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)

DL-alpha-Methyltryptophan (alphaMeTrp), a synthetic analogue of tryptophan, has been found to be a potent inducer of hepatic tyrosine aminotransferase activity in the adrenalectomized rat. alphaMeTrp is inactive in vitro. Unlike the action of other known inducers (tryptophan, hydrocortisone, adenosine cyclic 3:5-monophosphate, and glucagon), maximal stimulation of enzyme activity occurs only 16 to 30 hours after alphaMeTrp administration and the activity is still elevated at 96 hours. Only the L isomer of alphaMeTrp is active, and addition of a hydroxyl group to position 5 of the indole ring renders an inactive compound. The induction can be prevented by actinomycin D or cycloheximide but not galactosamine. Administration of alphaMeTrp together with hydrocortisone produced an additive stimulation of enzyme activity. alphaMeTrp given along with glucagon or adenosine cyclic 3:5-monophosphate caused a further but not additive increase in enzyme activity. Tryptophan given along with alphaMeTrp promoted no extra stimulation whatsoever. These data indicate that alphaMeTrp and tryptophan may act via a common pathway which in part requires RNA synthesis. Other enzymes, namely alanine and aspartate aminotransferase, ornithine aminotransferase, ornithine carbamoyltransferase, serine dehydratase, and histidine ammonialyase, were not affected by treatment of rats with alphaMeTrp.
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PMID:Stimulation of tyrosine aminotransferase activity by dl-alpha-methyltryptophan. 23 76

In previous studies, we reported that the age-dependent hepatotoxicity of galactosamine (GalN) was evident in hepatocytes maintained in primary cultures. Cellular proliferation and tissue repair are not manifested in response to injury in this in vitro system. Neonatal (5-day) rats have ongoing hepatocellular proliferation in contrast to adult (5-month) rats, and should be therefore resilient to GalN toxicity. Liver injury was assessed by serum transaminases (ALT, AST), 3H-thymidine (3H-T) incorporation into nuclear DNA, and content of hepatocellular nuclear DNA. While the dose of 400 mg/kg did not cause any significant liver injury in the neonates, it did produce significant liver injury in adult rats. At a dose of 800 mg/kg, GalN produced significant injury in the neonates. Because 400 mg/kg causes clearly demonstrable liver injury in the adult and no injury in the neonates, this dose was used for further studies. In addition to the above measures of injury, uracil nucleotides (UTP, UDP, and UMP), glycogen, histopathology, and autoradiographic examination of liver sections were used to assess the liver injury in neonatal and adult rats. In a time-course study, all of the above were measured at 0, 12, 24, 36, 48 and 72 h after GalN administration. Serum enzyme elevations as well as the appearance of necrotic and swollen hepatocytes were maximal at 24 h in the adults rats. In contrast to these observations in the adult rats, none of these measurements indicated significant liver injury in the neonates. 3H-T incorporation into nuclear DNA was much higher in the neonatal liver in comparison to the adults reflecting the difference in regeneration. Hepatocellular nuclear DNA was also higher in the neonate and was significantly decreased due to GalN treatment. In the adult rats, the quiescent normal level of 3H-T incorporation and nuclear DNA content were further decreased at 12 h, increased at 48 h and returned to normal low, quiescent levels at 72 h. In the neonates mitotic activity of hepatocytes was higher than in the adult rats. In the adult rats, mitotic activity was increased at 48 h after GalN administration and returned to normal at 72 h. In the neonates GalN did not alter the mitotic activity significantly. These findings demonstrate that in the presence of hepatocellular regeneration, galactosamine toxicity is minimal while in the absence of it, clear toxicity is manifested. In conclusion, while perturbation in uracil nucleotides and related biochemical events may explain the infliction of liver injury by GalN in an age-dependent fashion, the extent of tissue repair impacts decisively on the final outcome of injury.
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PMID:Ongoing hepatocellular regeneration and resiliency toward galactosamine hepatotoxicity. 129 Apr 5

The present study examined the preventive effects of green tea extract on D-galactosamine (GalN)-induced hepatic injury in rats, an animal model of viral hepatitis. A single i.p.-injection of GalN (700 mg/kg) to male Wistar rats caused fulminant hepatitis by 48 hr as assessed by marked increases in the serum aspartate aminotransferase (GOT), alanine aminotransferase (GPT) and alkaline phosphatase (ALP) activities; decreases in the serum protein and cholesterol levels and the amount of liver microsome P-450; and marked changes in organ weights. The lecithin: cholesterol acyltransferase (LCAT) activity markedly increased at 8 hr and markedly decreased at 24 hr after the GalN injection. In the experiment, animals were orally administered green tea extract at doses of 50, 100 or 200 mg/kg five times each before and after the GalN injection. Treatment with green tea extract significantly prevented the increases in the GOT, GPT and ALP activities in a dose-related manner. It also significantly prevented the decreases in serum albumin and total cholesterol, although not in a dose-related manner. A tendency to prevent the increase in LCAT activity and the decrease in liver microsome P-450 was also noted. Little effect was found on the other abnormal changes in the serum lipids and proteins and the organ weights. These results suggest that green tea may have an ameliorating effect on hepatic dysfunction.
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PMID:[Effects of green tea extract on galactosamine-induced hepatic injury in rats]. 146 98

The possible aggravation of liver injury by impaired cellular antioxidant function was investigated. A vitamin E-deficient diet (0.5 mg/kg alpha-tocopherol; control 100 mg/kg) significantly reduced rat liver alpha-tocopherol concentrations after 4 weeks (1.8 +/- 1.7 micrograms/g; control 34.4 +/- 2.4 micrograms/g, p < 0.001). The effects of copper loading (Cu, 3 g/kg diet); galactosamine (GalN, 0.85 g/kg i.p.); or carbon tetrachloride (CCl4, 10 mmol/kg i.p.) were examined. Serum aspartate transaminase activity was elevated slightly by vitamin E deficiency but not by hepatic copper accumulation. In vitamin E-replete (E+) and vitamin E-deficient (E-) rats, GalN or CCl4 caused a large and comparable elevation in serum AST and OCT activity. This effect on AST was markedly reduced by copper loading in vitamin E replete (E+) rats, but in E(-) rats copper had significantly less protective effect. Copper also diminished the OCT response to GalN in E+, though not E-, rats. A significant rise in total hepatic alpha-tocopherol content followed administration of GalN or CCl4 in both normocupric and copper-laden E(-) rats. Thus alpha-tocopherol deficiency (a) was not hepatotoxic per se; (b) failed to potentiate the toxicity of copper, GalN or CCL4; but (c) partially abolished the protection by copper against toxin-induced liver injury. Retention of hepatic alpha-tocopherol after liver damage may partly explain low serum vitamin E levels seen in clinical liver disease.
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PMID:Alpha-tocopherol deficiency fails to aggravate toxic liver injury but liver injury causes alpha-tocopherol retention. 148 10

Lead markedly augments the lethality of endotoxin lipopolysaccharide (LPS) in rats. In this model of LPS toxicity, the liver is severely injured. Much of the tissue injury produced by LPS is thought to be mediated by the cytokine tumor necrosis factor (TNF). Tumor necrosis factor recently has been speculated to be a mediator of several models of liver injury such as that produced by galactosamine. To investigate the possible role of TNF in the lead-enhanced LPS toxicity model, we administered doses of lead acetate (15 mg/kg), LPS (100 micrograms/kg), or TNF (6.25 x 10(6) U/kg) that produced minimal changes in liver enzymes. However, when lead was administered simultaneously with either LPS or TNF, serum aspartate transaminase, alanine transaminase, alkaline phosphatase, glutamyl transpeptidase, and plasma triglyceride levels were markedly increased. Lead + LPS treatment increased both peak serum TNF concentrations and TNF "area under the curve" as compared with LPS alone. We conclude that lead not only enhances LPS lethality but also LPS liver injury. Furthermore, lead enhances TNF liver injury and increases LPS-stimulated serum TNF levels. These data suggest that the lead-enhanced LPS model offers a system for studying TNF-induced liver injury.
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PMID:Lead enhances lipopolysaccharide and tumor necrosis factor liver injury. 167 39

A study was conducted to investigate morphologic as well as metabolic characteristics of microcarrier-attached hepatocytes in culture, and also to evaluate the effect of intraperitoneal transplantation of the microcarrier-attached hepatocytes on acute hepatic failure in rats induced by D-galactosamine (GalN). Rat hepatocytes were isolated by collagenase perfusion, and cultured on collagen-coated microcarriers. Protein synthesis estimated by [14C] leucine incorporation was four-fold higher in microcarrier culture than in cell suspension. The rates of albumin, transthyretin and bile acid syntheses in hepatocytes cultured on microcarriers were similar to those in monolayer culture. When microcarrier-attached hepatocytes were intraperitoneally transplanted into rats with Galn-induced acute liver failure, a marked improvement in survival rate was observed as compared with control rats which received injections of microcarriers alone (80% vs 0% beyond 6 days of transplantation). Mean serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), methionine and glucose levels were similar in both groups, while serum bilirubin and ammonia levels were lower (P less than 0.1, P less than 0.05) in rats transplanted with the microcarrier-attached hepatocytes. Immunohistochemical examinations revealed that the transplanted hepatocytes around microcarriers had albumin synthesis activity, whereas almost no albumin synthesis was demonstrated in recipient liver. In conclusion, intraperitoneal transplantation of the microcarrier-attached hepatocytes will provide sufficient metabolic support, representing detoxication of ammonia (and presumably bilirubin) and synthesis of albumin, to allow GalN-damaged liver function to restore. Microcarrier culture of isolated hepatocytes seems to be one of the most appropriate tools for an artificial liver support.
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PMID:Effects of intraperitoneal transplantation of microcarrier-attached hepatocytes on D-galactosamine-induced acute liver failure in rats. 168 85

The present study was conducted to observe the effect of platelet activating factor antagonist-WEB 2086 on the galactosamine/endotoxin (GalN/E)-induced rat liver injury. The results showed that the WEB 2086 (1, 20 or 40 mg/kg, ip) diminished significantly GaIN/E induced elevations of ALT.AST and ACP in the serum (P less than 0.01). Histological changes of the liver were also found to be improved significantly by WEB 2086 administration. Additionally, WEB 2086 decreased significantly the GaIN/E-induced increase of Malondialdehyde (MDA) and Myeloperoxidase (MPO) in the liver (P less than 0.05-0.01), and prevented the decreasing of superoxide dismutase (SOD) in the liver (P less than 0.01). The results obtained with WEB 2086 confirm that platelet activating factor (PAF) has an important role in the pathophysiology of liver injury, PAF-antagonists may have protective effects on liver injury.
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PMID:[Protective effect of a platelet activating factor antagonist in experimental liver injury]. 217 27

Intravenous injection of lipopolysaccharide and D-galactosamine, at doses of 0.2 micrograms/kg and 800 mg/kg, respectively, elicited massive hepatic necrosis within 24 hr in C3H/HeN mice. The plasma L-alanine aminotransferase (ALT, E.C. 2.6.1.2) or L-aspartate aminotransferase (AST, E.C. 2.6.1.1) activities at this point reached more than 2,000 IU/L. However, overt hepatic injury as evaluated by the plasma aminotransferase activities did not develop in mice in which only lipopolysaccharide or only D-galactosamine was injected. No tumor necrosis factor-like activities could be detected in the plasma of galactosamine- and lipopolysaccharide-injected mice as determined by the assay of cytotoxicity to highly tumor necrosis factor-sensitive L-P3 cells through the experimental period of 24 hr. However, passive immunization against mouse tumor necrosis factor-alpha with polyvalent rabbit anti-mouse tumor necrosis factor-alpha antiserum, which was able to neutralize the cytotoxic effects of recombinant mouse tumor necrosis factor-alpha on L-P3 cells, could protect the mice from the development of hepatic injury in a dose-dependent manner. Simultaneous injection of recombinant human tumor necrosis factor-alpha, instead of lipopolysaccharide, with 800 mg/kg of D-galactosamine in lipopolysaccharide-resistant C3H/HeJ mice sensitized the animals more than one thousand-fold to the development of hepatic injury. The livers appeared to be morphologically similar to those of galactosamine- and lipopolysaccharide-injected C3H/HeN mice.
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PMID:Involvement of tumor necrosis factor-alpha in development of hepatic injury in galactosamine-sensitized mice. 222 17

The activity of dipeptidyl aminopeptidase IV was studied in the sera of 378 hospitalized patients. The mean activity of dipeptidyl aminopeptidase IV was elevated significantly in patients with neoplasmata and hepatitis, but not in patients with liver cirrhosis. Significant correlations (p less than 0.001) existed with gamma-glutamyl transferase, glutamate dehydrogenase, alkaline phosphatase and leucine aminopeptidase. A significant correlation with lactate dehydrogenase existed only in patients with neoplasmata. Principal component analysis, performed with aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, leucine aminopeptidase, lactate dehydrogenase and dipeptidyl aminopeptidase IV, revealed correlations between the activities of aspartate aminotransferase and alanine aminotransferase, and between alkaline phosphatase and leucine aminopeptidase, but neither dipeptidyl aminopeptidase IV nor lactate dehydrogenase showed any correlation with either of these two groups. In lectin affinity chromatography with concanavalin A and wheat germ lectin sepharose, serum dipeptidyl aminopeptidase IV from liver cirrhosis patients showed the same binding pattern as that from healthy subjects. The activity and glycosylation of dipeptidyl aminopeptidase IV in serum and hepatic plasma membranes was investigated in rats, following the induction of hepatitis with galactosamine. In the serum, dipeptidyl aminopeptidase IV activity was elevated as early as 6 h after galactosamine injection, and the elevated activity persisted until the 7th day. At the same time dipeptidyl aminopeptidase IV activity was also elevated in the hepatic plasma membrane. Ninety eight percent of hepatic dipeptidyl aminopeptidase IV bound to concanavalin A as well as to wheat germ lectin and this value was unchanged during hepatitis. In the serum of control rats, 90% of dipeptidyl aminopeptidase IV bound to concanavalin A but only 39% to wheat germ lectin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Dipeptidyl aminopeptidase IV in hospitalized patients and in galactosamine hepatitis of the rat: Activity and lectin affinity chromatography in serum and hepatic plasma membranes]. 257 17

In an attempt to elucidate the role of hepatic macrophages in liver injury, we investigated galactosamine-treated rats (500 mg per kg body weight). The rats received an i.v. injection of latex particles (2 x 10(9) particles per animal) prior to (latex-galactosamine) or 12 to 16 hr subsequent to the galactosamine treatment (galactosamine-latex). Effect of superoxide dismutase on hepatic injury induced by galactosamine or galactosamine-latex treatment was also examined. Oxygen-derived free radical-generating capacity of isolated hepatic macrophages was measured as chemiluminescence with the stimulation of phorbol myristate acetate or latex particles. As compared with normal rats, chemiluminescence of hepatic macrophages from galactosamine-treated rats was 5- to 10-fold enhanced 12 hr following galactosamine treatment and remained elevated for 48 hr. Chemiluminescence of the latex particle-pretreated macrophages in the liver was markedly suppressed even following the galactosamine treatment (p less than 0.01). Compared to galactosamine-treated rats, both lipid peroxide level in the liver tissue and AST and ALT concentration in serum were significantly decreased in the latex-galactosamine-treated rats (p less than 0.01) and increased in the galactosamine-latex-treated rats (p less than 0.01). Furthermore, superoxide dismutase supplementation protected against liver injury induced by the galactosamine-latex treatment. From these results, pretreatment with latex particles suppressed the free radical-generating capacity of hepatic macrophages and protected against hepatic injury induced by galactosamine. In contrast, injection of latex particles after galactosamine treatment aggravated hepatic injury, which was prevented by superoxide dismutase. These data suggest that liver injury induced by galactosamine is modulated by oxygen-derived free radicals from hepatic macrophages.
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PMID:Modulation of hepatotoxicity by macrophages in the liver. 283 5


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