicity and to further elucidate the role of cytochrome P450 in the metabolism and toxicity of these compounds. In a study design employing one animal per dose level, Fischer-344 rats were gavaged with up to 25 different dosages, then evaluated 24 h later. Hepatic necrosis, serum alanine aminotransferase, and serum aspartate aminotransferase exhibited similar patterns demonstrating that ortho-DCB (o-DCB) was the most toxic in terms of both earliest onset and degree of response at higher dosages. For these three endpoints, meta-DCB (m-DCB) exhibited a lesser toxicity. Para-DCB (p-DCB) did not cause changes in these three endpoints, but hepatic degenerative changes were found. Total hepatic cytochrome P450 responses were also different after treatment with each isomer. The o-DCB produced a dose-dependent decrease in P450 beginning at dosages lower than the onset of necrosis and appeared to be a suicide substrate for P450. The m-DCB treatment increased P450 at dosages below the onset of necrosis and decreased P450 at higher dosages, with the decline preceding the onset of hepatocyte death. Treatment with p-DCB increased P450 beginning at 380 mg/kg. The combination of toxicity and P450 profiles has provided a framework for interpreting literature data on the metabolism and toxicity of the DCBs in rats. It is also noteworthy that o-DCB and p-DCB were administered at dosages several times the oral rat LD-50 (RTECS) without any lethality.
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PMID:The differential hepatotoxicity and cytochrome P450 responses of Fischer-344 rats to the three isomers of dichlorobenzene. 129 13

[3H]Glutamate uptake into astrocytes in primary culture was potently inhibited by the aspartate analogues L- and D-aspartic acid, DL-threo-beta-hydroxy-aspartic acid-beta-hydroxymate (IC50's: 136, 259, 168, and 560 microM, respectively) and by beta-DL-methylene-aspartate, a suicide inhibitor of aspartate aminotransferase (IC50: 524 microM), and by the endogenous sulphur-containing amino acid L-cysteinesulfinic acid (IC50: 114 microM), [3H]Glutamate uptake was not significantly affected by either N-methyl-D-aspartate or DL-homocysteine thiolactone. These results demonstrate that other excitatory amino acids including aspartate and L-cysteinesulfinic acid (but excluding L-homocysteic acid) interact with the glutamate transport system of astrocytes. Inhibition of glutamate uptake may significantly increase the level of neuronal excitability.
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PMID:Beta-DL-methylene-aspartate, an inhibitor of aspartate aminotransferase, potently inhibits L-glutamate uptake into astrocytes. 257 Oct 95

beta-Ethylidene-DL-aspartate (beta EA) and beta-methylene-DL-glutamate (beta MG) were synthesized and tested as potential suicide inhibitors of soluble pig heart glutamate-aspartate transaminase (sGAT). beta MG was found to be a) a substrate with a very low turnover number relative to glutamate and b) a competitive inhibitor with respect to aspartate (albeit with a large binding constant). At high concentrations beta MG inactivated the enzyme but only very slowly. beta EA was also found to be a substrate with a very low turnover number; it did not inactivate the enzyme (1 hr, 25 degrees C) even at a high concentration. However, beta EA was found to bind to the enzyme with an affinity comparable to that of aspartate and glutamate. beta-Methylene-DL-aspartate (beta MA) has been shown to rapidly inactivate glutamate-aspartate transaminase. Therefore, it appears that glutamate-aspartate transaminase can bind analogues of aspartate with alkene groups in the beta position. The conjugated carbonyl groups of beta MA and beta EA will enhance Michael addition in comparison with that expected for vinylglycine. On the other hand, the presence of the methyl groups should reduce the electrophilicity of the double bond of beta EA compared to beta MA. This deactivation and/or steric hindrance to Michael attack may account for the inability of beta EA to inactivate sGAT. Therefore, it may be possible to design selective suicide inhibitors of glutamate-aspartate++ transaminase with the following structure: HO2CC(= CHX)CH(CO2H)NH2, where X is an electron-withdrawing group. Ideally, X would increase the reactivity of the double bond while affording a minimum of steric hindrance to susceptible enzyme-bound bases.
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PMID:Interaction of soluble pig heart glutamate-aspartate transaminase with various beta,gamma-unsaturated amino acids. 286 Sep 2

Active site titration provides a means of calibrating enzyme reference materials in molecular concentration units independent from the incubation conditions used in kinetic assays. Such reference materials may serve as primary standards for calibrating any kinetic assay using the same active site. Active site titration of aspartate aminotransferase has been done by fluorimetric measurement of the half-cycle transamination of the phosphopyridoxal form. Another promising approach is the stoichiometric titration with specific suicide substrates such as vinylglycine. Expression of results in molecular concentration units requires that both the primary enzyme standard and the enzyme as measured in blood plasma show similar turnover numbers and substrate specificity in the kinetic assay being used. This is best achieved with purified reference materials of human origin. If the assay in plasma measures the sum of several isoenzymes having different turnover numbers, then the calibration is no longer absolute but becomes method-dependent.
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PMID:Molecular titration as a means of calibrating enzyme reference materials. 338 22

The inactivation mechanism of pyridoxal phosphate-linked mitochondrial aspartate transaminase (pig heart) by gostatin (5-amino-2-carboxy-4-oxo-1,4,5,6-tetrahydropyridine-3-acetic acid), a novel amino acid produced by Streptomyces sumanensis, was investigated. Gostatin is a time-dependent inhibitor of the enzyme giving an enzyme half-life of 1.8 min at 3.1 microM (25 degrees C). The kinetic properties of the inhibitor suggest that it is a suicide substrate (mechanism-based inhibitor) of the enzyme, and the observed Ki is 59 microM and Kcat is 0.11S-1 at 25 degrees C. Incubation of the enzyme with a stoichiometric amount of the inhibitor (1 mol of inhibitor/1 mol of enzyme monomer) results in complete inactivation. Spectrophotometric titration and gel filtration experiments indicate the binding of 1 mol of gostatin with 1 mol of enzyme monomer. Gostatin serves as an efficient titrant for the enzyme. Liberation of a compound having inhibitory activity against the apo-form enzyme from the enzyme-inhibitor complex under denaturing conditions suggests irreversible modification of the cofactor.
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PMID:Mechanism of inactivation of pyridoxal phosphate-linked aspartate transaminase by gostatin. 674 7

Ornithine aminotransferase is shown to bind 1 mol of amino[14C]hexynoate per mol of coenzyme in the 'suicide' inactivation process. At the same time the coenzyme pyridoxal phosphate becomes irreversibly bound to the enzyme protein. Apart from the inactivation, the labelled enzyme is indistinguishable from native ornithine aminotransferase by several separation techniques. Because the rate of degradation of the labelled enzyme is the same as that of the normal enzyme it is concluded that loss of coenzyme does not initiate turnover. Free aminohexynoate is rapidly eliminated from the liver, and 70% of the compound is excreted unchanged in 7.5 h. Inactivated ornithine aminotransferase accounts for 11% of the total labelled liver protein and significant amounts of label are found in aspartate aminotransferase which is also extensively inactivated. The rate of return of enzyme activity is determined and found to be more rapid than expected for a process in which the enzyme is synthesized at a constant rate and degraded in a single, first-order process.
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PMID:An investigation of the properties of ornithine aminotransferase after inactivation by the 'suicide' inhibitor aminohexynoate and use of the compound as a probe of intracellullar protein turnover. 684 11

We describe the effects of the neurotoxin 3-nitropropionic acid (3-NPA) on fatty acid oxidation in neonatal rat brain astrocytes in primary culture, using a sensitive assay for beta-oxidation which depends on the release of 3H2O from [9,10(n)-3H]palmitic acid. 3-NPA is a suicide inhibitor of succinate dehydrogenase, a constituent of both Krebs cycle and complex II of the mitochondrial respiratory chain. It is widely distributed in plants and fungi. Neurotoxicity of 3-NPA to humans and animals, leading to selective neuronal cell death, appears mediated by the reduced level of ATP induced by the toxin. We demonstrated that 3-NPA can also impair energy metabolism in astrocytes. Exposure of astroglial cells in culture to 3-NPA leads to inhibition of the release of 3H2O from [9,10(n)-3H]palmitic acid. Addition of 2 mM 3-NPA to the culture medium caused a rapid decrease in beta-oxidation activity, which reached a plateau after 90 min. This inhibition was concentration-dependent. Concentration as low as 0.05 mM for 5 h significantly decreased beta-oxidation activity (25% inhibition). Half-maximal inhibition was obtained after treatment with 0.5 mM 3-NPA, and 3 mM induced a maximal response (63% inhibition) 3-NPA is clearly a potent inhibitor of beta-oxidation activity. We also show that 3-NPA 3 mM inhibits partially complex II (succinate ubiquinone reductase) and aspartate aminotransferase by 60 and 49% after 4 h treatment respectively. It has been shown that fatty acid is the preferred substrate for energy production in cultured astrocytes from developing brain. As astrocytes may also provide substrates alternative for energy metabolism in neurons and oligodendrocytes, it is likely that the inhibition of beta-oxidation by 3-NPA may contribute significantly to the damage induced by this toxin in the central nervous system.
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PMID:Inhibition of fatty acid beta-oxidation in rat brain cultured astrocytes exposed to the neurotoxin 3-nitropropionic acid. 921 76

To determine the influence of psychosocial factors in accidental and deliberate acetaminophen overdose, we reviewed the charts of 207 overdose patients, and 48 met our criteria for acetaminophen toxicity. Two patients died. A psychiatric history was present in 75%, and 25% had a previous or subsequent suicide attempt. A substance abuse history was elicited from 46% and 36% of adolescent teenagers had a teen pregnancy. The mean time to starting N-acetylcysteine was 18.5 hr. Delayed N-acetylcysteine administration led to higher transaminase levels. Alcohol abuse was associated with a longer hospital stay. Mean AST was 8,860 IU/liter in the accidental and 3,013 IU/liter in the suicide groups. We concluded that management of acetaminophen toxicity can be optimized by early identification, obtaining a complete drug screen, starting N-acetylcysteine early or whenever toxic acetaminophen levels or elevated transaminases are identified, and referring patients with acetaminophen toxicity to a liver center.
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PMID:Acetaminophen hepatoxicity. 1100 5

The aim of the study was to determine the level of total cholesterol and LDL-cholesterol in blood samples taken from 102 patients with recurrent major depression (according to DSM-IV). The analysis was performed during the acute period of major depression in 3 subgroups: with and without suicidal ideation (S+, S-), and after suicidal attempts (AS), and during remission of depressive symptoms. Putative correlations between the level of total cholesterol and severity of depressive symptoms and between total serum cholesterol and LDL-cholesterol and suicidal risk were evaluated. The patients did not suffer from any additional disorders, factors such as specific diet or pharmacotherapy, which could influence the levels of lipids, were absent. The subgroups were identified using clinical evaluation, medical records and Hamilton Depression Rating Scale--HAMD-S as well as a subscale of MMPI-DMS. Biochemical analyses were performed twice in all patients, in the acute period, before pharmacotherapy and after effective pharmacotherapy, in remission. The following parameters were evaluated: total serum cholesterol and LDL-cholesterol, T3, T4, TSH, ALT, AST, proteinogram. In all depressed patients with acute depression symptoms, low levels of total cholesterol and LDL-cholesterol were shown. The level of total cholesterol 160 mg/dl or less and the level of LDL-cholesterol 100 mg/dl or less were observed in persons with suicidal behavior only (S+ and AS). Low total cholesterol and LDL-cholesterol levels in persons in the acute period of major depression provided a useful parameter of suicide risk. A significant statistical correlation between the low level of total cholesterol and suicidal ideation was also found (r = 0.82, p < 0.05) as well as between the low level of serum total cholesterol and severity of depression, as evaluated by HAMD-S (r = 0.27, p < 0.05). During the remission of depressive symptoms, total cholesterol level and LDL-cholesterol increased significantly (p < 0.05) but a significant difference (p < 0.05) between subgroups (S-, S+, AS) were still observed. Low total cholesterol and LDL-cholesterol levels in remission in persons with the diagnosis of recurrent major depression may help to estimate the risk of suicidal behavior in the next depressive disorder. Possibly, low level of serum total cholesterol is a stable feature in some persons with recurrent major depression, probably dependent on their predisposition to autoaggression and presence of depressive disorder.
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PMID:Levels of serum total cholesterol and LDL-cholesterol in patients with major depression in acute period and remission. 1120 67

Abamectin is widely used as an insecticide and an anthelmintic. A previous report indicated that abamectin was used to commit suicide and led to death in Taiwan. This investigation focused on the toxicological effects of abamectin on serum aspartate aminotransferase (AST) and nitrate/nitrite (NO) levels in rats. After rats were gavaged with abamectin ranging from 1 to 20 mg/kg/body weight, AST and NO levels were examined within 12 h. AST and NO levels were elevated in abamectin-dosed rats in a dose-dependent manner. The least increase of AST corresponded to the highest enhancement of NO release at 6 h. A negative correlation coefficient (r=-0.55) between AST and NO was found. Both NG-nitro-L-arginine-methyl ester and aminoguanidine, inhibitors of nitric oxide synthase, increased the AST level induced by abamectin. These findings suggest that NO may be involved in the alteration of AST release induced by abamectin in rats.
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PMID:Abamectin effects on aspartate aminotransferase and nitric oxide in rats. 1152 77


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