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)

We determined whether the paracrine liver endothelin (ET) system participates in the pathogenesis of CCl4-induced hepatotoxicity. Wistar-Kyoto rats were divided into four groups: a bosentan-treated group with CCl4 intoxication, a vehicle-treated group with CCl4 intoxication, a nontreated control group, and a bosentan-treated control group. Hepatotoxicity was assessed by determination of serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Tissue ET-1 concentrations and expression of endothelin receptor subtypes were analyzed. The liver tissue levels of ET-1 in rats with CCl4 intoxication were significantly higher than in normal rats. Scatchard analysis revealed no differences in the density and binding constants of ETA and ETB receptors between rats with CCl4 intoxication and controls. Bosentan treatment of rats undergoing CCl4 inhalation resulted in significant protection against elevation of ALT, AST, LDH, and bilirubin. In conclusion, this study showed that the paracrine ET system in involved in the pathogenesis of CCl4-induced hepatotoxicity and that blockade of the stimulated liver endothelin system reduces CCl4-induced liver injury.
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PMID:Protective effects of the mixed endothelin receptor antagonist bosentan in rats with CCL4-induced liver injury. 858 41

This study analyzed if the paracrine liver endothelin system participates in the pathogenesis of CCl4-induced hepatotoxicity. Wistar Kyoto rats were divided into four groups: a bosentan (mixed endothelin ETA and ETB receptor antagonist) treated group with CCl4 intoxication, a vehicle treated group with CCl4 intoxication, a nontreated control group and a bosentan treated control group. Hepatotoxicity was assessed by determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) followed by histopathological examinations. Tissue endothelin-1 concentrations and expression of endothelin receptor subtypes were analyzed. The tissue levels of endothelin-1 in the liver of rats with CCl4 intoxication were significantly higher than those in normal rats. Scatchard analysis revealed no differences in the density and binding constant of endothelin ETA and ETB receptor between rats with CCl4 intoxication and controls. Bosentan treatment of rats undergoing CCl4 inhalation resulted in a significant protection against elevation of ALT, AST, LDH and bilirubin. Histopathological examination of live sections for necrotic, swollen and lipid-laden cells revealed findings that were in agreement with the serum enzyme data. In conclusion, this study showed that the paracrine endothelin system is involved in the pathogenesis of CCl4-induced hepatotoxicity and that the blockade of the stimulated liver endothelin systems reduces CCl4-induced liver injury.
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PMID:Role of the paracrine liver endothelin system in the pathogenesis of CCl4-induced liver injury. 874 89

Endothelin evokes strong and longlasting constriction of postischemic sinusoids, leading to microcirculatory disturbances and local hypoxia, thereby causing liver damage. The aim of the study was to avoid the constrictive response of sinusoids by blocking endothelin receptors. In an in vivo ischemia-reperfusion model (21 female Wistar rats, 250-300 g) with portal decompression by a splenocaval shunt, hepatic ischemia was induced for 30 min by cross clamping of the hepatoduodenal ligament. The endothelin receptor antagonist bosentan (10 mg/kg bw IV) was administered before ischemia. The effect of the receptor antagonist was assessed by serum levels of aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) that were determined prior to ischemia, 2 and 6 h postoperatively. The local tissue pO2 was measured prior to inducing ischemia, 30 and 60 min after reperfusion. Application of 10 mg/kg bw endothelin receptor antagonist (ERA) intravenously did not influence the systemic blood pressure. The postischemic increase in serum ASAT and ALAT levels was diminished after receptor antagonist treatment (ASAT: p < .05). Local postischemic hepatic tissue pO2 was significantly decreased to 45% of basal values after 30 min and to 54.8% after 60 min of reperfusion (p < .05). Application of ERA results in a significant increase in local tissue pO2 to 110.9% of basal values after 30 min and to 90.7% after 60 min of reperfusion (p < .05). These data indicate that the endothelin receptor antagonist treatment results in a prevention of postischemic sinusoidal constriction avoiding hypoxia and leading to improved hepatocellular recovery.
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PMID:Effect of the endothelin receptor antagonist bosentan on postischemic oxygen supply of the liver. 898 Dec 17

This study was performed to determine whether ischemia/reperfusion (I/R) injury in rat liver results in alterations in endothelin receptor expression. Hepatic ischemia was produced in rats for 60 min followed by 6 or 24 h reperfusion. Portal inflow pressure was increased (7.38+/-0.60 mmHg) at 24 hours after reperfusion. Serum ALT increased significantly at both 6 and 24 h (6 h; 258.3+/-74.3, 24 h; 243.1+/-74.8 IU/L). Portal vascular response to an endothelin-B receptor agonist (IRL 1620) was significantly increased in the I/R livers compared to control and this was potentiated by L-NAME. IRL 1620 also caused LDH release from I/R livers but not controls. LDH release after IRL 1620 in I/R livers correlated with increased portal pressure response. To determine whether the altered response might be the result of altered endothelin receptor expression, livers were harvested after reperfusion and total endothelin binding sites were determined by competitive binding with ET-1. Proportion of endothelin receptor subtypes (ET(A)/ET(B)) was determined using the ET(A) antagonist BQ-610 (1 microM) and ET(B) agonist IRL-1620 (100 nM). There were no significant changes in Kd but Bmax for endothelin-1 was decreased in I/R group especially non-ischemic lobe at 24 h. ET(A) receptors were significantly decreased whereas ET(B) receptors were increased. These changes were more pronounced at 24 h after reperfusion than at 6 h. Interestingly, the changes in ET receptors was observed identically both in ischemic and non-ischemic lobes (ischemic lobe ET(A) 41.9%, ET(B) 51%; non-ischemic lobe ET(A) 38.8%, ET(B) 49.5%). These results indicate that the major functional endothelin receptor subtype upregulated in I/R is the ET(B) receptor and that this upregulation may contribute to microvascular dysregulation and hepatic injury.
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PMID:Altered endothelin receptor subtype expression in hepatic injury after ischemia/reperfusion. 1063 73

It is well known that endothelin-1(ET-1) is a factor involved in the pathogenesis of ischemia-reperfusion injury. This study was undertaken to investigate the optimal route (intravenous vs intraportal) for administering mixed endothelin receptor antagonist (TAK-044) in a liver transplantation. First, in a rat isolated liver cold-perfusion model, the pharmacodynamics of TAK-044 and endothelin-1 (ET) in the liver tissue and the systemic circulation after cold perfusion were compared in the different administration routes. Next, in a rat orthotopic transplantation model, we compared the hepatoprotective effect of TAK-044 among different administration routes. In each model, there were three groups: IV group, intravenous injection of TAK-044 (10mg/kg) immediately before cold perfusion or anhepatic phase; IP group, intraportal administration with cold perfusion solution or with reflush solution for the graft; control group, no treatment. In the cold perfusion model, liver tissue ET level increased to a similar extent after reperfusion in the three groups, and the plasma and liver tissue TAK-044 concentrations after reperfusion were highest in the IV group. However, the increase in plasma ET was also greatest, and therefore, the ratio of liver tissue to plasma TAK-044 was lower in the IV group compared with the IP group. In the transplantation model, elevation of plasma ET was significantly higher in the IV group. Leakage of serum alanine aminotransferase (ALT), sinusoidal narrowing, and cell swelling after grafting were significantly suppressed in the IP group. We conclude that intraportal administration before reperfusion offers more efficient accumulation of TAK-044 in the liver tissue, without harmful systemic elevation of ET, and achieves a hepatoprotective effect on the graft compared with intravenous administration.
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PMID:Optimal route of administration of mixed endothelin receptor antagonist (TAK-044) in liver transplantation. 1068 Jun 67

The efficacy and safety of IFN alpha 2a and Thymosin alpha1 combination therapy in patients with chronic hepatitis C were determined. Twelve chronic hepatitis C patients (9 M, 3F), with positive HCV-RNA and histology compatible with chronic hepatitis C were included in this open, prospective study. Each patient received a combination therapy of IFN alpha 2a 3 mU s.c. TIW and Thymosin alpha1 1.6 mg s.c. twice a week for 52 weeks. Up to the present, 11 patients are still being followed-up after the end of 52 weeks' treatment. One patient dropped out after 32 weeks of follow-up due to noncompliance. Responses to treatment were evaluated by measuring serum HCV-RNA levels determined by RT-PCR. and serum amino transferases at the end of 48 weeks of treatment (end of treatment response: ETR). There were 8 naive and 4 previously IFN treated patients with partial response with a mean age of 45.0 +/- 10.1 (mean +/- SD). The mean duration from diagnosis until treatment was 25.1 +/- 22.9 months. The mean AST, ALT, and HCV-RNA levels before treatment were 79.5 +/- 36.8 U/L, 128.3 +/- 68.5 U/L, and 3.9+1.9 x 10(5) copies/ml respectively. Serum AST, ALT, and HCV-RNA levels were significantly lower at week 24 and 48 after treatment compared to before treatment (p<0.05). Of 11 cases, complete HCV-RNA clearance at week 24 was noted in 33.3 per cent, whereas, normal alanine aminotransferase values (ALT < 40 U/L) were observed in 41.7 per cent of patients. Complete HCV-RNA clearance and normal alanine aminotransferase at week 48 were seen in 45.5 per cent of the patients. At the end of week 48, complete response occurred in 4 of 5 naive patients. Minor side effects were observed during treatment with this combination therapy and these included myalgia (33.3%), mild form of alopecia (33.3%), and weight loss (8.3%). In patients with chronic hepatitis C, Interferon alpha 2a and Thymosin alpha1 combination therapy produced a good response rate especially in naive patients with acceptable safety profile. The sustained response will be determined after the completion of follow-up for another 6 months.
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PMID:The combined treatment of interferon alpha-2a and thymosin alpha 1 for chronic hepatitis C: the 48 weeks end of treatment results. 1152 76

Recurrent hepatitis C is a common problem after liver transplantation that can progress to liver cirrhosis of the graft. Preliminary reports of combination treatment with interferon (IFN) and ribavirin have been promising, but long-term follow-up data are not yet available. We report our experience with 1 year of combination therapy with IFN (3 million units thrice weekly) and low-dose ribavirin (600 mg/d), followed by long-term ribavirin monotherapy in 18 patients with moderate to severe recurrent hepatitis C and a median follow-up of 32 months after the completion of combined therapy. All patients were followed up clinically and histologically at regular intervals. Overall, in an intention-to-treat analysis, 15 patients had normal alanine aminotransferase levels (biochemical end-treatment response [ETR], 83%), and 8 patients were also hepatitis C virus RNA negative in serum (virological ETR, 44%) at the end of combined treatment. At last follow-up after the completion of combined therapy (median, 32 months; range, 18 to 73 months), 13 patients were biochemical responders (biochemical long term-sustained response [LT-SR], 72%), and 5 patients also maintained viral clearance (virological LT-SR, 27%). Comparison of liver biopsy specimens before and after 12 months of combined therapy showed improvement in grading scores of at least two points in the majority of the patients (73%). Notably, a trend toward fibrotic progression was only noted in nonresponders. Regarding side effects, despite the low dose of ribavirn, almost half the patients developed hemolytic anemia requiring dose reductions. In addition, long-term ribavirin monotherapy was not associated with iron accumulation. We conclude that combined therapy with low-dose ribavirin followed by long-term ribavirin monotherapy can be recommended because it favorably modifies the natural history of recurrent hepatitis C in most patients and possibly halts histological disease progression without causing iron accumulation.
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PMID:Combined therapy with interferon and low-dose ribavirin in posttransplantation recurrent hepatitis C: a pragmatic study. 1167 85

We investigated the relationship between endothelin, a potent vasoconstrictor peptide, and the pathophysiology of disseminated intravascular coagulation (DIC), using two models of DIC. Experimental DIC was induced by sustained infusion of 50 mg/kg lipopolysaccharide (LPS), or 3.75 U/kg thromboplastin, for 4 h via the rat tail vein. The effect of administration of a non-selective endothelin receptor antagonist (TAK-044) (2, 10, or 50 mg/kg, from -0.5 to 4 h) on thromboplastin-induced DIC was not significant. However, LPS-induced elevation of alanine aminotransferase, creatinine and glomerular fibrin deposition was significantly suppressed by co-administration of TAK-044 in a dose-dependent manner, although no effect of TAK-044 was observed on the platelet count, fibrinogen concentration or the level of thrombin-antithrombin complex. Moreover, plasma levels of D-dimer, which reflect the grade of fibrinolysis of cross-linked fibrin, were significantly increased by co-administration of each dose of TAK-044 in the LPS-induced DIC model in rats. Our results suggest that vasoconstriction, as well as depressed fibrinolysis, contribute to severe organ dysfunction in LPS-induced, but not thromboplastin-induced, DIC, and that endothelin plays a role in the development of organ injury in LPS-induced DIC in rats.
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PMID:Relationship between endothelin and the pathophysiology of tissue factor-induced and lipopolysaccharide-induced disseminated intravascular coagulation in rats: a study examining the effect of an endothelin receptor antagonist. 1538 27

The aim of the study was comparison of the efficacy of treatment with INF and lamivudine in chronic hepatitis B. 103 patients with chronic hepatitis B were included in this trial and divided into two groups. Group I consisted of 34 patients treated with INF-alpha (5MU 3x per week during 4-6 months), group II included 69 patients treated with lamivudine (100mg per day during 1-4 years). Virologic, serologic and biochemical factors at ETR were analyzed. Costs of these two therapies were estimated too. In group I HBV DNA clearance was observed in 26/34 cases (76%), seroconversion HBeAg/anti-HBe in 5/34 (15%) and normalization of ALT in 22/30 patients (73%). In group II virological response occurred in 37/69 cases (53%), serological in 16/41 (39%) and biochemical in 34/50 (68%). Patients from group I suffered from adverse events typical for INF therapy. No adverse events were observed in group II. Cost of virological response in group I was 4 500 zl, in group II 8 000 zl, biochemical--INF 4 700 zl, lamivudine 5 700 zl and serological--group I 18 600 zl, in group II 18 700 zl.
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PMID:[Treatment of chronic hepatitis B]. 1580 74

The aim of this study was to investigate a possible protective role of a selective endothelin-A receptor antagonist on hepatic microcirculation after ischemia/reperfusion. In a rat model, warm ischemia of the left liver lobe was induced for 90 minutes under intraperitoneal anesthesia with xylazine and ketamine. Shamoperated and untreated ischemic groups and a group treated with BSF 208075 were investigated. The effect of the endothelin-A receptor antagonist on ischemia/reperfusion was assessed by in-vivo microscopy and measurement of aspartate aminotransferase and alanine aminotransferase levels. In the untreated group, sinusoidal constriction to 70% of basal diameters was observed, leading to a significant decrease in perfusion rate. In addition, we found an increased percentage of stagnant leukocytes and platelets in sinusoids and in postsinusoidal venules (P < 0.05). A significant increase in liver enzymes was detected 6 hours after reperfusion (P < 0.05). In the treatment group, sinusoidal diameters were maintained at 108%, and perfusion rate was significantly increased (P < 0.05). Hepatocellular damage was decreased and leukocyte and platelet-endothelium interactions were reduced (P < 0.05). Our results provide evidence that the new therapeutic approach using an endothelin-A receptor antagonist is effective in reducing hepatic ischemia/reperfusion injury. It could be shown for the first time that endothelin receptor blockade also influences platelet-endothelium interactions.
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PMID:Endothelin-A receptor blockade improves postischemic hepatic microhemodynamics. 1583 53


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