Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antioxidants are likely potential pharmaceutical agents for the treatment of alcoholic liver disease. Metallothionein (MT) is a cysteine-rich protein and functions as an antioxidant. This study was designed to determine whether MT confers resistance to acute alcohol-induced hepatotoxicity and to explore the mechanistic link between oxidative stress and alcoholic liver injury. MT-overexpressing transgenic and wild-type mice were administrated three gastric doses of alcohol at 5 g/kg. Liver injury, oxidative stress, and ethanol metabolism-associated changes were determined. Acute ethanol administration in the wild-type mice caused prominent microvesicular steatosis, along with necrosis and elevation of serum alanine aminotransferase. Ultrastructural changes of the hepatocytes include glycogen and fat accumulation, organelle abnormality, and focal cytoplasmic degeneration. This acute alcohol hepatotoxicity was significantly inhibited in the MT-transgenic mice. Furthermore, ethanol treatment decreased hepatic-reduced glutathione, but increased oxidized glutathione along with lipid peroxidation, protein oxidation, and superoxide generation in the wild-type mice. This hepatic oxidative stress was significantly suppressed in the MT-transgenic mice. However, MT did not affect the ethanol metabolism-associated decrease in NAD(+)/NADH ratio or increase in cytochrome P450 2E1. In conclusion, MT is an effective agent in cytoprotection against alcohol-induced liver injury, and hepatic protection by MT is likely through inhibition of alcohol-induced oxidative stress.
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PMID:Metallothionein protection against alcoholic liver injury through inhibition of oxidative stress. 1185 21

Specimens of the fruit beetle Pachnoda sinuata were starved for up to 30 days. The weight of the beetles declined consistently throughout the starvation period. Concentrations of carbohydrates and alanine in flight muscles, fat body and haemolymph decreased rapidly after onset of starvation, while the concentration of proline remained high. Whereas the lipid concentrations in the haemolymph did not change significantly upon starvation, the lipid content in flight muscles and fat body decreased significantly.Beetles that had been starved for 14 days responded to injection of Mem-CC, the endogenous neuropeptide from its corpora cardiaca, with hyperprolinaemia and a decrease in the alanine level, but no such effect was monitored after prolonged starvation of 28 days. Regardless of the period of starvation, Mem-CC injection could not cause hypertrehalosaemia or hyperlipaemia, although carbohydrates were increased in fed beetles after injection.Flight ability of beetles that had been starved for 15 or 30 days was apparently not impaired. During such periods, beetles used proline exclusively as fuel for flight as evidenced by the increase in the level of alanine in the haemolymph and decrease of the level of proline; the concentrations of carbohydrates and lipids remained unchanged.Activities of malic enzyme and alanine aminotransferase (enzymes involved in transamination in proline metabolism), glyceraldehyde-3-phosphate dehydrogenase (enzyme of glycolysis), 3-hydroxyacyl-CoA dehydrogenase (enzyme of beta-oxidation of fatty acids) and of malate dehydrogenase (enzyme of Krebs cycle) were measured in fat body and flight muscles. In flight muscle tissue the maximum activity of NAD(+)-dependent malic enzyme increased, while that of glyceraldehyde-3-phosphate dehydrogenase decreased during starvation, and malate dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase and alanine aminotransferase were unchanged. In fat body tissue, activities of NADP(+)-dependent malic enzyme and 3-hydroxyacyl-CoA dehydrogenase increased during food deprivation and activities of glyceraldehyde-3-phosphate dehydrogenase, malate dehydrogenase and alanine aminotransferase remained unchanged.
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PMID:Metabolic changes in the African fruit beetle, Pachnoda sinuata, during starvation. 1277 Feb 39

A comparative assay of nitrogen metabolism enzymes in the Yarrowia lipolytica mutant N1 grown under conditions promoting the overproduction of either alpha-ketoglutaric acid (KGA) or citric acid showed that the overproduction of KGA correlates with an increase in the activities of the NAD- and NADP-linked glutamate dehydrogenase, glutamic-pyruvic transaminase, and glutamic-oxaloacetic transaminase reactions. These reactions are likely to be responsible for the overproduction of KGA by this mutant. In contrast, the overproduction of citric acid correlated with a decline in the activities of the NAD- and NADP-linked glutamate dehydrogenases and with an increase in the activities of glutamine synthetase and glutamate synthase.
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PMID:[Biochemical characterization of the yeast Yarrowia lipolytica overproducing carboxylic acids from ethanol. Nitrogen metabolism enzymes]. 1452 35

Few studies demonstrate at a biochemical level the metabolic profile of both cumulus cells and the oocyte during maturation. The aim of the present study was to investigate the differential participation of enzymatic activity in cumulus cells and in the oocyte during in vitro maturation (IVM) by studying the activity of enzymes involved in the control of amino acid metabolism, alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and the tricarboxylic acid (TCA) cycle, isocitrate dehydrogenase (IDH) and malate dehydrogenase (MDH). No NAD-dependent isocitrate dehydrogenase (NAD-IDH) activity was recorded in cumulus-oocyte complexes (COCs). ALT, AST, NADP-dependent isocitrate dehydrogenase (NADP-IDH) and MDH enzymatic units remained constant in cumulus cells and oocytes during IVM. Specific activities increased in oocytes and decreased in cumulus cells as a result of IVM (P<0.05). Similar activity of both transaminases was detected in cumulus cells, unlike in the oocyte, in which activity of AST was 4.4 times greater than that of ALT (P<0.05). High NADP-IDH and MDH activity was detected in the oocyte. Addition of alanine, aspartate, isocitrate + NADP, oxaloacetate or malate + NAD to maturation media increased the percentage of denuded oocytes reaching maturation (P<0.05), in contrast to COCs in which differences were not observed by addition of these substrates and co-enzymes. The activity of studied enzymes and the use of oxidative substrates denotes a major participation of transaminations and the TCA cycle in the process of gamete maturation. The oocyte thus seems versatile in the use of several oxidative substrates depending on the redox state.
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PMID:Involvement of enzymes of amino acid metabolism and tricarboxylic acid cycle in bovine oocyte maturation in vitro. 1474 94

Drug-metabolizing enzymes and membrane transporters are responsible for the detoxication and elimination of xenobiotics from the body. The goal of this study was to identify alterations in mRNA expression of various transport and detoxication proteins in mouse liver after administration of the hepatotoxicants, acetaminophen or carbon tetrachloride. Therefore, male C57BL/6 J mice received acetaminophen (APAP, 200, 300, or 400 mg/kg, ip) or carbon tetrachloride (CCl4, 10 or 25 microl/kg, ip). Plasma and liver samples were collected at 6, 24, and 48 h for assessment of alanine aminotransferase (ALT) activity, total RNA isolation, and histopathological analysis of injury. Heme oxygenase-1 (Ho-1), NAD(P)H quinone oxidoreductase-1 (Nqo1), organic anion-transporting polypeptides (Oatp1a1, 1a4 and 1b2), sodium/taurocholate-cotransporting polypeptide (Ntcp), and multidrug resistance-associated protein (Mrp 1-6) mRNA levels in liver were determined using the branched DNA signal amplification assay. Hepatotoxic doses of APAP and CCl4 increased Ho-1 and Nqo1 mRNA levels by 22- and 2.5-fold, respectively, and reduced Oatp1a1, 1a4, and Ntcp mRNA levels in liver. By contrast, expression of Mrps 1-4 was increased after treatment with APAP and CCl4. Notably, a marked elevation of Mrp4 mRNA expression was observed 24 h after APAP 400 mg/kg (5-fold) and CCl4 25 microl/kg (37-fold). Collectively, these expression patterns suggest a coordinated regulation of both transport and detoxification genes during liver injury. This reduction in expression of uptake transporters, as well as enhanced transcription of detoxication enzymes and export transporters may limit the accumulation of potentially toxic products in hepatocytes.
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PMID:Differential expression of mouse hepatic transporter genes in response to acetaminophen and carbon tetrachloride. 1645 59

Chronic ethanol ingestion alters mitochondrial function in the liver including inhibition of complex I of the electron transport chain. This leads to a shift in the NAD/NADH ratio to the reduced state when blood ethanol levels are high. Rotenone also inhibits complex I and induces a reduced state. The combination of ethanol feeding and rotenone toxicity should amplify the reduced state and block the cyclic increase and decrease in the rate of metabolism in the liver. The change in the redox state occurs during the urinary ethanol cycle in the intragastric tube feeding rat model of alcoholic liver disease. To test this hypothesis, rats were fed ethanol with rotenone and the 24-h urinary ethanol levels were measured daily. When ethanol was fed alone, the urinary ethanol cycle occurred. However, when ethanol was fed with rotenone the cycle was prevented and the urinary ethanol levels remained at the 200-mg% range. The rats fed ethanol or fed ethanol plus rotenone had the same increase in the pathology score and ALT elevations in the blood. Rotenone fed alone had the same normal values as the dextrose pair fed control rats. The results indicate that the UAL cycle is driven by fluctuation in the NAD/NADH ratio. When this fluctuation is blocked by rotenone, the cycle does not occur. It is concluded that the urinary ethanol cycle is dependent on cyclic fluctuation of the NAD/NADH ratio, which regulates the rate of ethanol elimination.
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PMID:The effect of rotenone on the urinary ethanol cycle in rats fed ethanol intragastrically. 1550 38

The blood alcohol level cycle (BALC) of the intragastric tube feeding model first described by Tsukamoto et al., has three separate essential mechanistic components. The first is the requirement for an intact functioning thyroid. The evidence for this is that propylthiouracil or severance of the pituitary stalk completely prevents the cycle. What happens instead of the cycle is that the blood alcohol level rises to a lethal level when ethanol is given continuously at a dose of 11 g/kg/day by stomach tube. When excess thyroid hormone is given orally it markedly attenuates the cycle because it interferes with the changes in the level of thyroid hormone during the cycle. The second component is norepinephrine. Catecholamines are markedly elevated at the peaks of the cycle. Both propranolol and phenoxybenzamine, which are beta- and alpha-blockers, prevent the cycle. Also, when catecholamines are fed in excess in the form of ephedrine, the cycle is eliminated. The third element essential to the cycle is the generation of NAD to support the oxidation of alcohol by alcohol dehydrogenase. When complex I (NADH dehydrogenase) of the mitochondrial electron transport chain is inhibited by feeding rotenone, the cycle is totally eliminated and blood alcohol levels remain constant at 200 mg/%. Thus NADH increases and NAD decreases at the peak of the cycle. Without the fluxuation of NAD, ADH activity cannot fluctuate during the cycle and the cycle is prevented. The significance of the BALC in the understanding of alcohol liver disease pathogenesis is that there's a marked difference in the gene expression and liver toxicity when the peaks and troughs of the cycle are compared. The expression of 1000+ genes is either two-fold up or down regulated as determined by microarray analysis. At the peaks there is increased liver pathology, especially inflammatory changes in the liver associated with an increase of iNOS expression. The genes responsive to hypoxia inducible factor 1alpha (HIF1alpha) regulation are increased including the expression of erythropoietin, adrenomedullin and adrenergic receptor alpha 1a and d. The expression of prolyl hydroxylase, which destabilizes HIF1alpha, increases when the BAL drops to low levels during the cycle. The level of oxygen, as measured on the surface of the liver, is decreased at the peaks, compared to control livers. The NADH/NAD ratio is markedly increased and ATP levels are markedly decreased at the BAL peaks. Also, endotoxin in the blood is very high at the peaks and very low at the troughs. When the blood alcohol levels fall during the cycle, there is an increase in ALT, suggesting that reoxygenation from the hypoxic state at the peaks causes an ischemic reperfusion injury-like lesion in the liver. At this time there is also an increase in expression of many important enzymes such as manganese SOD. Genes such as c-fos and CTGF are increased in expression. These contrasting findings at the peaks and troughs indicate that the blood alcohol levels, which fluctuate up and down, change the gene expression and the pathology of the liver.
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PMID:The pathogenesis and significance of the urinary alcohol cycle in rats fed ethanol intragastrically. 1634 1

Labeled glutamate was rapidly converted to gamma-aminobutyrate in intact, excised radish (Raphanus sativus L., var. Champion) leaves. Labeled gamma-aminobutyrate was metabolized via succinate and the Krebs cycle and was not carboxylated to form glutamate. Administration of carbon-14 and tritium-labeled succinate indicated that less than 10% of the gamma-aminobutyrate formation occurs by amination of succinic semialdehyde. Therefore, most gamma-aminobutyrate formation must be via glutamate decarboxylation.Radish leaf extracts were more active in catalyzing transamination between gamma-aminobutyrate and pyruvate than that between gamma-aminobutyrate and alpha-ketoglutarate. Glutamate decarboxylase was approximately 20 times more active than gamma-aminobutyrate: pyruvate transaminase. Succinic semialdehyde dehydrogenase was found in the extracts, and NAD was much more active as a hydrogen acceptor than NADP. No reduction of succinate to succinic semialdehyde by the NAD-linked dehydrogenase could be demonstrated. The following pH optima were determined: glutamate decarboxylase, 5.9; gamma-aminobutyrate: pyruvate transaminase, 8.9; succinic semialdehyde: NAD dehydrogenase, about 9.0.
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PMID:In Vivo and In Vitro Studies on gamma-Aminobutyric Acid Metabolism with the Radish Plant (Raphanus sativus, L.). 1665 5

The succulent, cylindrical leaves of the C(4) dicot Portulaca grandiflora possess three distinct green cell types: bundle sheath cells (BSC) in radial arrangement around the vascular bundles; mesophyll cells (MC) in an outer layer adjacent to the BSC; and water storage cells (WSC) in the leaf center. Unlike typical Kranz leaf anatomy, the MC do not surround the bundle sheath tissue but occur only in the area between the bundle sheath and the epidermis. Intercellular localization of photosynthetic enzymes was characterized using protoplasts isolated enzymatically from all three green cell types.Like other C(4) plants, P. grandiflora has ribulose 1,5-bisphosphate carboxylase and the decarboxylating enzyme, NADP(+)-malic enzyme, in the BSC. Unlike other C(4) plants, however, phosphoenolpyruvate carboxylase, pyruvate, Pi dikinase, and NADP(+)-malate dehydrogenase of the C(4) pathway were present in all three green cell types, indicating that all are capable of fixing CO(2) via phosphoenolpyruvate carboxylase and regenerating phosphoenolpyruvate. Other enzymes were about equally distributed between MC and BSC similar to other C(4) plants. The enzyme profile of the WSC was similar to that of the MC but with reduced activity in most enzymes, except mitochondrion-associated enzymes.Intracellular localization of enzymes was studied in organelles partitioned by differential centrifugation using mechanically ruptured mesophyll and bundle sheath protoplasts. Phosphoenolpyruvate carboxylase was a cytosolic enzyme in both cells; whereas, ribulose 1,5-bisphosphate carboxylase and NADP(+)-malic enzyme were exclusively compartmentalized in the bundle sheath chloroplasts. NADP(+)-malate dehydrogenase, pyruvate, Pi dikinase, aspartate aminotransferase, 3-phosphoglycerate kinase, and NADP(+)-triose-P dehydrogenase were predominantly localized in the chloroplasts while alanine aminotransferase and NAD(+)-malate dehydrogenase were mainly present in the cytosol of both cell types. Based on enzyme localization, a scheme of C(4) photosynthesis in P. grandiflora is proposed.Well-watered plants of P. grandiflora exhibit a diurnal fluctuation of total titratable acidity, with an amplitude of 61 and 54 microequivalent per gram fresh weight for the leaves and stems, respectively. These changes were in parallel with changes in malic acid concentration in these tissues. Under severe drought conditions, diurnal changes in both titratable acidity and malic acid concentration in both leaves and stems were much reduced. However, another C(4) dicot Amaranthus graecizans (nonsucculent) did not show any diurnal acid fluctuation under the same conditions. These results confirm the suggestion made by Koch and Kennedy (Plant Physiol. 65: 193-197, 1980) that succulent C(4) dicots can exhibit an acid metabolism similar to Crassulacean acid metabolism plants in certain environments.
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PMID:Photosynthetic Characteristics of Portulaca grandiflora, a Succulent C(4) Dicot : CELLULAR COMPARTMENTATION OF ENZYMES AND ACID METABOLISM. 1666 54

Pea (Pisum sativum L. cv ;Little Marvel') plants were exposed to SO(2) for short term (3 hours) and long term (2 days) at 0.2 and at 0.5 microliter per liter (ppm) levels. The effect of this treatment on the activity of phosphoenolpyruvate carboxylase, NAD- and NADP-malate dehydrogenases, and alanine aminotransferase from epidermis and whole leaves was investigated. Short-term exposure to SO(2) at 0.2 or 0.5 ppm decreased the activity of the carboxylase and the dehydrogenases in the epidermis. In contrast, the activity of the same three enzymes increased in whole leaves with either short- or long-term exposure to SO(2). Alanine aminotransferase in epidermis or whole leaves was not much affected by short-term exposure, but the epidermal activity was decreased and whole leaf activity was increased with long-term exposure. SO(2) exposure which was initiated prior to illumination decreased the free thiol content of both epidermis and of whole leaf. Net photosynthesis was reversibly inhibited by long-term exposure to SO(2) at 0.5 ppm. No effect of 0.5 ppm SO(2) on stomatal conductance was detectable after 3 hours. Stomatal conductance appeared to decrease after longer exposure times (2 days) at 0.5 ppm.
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PMID:Effects of SO(2) on Stomatal Metabolism in Pisum sativum L. 1666 45


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