Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biphasic behaviour observed in endotoxin-induced shock attributed to a direct interaction of bacterial lipopolysaccharides with the cell membrane and an indirect activation of multiple homeostatic regulatory mechanisms, cannot be completely elucidated with in vivo studies. In primary cultures of adult rat hepatocytes, lipopolysaccharide from Escherichia coli 0111:B4 affects the cytochrome P450 levels directly; however, albumin and aspartate aminotransferase secretion are induced by some mediators present in the sera of animals in acute-phase shock.
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PMID:Direct and mediated Escherichia coli lipopolysaccharide action in primary hepatocyte cultures. 329 5

Rats and mice infected with Trypanosoma lewisi and Trypanosoma musculi, respectively, showed hyperreactivity to lipopolysaccharide (LPS) from gram-negative bacteria. Fatal shock could be precipitated with a dose of LPS 100 to 1,000 times less in infected compared with noninfected animals. In trypanosome-infected rats and mice, extensive liver damage was evident after LPS challenge. These animals showed a pronounced hypoglycemia, marked elevation of blood aspartate transaminase level, and diffuse severe degeneration and total depletion of glycogen in hepatocytes. Only minor changes were observed in noninfected animals given the same dose of LPS. No mononuclear phagocytic cell infiltration was observed in the liver of infected animals. The most striking change was the great increase in size and the probable increase in phagocytic activity and number of sinusoidal Kupffer cells. We suggest that elevated Kupffer cell activity in trypanosome-infected animals may play a role in LPS-induced hepatotoxicity.
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PMID:Lipopolysaccharide hyperreactivity of animals infected with Trypanosoma lewisi or Trypanosoma musculi. 650 Jul

A systemic BCG infection in mice induced multiple small granulomas located mainly in the periportal areas of the liver. Following systemic challenge of such mice with purified protein derivative of tuberculin (PPD), a rapidly developing hepatitis with diffuse intralobular mononuclear cell infiltration was precipitated, accompanied by high levels of aspartate transaminase in peripheral blood, hypoglycemia, focal hepatocyte necrosis, and accumulation of fibrinogen in liver. Bacterial lipopolysaccharide (LPS) also provoked acute hepatic damage both in BCG-infected mice and in mice pretreated with Corynebacterium parvum. PPD was not active in the latter. There were also lymphoid cell destruction and fibrinogen accumulation in the spleen of BCG-PPD-treated mice. Possible involvement of inflammatory and hepatotoxic mediators is suggested, and a T-lymphocyte-macrophage regulatory role in the pathogenesis of hepatitis is discussed.
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PMID:Tuberculin hypersensitivity hepatitis in mice infected with Mycobacterium bovis (BCG). 702 5

(AxT6)F1 hybrid mice received s.c. transplants from (AxT6)F1 mammary carcinomas. At 1, 2 or 4 weeks after tumour transplantation, the mice were bled to obtain plasma and then challenged with 25 micron E. coli lipopolysaccharide (LPS) endotoxin i.v. The mice were killed 24 hr later, further plasma was obtained and their liver ratios and spleen ratios were determined. A similar procedure was carried out on non-tumour-bearing mice. Progressive tumour growth was associated with an increase in the liver ratio. In parallel, mice with 4-week tumour transplant showed increased uptake of colloidal carbon particles and 51Cr-labelled sheep red blood cells in the liver. The plasma amino aspartate transaminase (AST) and the ornithine carbamoyl transferase (OCT) showed a constant rise in all groups of mice after LPS injection. However, at 24 hr after LPS injection, the AST level showed the greatest rise in mice with 4-week tumour transplants. By contrast, OCT, which is liberated only from hepatocytes, showed the greatest rise in non-tumour-bearing mice.
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PMID:Hyperphagocytosis and the effect of lipopolysaccharide injection in tumour-bearing mice. 745 24

Nitric oxide synthase produces NO, citrulline, water, and NADP at the expense of arginine, NADPH, and dioxygen. While citrulline has been considered to be an inert by-product of the high output inducible isoform of NO synthase (iNOS), we show here that immunostimulants induce a metabolic pathway in vascular smooth muscle cells, which enables them to regenerate arginine from citrulline. Regeneration of arginine from citrulline is accomplished by two urea cycle enzymes: arginino-succinate synthetase (AS) and argininosuccinate lyase (AL). Whereas AL is constitutive to vascular smooth muscle cells, AS mRNA and enzyme activity is markedly induced in cells by treatment with bacterial lipopolysaccharide (LPS). The induction of AS mRNA and activity by LPS follows a time course which mirrors that for iNOS but lags 1-2 h behind. As shown for iNOS, interferon-gamma does not itself induce AS but is synergistic with LPS. AS induction is suppressed by glucocorticoids, actinomycin D, and, to a lesser extent, cycloheximide. On the other hand, AS induction is unaffected by an excess of citrulline or the inhibitor of iNOS, N omega-methyl-L-arginine. Our results show the urea cycle enzymes AS and AL confer cells with the capacity to produce NO without a need for exogenous arginine. In conjunction with NOS, citric acid cycle enzymes that covert fumarate to oxaloacetate (fumarase and malate dehydrogenase) and oxaloacetate to aspartate (aspartate transaminase), AS and AL form a novel arginine-citrulline cycle that enables high output NO production by cells.
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PMID:Argininosuccinate synthetase mRNA and activity are induced by immunostimulants in vascular smooth muscle. Role in the regeneration or arginine for nitric oxide synthesis. 751 85

Previous research with pentoxifylline (PTX), a methylxanthine phosphodiesterase inhibitor, suggests that this drug may be capable of suppressing the activation of Kupffer cells and thereby help decrease liver injury after transplantation. To investigate this possibility, the current study sought to determine whether the release of O2- and tumor necrosis factor (TNF) from Kupffer cells in donor livers can be suppressed if the organs are exposed to PTX before preservation. In an in vitro experiment, rat livers were flushed with PTX (25 mg/kg body weight) in University of Washington (UW) solution or UW solution alone (control) and then and stored in UW solution for either 4 or 24 hours. Kupffer cells then were purified and their degree of activation determined by measuring O2- release and the production of TNF after lipopolysaccharide stimulation. In an in vivo experiment, a group of rats underwent orthotopic liver transplantation with grafts prepared in the same manner as in the in vitro study. TNF and aspartate transaminase (AST) were measured in blood samples taken 3 hours and 24 hours after transplantation. Compared with controls, the Kupffer cells from grafts pretreated with PTX produced significantly less O2- and TNF, and the recipients of PTX-pretreated grafts had lower levels of TNF and AST 3 hours after transplantation. The current data indicate that O2- and TNF production in liver grafts is suppressed by PTX pretreatment. Through its suppressive effect on Kupffer cells, PTX may help minimize preservation-reperfusion injury and improve graft survival.
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PMID:Effects of pentoxifylline pretreatment on Kupffer cells in rat liver transplantation. 770 82

Liver injury is common in patients following hemorrhage and sepsis. There are multiple etiologies for this liver injury which involve both decreased nutrient blood flow and direct cellular injury. Enteral nutrients vasodilate gut blood vessels and increase blood flow to the intestines and liver. Since enteral nutrients vasodilate gut blood vessels, we wondered whether luminal nutrition would prevent hepatic injury during shock states. We randomized Sprague-Dawley rats to saline or enteral nutrition via duodenal feeding tubes. Animals were then subjected to 60 min of hemorrhagic hypotension or intraperitoneal injection of lipopolysaccharide (LPS). Liver injury was assessed by measuring levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) before and after hemorrhage or LPS. Enteral nutrients significantly decreased liver injury following hemorrhage. AST increased from 246 +/- 17 to 1605 +/- 593 U/L in saline animals and 283 +/- 39 to 551 +/- 94 U/L in enterally fed animals. ALT increased from 60 +/- 4 to 726 +/- 355 U/L in saline animals and 61 +/- 6 to 161 +/- 38 U/L in enterally fed animals. Enteral nutrients did not significantly alter the increase in AST/ALT following LPS. These results indicate that enteral nutrients can decrease liver injury following hemorrhagic hypotension.
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PMID:Enteral feeding minimizes liver injury during hemorrhagic shock. 774 61

Tumor necrosis factor-alpha is a principal mediator of the pathophysiological effects of endotoxemia and endotoxin shock. Tumor necrosis factor-alpha also contributes to the stimulation of nitric oxide synthesis by the induction of the enzyme nitric oxide synthase in a variety of tissues. Although the importance of tumor necrosis factor-alpha in the induction of nitric oxide synthase activity in vitro is well known, its role in in vivo nitric oxide synthesis has not been convincingly established. We were interested in determining whether tumor necrosis factor-alpha plays a significant role in the in vivo induction of nitric oxide synthesis. In Corynebacterium parvum-primed mice, lipopolysaccharide injection resulted in elevated serum tumor necrosis factor-alpha levels early and increased hepatic enzyme release (641 +/- 80 IU AST/L; 22.7 +/- 1.9 IU ornithine carbamoyltransferase per liter) and plasma nitrite and nitrate (804 +/- 84 mumol/L) 5 hr after lipopolysaccharide injection. Polyclonal rabbit anti-mouse anti-tumor necrosis factor-alpha reduced in vivo tumor necrosis factor-alpha levels (1 hr, 7,332 +/- 1,492 U tumor necrosis factor-alpha per milliliter) and reduced nitric oxide synthesis as measured by plasma nitrite and nitrate (352 +/- 69 mumol/L). Polyclonal rabbit anti-mouse anti-tumor necrosis factor-alpha also reduced lipopolysaccharide-induced hepatic enzyme release (428 +/- 33 IU AST/L; 16.0 +/- 2.5 IU ornithine carbamoyltransferase per liter). NG-monomethyl-L-arginine, a competitive inhibitor of nitric oxide synthesis, also decreased plasma nitrite and nitrate (104 +/- 9 mumol/L) but increased the lipopolysaccharide-induced hepatic injury (797 +/- 66 IU AST/L; 33.1 +/- 2.1 IU ornithine carbamoyltransferase per liter).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumor necrosis factor-alpha regulates in vivo nitric oxide synthesis and induces liver injury during endotoxemia. 792 8

Gentiopicroside (GPS), a main bitter secoiridoid constituent of roots of Gentiana macrophylla Pall., was tested for therapeutic effects on the two hepatic injury models, the CCl4-induced and lipopolysaccharide (LPS)/bacillus Calmette-Guerin (BCG)-induced hepatitides. An increase in serum level of hepatic aminotransferases (GOT: EC 2.6.1.1. and GPT: EC 2.6.1.2.) induced by a p.o. treatment of CCl4 was suppressed by pretreatment with GPS at 30-60 mg/kg/day for 5 consecutive days. An increase of these enzymes triggered by an i.v. treatment with LPS in mice primed with bacillus Calmette-Guerin (BCG) was also inhibited by GPS pretreatment at the same dose of GPS. In the BCG/LPS model, tumor necrosis factor (TNF), a major inflammatory mediator, was increased in serum with a peak at 90-120 min, followed by an increase of serum transaminase activities. GPS treatment significantly suppressed the increase of TNF in serum at the therapeutic doses, suggesting that GPS protected against hepatitis by inhibiting the production of TNF.
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PMID:Suppression of chemically and immunologically induced hepatic injuries by gentiopicroside in mice. 799 67

We examined the early changes after lipopolysaccharide (LPS) injection in chronically alcohol-fed rats with or without splenectomy. Administration of 2 mg/kg body weight LPS caused severe hepatic injury. The plasma aspartate aminotransferase (ASAT) activity was significantly higher in sham-operated rats 8 hr after LPS injection than in splenectomized rats. The plasma tumor necrosis factor (TNF) activity was also significantly higher 1 hr after LPS injection in sham-operated rats than in splenectomized rats. The plasma thromboxane (TX) B2/6-keto-prostaglandin (PG) F1 alpha ratio increased in sham-operated rats after LPS injection. Therefore, the balance of arachidonic acid metabolites was in a hypercoagulated state in sham-operated rats after the LPS injection. Neutrophil infiltration into liver tissue increased in sham-operated rats after the LPS injection. The cytokines and arachidonic acid metabolites released from the spleen after LPS injection in alcohol-fed rats may play important roles in severe hepatic injury.
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PMID:Roles of the splenic cytokines and arachidonic acid metabolites in severe hepatic injury after lipopolysaccharide injection in chronically alcohol-fed rats. 800 35


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