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)

The aim of this paper was to determine if NO modulation would influence liver damage induced by 3 day-biliary obstruction. L-Arginine (500 mg kg-1, p.o. twice a day) or L-NAME (100 mg kg-1, p.o. twice a day) or both were administered to male Wistar rats subjected to bile duct ligation (BDL). In the liver, BDL doubled lipid peroxidation and depleted glycogen (P < 0.05), L-arginine completely prevented the former and partially the latter. Alkaline phosphatase, alanine aminotransferase and gamma-glutamyl transpeptidase serum enzyme activities increased (P < 0.05) by BDL, again L-arginine treatment partially, but significantly, prevented the elevation in these three markers of liver damage. Although L-NAME treatment failed to induce a change in any marker of liver injury studied herein, it abolished the beneficial effects of L-arginine, suggesting that these effects are probably mediated by NO synthesis stimulation.
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PMID:Liver damage induced by acute cholestasis in the rat is ameliorated partially by L-arginine. 982 59

Biliary obstruction, produced by common bile duct ligation or alpha-naphthylisothiocyanate (ANIT) treatment in rats, has been associated with the development of type I biliary epithelial cell (BEC) hyperplasia. However, the exact mechanism(s) by which bile duct obstruction lead(s) to this proliferative lesion are not clear. The present studies were designed to determine if cholestasis, in the absence of biliary obstruction, would result in type I BEC hyperplasia. Male Sprague-Dawley rats were given a single oral dose of 150 mg/kg ANIT or i.v. doses of estradiol glucuronide (E2-17G; 21 mumol/kg/h for 48 h) to produce obstructive and non-obstructive cholestasis, respectively. E2-17G treatment resulted in cholestasis that was comparable in extent and duration to that observed following ANIT treatment. E2-17G and ANIT treatments produced comparable increases in serum bile acids (55- to 60-fold) and activities of ALT (36- to 38-fold), ALP (4- to 5-fold), and 5'-nucleotidase (7- to 11-fold), respectively, compared to controls. Both ANIT and E2-17G also increased serum bilirubin concentrations. ANIT treatment resulted in significant increases in biliary glucose concentrations that were associated with BEC damage/necrosis and obstruction of the bile duct lumen. Conversely, no evidence of BEC damage was observed in E2-17G-treated rats. Nonetheless, BEC hyperplasia was observed in the majority of rats following treatment with either ANIT or E2-17G, assessed by light microscopy and by BrdU immunohistochemistry. These data indicate that E2-17G treatment produces nonobstructive cholestasis and type I BEC hyperplasia, suggesting that biliary obstruction is not a prerequisite for type I BEC hyperplasia in rats. Differences in the time of onset of hyperplasia were observed: hyperplasia was noted immediately following 48 h of E2-17G-induced cholestasis but occurred several days after ANIT-induced cholestasis had subsided. Since the magnitude/duration of cholestasis was similar in the two models but the temporal association between cholestasis and type I BEC hyperplasia were different, these data suggest that the proliferative stimulus may be different in the two models and that E2-17G-induced type I BEC hyperplasia may not be attributed solely to cholestasis.
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PMID:Bile duct obstruction is not a prerequisite for type I biliary epithelial cell hyperplasia. 985 2

In the present research, we studied the effect of the administration of melatonin or S-adenosyl-L-methionine (S-AMe) on oxidative stress and hepatic cholestasis produced by double ligature of the extra-hepatic biliary duct (LBD) in adult male Wistar rats. Hepatic oxidative stress was evaluated by the changes in the amount of lipid peroxides and by the reduced glutathione content (GSH) in lysates of erythrocytes and homogenates of hepatic tissue. The severity of the cholestasis and hepatic injury were determined by the changes in the plasma enzyme activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), g-glutamyl-transpeptidase (GGT), and levels of albumin, total bilirubin (TB) and direct bilirubin (DB). Either melatonin or S-AMe were administered daily 3 days before LBD, and for 10 days after biliary obstruction. LDB caused highly significant increases in plasma enzyme activities and in bilirubin and lipid peroxides levels in erythrocytes and hepatic tissue. At the same time, this procedure produced a notable decrease in the GSH pools in these biological media. Both melatonin and S-AMe administration were effective as antioxidants and hepatoprotective substances, although the protective effects of melatonin were superior; it prevented the GSH decrease and reduced significantly the increases in enzyme activities and lipid peroxidation products produced by biliary ligature. S-AMe did not modify the increased GGT activity nor did it decrease greatly the TB levels (43% melatonin vs. 14% S-AMe). However, S-AMe was effective in preventing the loss of GSH in erythrocytes and hepatic tissue, as was melatonin. The obtained data permit the following conclusions. First, the LDB models cause marked hepatic oxidative stress. Second, the participation of free radicals of oxygen in the pathogenecity and severity of cholestasis produced by the acute obstruction of the extra-hepatic biliary duct is likely. Third, the results confirm the function of S-AMe as an antioxidant and hepatoprotector. Finally, melatonin is far more potent and provides superior protection as compared to S-AMe. Considering the decrease in oxidative stress and the intensity of cholestasis, these findings have interesting clinical implications for melatonin as a possible therapeutic agent in biliary cholestasis and parenchymatous liver injury.
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PMID:Protective effect of melatonin against oxidative stress induced by ligature of extra-hepatic biliary duct in rats: comparison with the effect of S-adenosyl-L-methionine. 1073

Fourteen dogs with enlarged gallbladders and immobile stellate or finely striated bile patterns on ultrasound are described. Smaller breeds and older dogs were overrepresented, with 4/14 Cocker Spaniels. Most dogs presented for nonspecific clinical signs such as vomiting, anorexia and lethargy. Abdominal pain, icterus and hyperthermia were the most common findings on physical examination. All dogs except one had serum elevation of total bilirubin and/or alkaline phosphatase, alanine aminotransferase and gamma glutamyl transferase. All dogs were diagnosed with a gallbladder mucocele upon histologic and/or macroscopic evaluation. Ultrasonographically, mucoceles are characterized by the appearance of the stellate or finely striated bile patterns and differ from biliary sludge by the absence of gravity dependent bile movement. On ultrasound, gallbladder wall thickness and wall appearance were variable and nonspecific. The cystic or common bile duct were normal sized in 5 dogs although all 5 had evidence of biliary obstruction at surgery or necropsy. Loss of gallbladder wall integrity and/or gallbladder rupture were present in 50% of the dogs, all located in the fundus. Gallbladder wall discontinuity on ultrasound indicated rupture whereas neither bile patterns predicted the likelihood of gallbladder rupture. Pericholecystic hyperechoic fat or fluid were suggestive of but not diagnostic for a gallbladder rupture. Cholecystectomy appears to be an appropriate treatment for mucoceles, if not to treat a gallbladder rupture, at least in most dogs to prevent it since gallbladder wall necrosis was identified by histology in 9 of 10 dogs. Mucosal hyperplasia was present in all gallbladders examined histologically. Positive aerobic bacterial culture was obtained from bile in 6 of 9 dogs. Cholecystitis was diagnosed histologically in 5 dogs and 4 dogs had signs of gallbladder infection solely upon bacterial bile culture. Gallbladder infection was not present with all the mucoceles suggesting that biliary stasis and mucosal hyperplasia may be the primary factors involved in mucocele formation. Based on the results of our study, we suggest two alternate courses of action in the presence of a distended gallbladder with an immobile ultrasonographic stellate or finely striated bile pattern: a cholecystectomy when clinical or biochemical signs of hepatobiliary disease are present or a medical treatment (antibiotics and choleretics) and patient monitoring by follow-up ultrasound examinations when the patient does not have clinical or biochemical abnormalities. An aerobic bile culture should be obtained in all patients, by ultrasound-guided fine needle aspirate or at surgery.
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PMID:Ultrasonographic appearance and clinical findings in 14 dogs with gallbladder mucocele. 1085 Aug 78

The anti-fibrotic effects of a hot-water extract form the traditional Chinese medicinal herb Salvia miltiorrhiza (Labiatae) on liver fibrosis induced by biliary obstruction was studied in rats. Liver fibrosis was induced in male Sprague-Dawley rats by bile duct ligation and scission (BDL). After surgery, the hot-water extract of S. miltiorrhiza roots (100 mg kg(-1), p.o.) was administered daily for 28 days. The concentrations of aspartate transaminase, alanine transaminase, alkaline phosphatase, total bilirubin and total cholesterol in serum and hydroxyproline and malondialdehyde contents in liver were significantly increased in BDL rats. Treatment with the extract of S. miltiorrhiza significantly reduced (P < 0.01) the serum aspartate transaminase, alanine transaminase, alkaline phosphatase, and total cholesterol concentrations in BDL rats. The liver hydroxyproline content in BDL rats treated with extract was also reduced to 68% of that in BDL control rats (P < 0.01). The liver malondialdehyde content in BDL rats treated with the extract was also reduced to 47% of that in BDL control rats (P < 0.01). The morphological characteristics of fibrotic livers were improved in BDL rats treated with extract. Immunohistochemical examination of fibrotic liver showed that the extract of S. miltiorrhiza markedly reduced protein expression of alpha-smooth muscle cell-like actin, which indicates that hepatic stellate cell activation was inhibited during liver fibrosis development. The results indicate that the hot-water extract of S. miltiorrhiza roots inhibits fibrosis and lipid peroxidation in rats with liver fibrosis induced by biliary obstruction.
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PMID:Anti-fibrotic effects of a hot-water extract from Salvia miltiorrhiza roots on liver fibrosis induced by biliary obstruction in rats. 1127 16

Patients with obstructive jaundice (OJ) that requires surgery often have malnutrition associated with increased perioperative morbidity. This study investigated the factors influencing nutritional derangements in these patients. A series of 46 OJ patients were investigated prospectively (28 malignant tumors, 18 benign obstructions). A nutritional risk index of < 83.5 was used to define protein-calorie malnutrition. Liver function, cholecystokinin (CCK), tumor necrosis factor-alpha (TNFalpha), and endotoxin levels were determined. A multivariate analysis was performed, and an obstructive jaundice malnutrition index (OJMI) was obtained. Altogether, 22 (48%) OJ patients had malnutrition (33% with benign obstructions, 57% with malignant disease). Malnourished patients had higher serum bilirubin levels (258 +/- 120 vs. 154 +/- 62 mmol/L; p = 0.005), longer duration of jaundice (16 +/- 9 vs. 9 +/- 5 days; p = 0.03), and higher plasma levels of CCK (4.0 +/- 1.3 vs. 1.7 +/- 1.0 pmol/L; p = 0.005), alanine aminotransferase (ALT) (226 +/- 209 vs. 187 +/- 161 UI/L; p = 0.01), endotoxin (15 +/- 10 vs. 6.5 +/- 7.0 EU/L; p = 0.007), and TNFalpha (69 +/- 82 vs. 23 +/- 15 pg/ml; p = 0.008) than those without malnutrition. However, only serum bilirubin, CCK, ALT, and patient age were predictors for malnutrition by multivariate analysis. Malnutrition might be expected (95% confidence interval) in patients older than 68 years with increased bilirubin (> 290 mmol/L) and ALT (> 210 UI/L) levels that corresponded with an OJMI > 55. It was concluded that nutritional alterations in patients with obstructive jaundice were determined by the intensity of the biliary obstruction correlated with increased plasma CCK levels as well as with liver dysfunction and patient age.
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PMID:Factors predicting nutritional derangements in patients with obstructive jaundice: multivariate analysis. 1134 90

A case of a 58-year-old woman with history of bilateral lung transplant secondary to alpha-1 antitrypsin deficiency (PIZZ), who presented with a severe drug-induced cholestasis secondary to prochlorperazine is reported. After 27 months of prochlorperazine use, she developed liver failure consisting of jaundice with ascites. Computed tomography of the abdomen, abdominal ultrasonography as well as an endoscopic retrograde cholangiopancreatography showed no evidence for biliary obstruction. Liver biopsy demonstrated diffuse ongoing advanced chronic cholestasis, moderate portal and periportal inflammation as well as bridging fibrosis. During her hospitalization, her total bilirubin increased to 38.6 mg/dL; alkaline phosphatase to 362 IU/L, alanine aminotransferase to 71 IU/L and aspartate aminotransferase to 88 IU/L. After several weeks of ursodiol therapy without clinical improvement the prochlorperazine was discontinued and was followed by a rapid improvement in her measures of liver injury. An immediate decline of her serum total bilirubin and alkaline phosphatase to 21.4 mg/dL and 258 IU/L, respectively, occurred strongly suggesting the idea of a prochlorperazine-induced injury.
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PMID:Prochlorperazine-induced cholestasis in a patient with alpha-1 antitrypsin deficiency. 1457 32

Oxidative stress, in particular lipid peroxidation, induces collagen synthesis. Thus, we administered various antioxidants to bile duct-ligated rats for 28 days and lipid peroxidation, glutathione content, fibrosis, necrosis and cholestasis were evaluated. Extrahepatic cholestasis was induced by double ligation and section of the common bile duct. The study included eight groups (n=6), four groups were bile duct-ligated and received either vitamin C (50 mg/kg/day, orally), vitamin E (400 IU/rat/day, orally), silymarin (50 mg/kg/12 hr, orally) or vehicles; four groups were sham-operated controls. Collagen content was determined by measuring hydroxyproline in liver samples; malondialdehyde was used to estimate lipid peroxidation levels; reduced and oxidized glutathione were determined fluorometrically; alanine aminotransferase and bilirubins colorimetrically. Bilirubins increased several times, alanine aminotransferase once, reduced/oxidized glutathione ratio decreased three times, lipid peroxidation and collagen increased about three-times by biliary obstruction (p<0.05). Silymarin, vitamin E or C failed to prevent these effects significantly. It is not possible to clarify the role of oxidative stress in the fibrotic process induced by chronic biliary obstruction with the present results. Therefore, it seems reasonable to propose that a wide mixture of antioxidants, administered by the parenteral route (because cholestasis decreased the absorption of lipophilic compounds), is needed to counteract the oxidant stress produced by cholestasis.
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PMID:Effects of silymarin and vitamins E and C on liver damage induced by prolonged biliary obstruction in the rat. 1474 53

Ethyl pyruvate has been shown to ameliorate liver injury and decrease expression of several proinflammatory cytokines when used to treat mice with hemorrhagic shock or alcoholic hepatitis. Herein we sought to determine whether delayed treatment with ethyl pyruvate dissolved in a Ringer's-type balanced salt solution--Ringer's ethyl pyruvate solution (REPS)--would be beneficial in a murine model of common bile duct ligation (CBDL)-induced liver injury. Male C57BL/6 mice were subjected to a sham (n = 6) procedure or CBDL (n = 27). Twenty-four hours after operation, mice subjected to CBDL were randomized to receive treatment with either REPS (40 mg/kg of ethyl pyruvate per dose) or Ringer's lactate solution (RLS) every 8 h over a 72 h period. Compared with sham-treated controls, CBDL in RLS-treated mice was associated with histological evidence of hepatocellular necrosis as well as significant increases in the plasma concentrations of alanine aminotransferase and total bilirubin. Relative to sham-treated controls, CBDL in RLS-treated mice also was associated with increased hepatic lipid peroxidation and increased hepatic expression of transcripts for TNF, IL-6, and iNOS. All of these changes were significantly attenuated by delayed treatment with REPS after CBDL. In the RLS-treated group, CBDL was associated with increased NF-kappaB DNA binding in nuclear extracts prepared from liver tissue. Treatment with REPS increased NF-kappaB DNA binding still further. CBDL was associated with increased hepatocellular apoptosis in both the RLS- and REPS-treated groups. These data support the view that ethyl pyruvate ameliorates hepatic inflammation, lipid peroxidation, and necrosis in mice subjected to CBDL. Ethyl pyruvate warrants further evaluation as an adjunctive treatment to ameliorate liver injury from extrahepatic biliary obstruction.
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PMID:Ethyl pyruvate reduces liver injury in a murine model of extrahepatic cholestasis. 1537 94

Forty-eight rats with biliary obstruction induced by double ligation and section of the common bile duct were randomly and blindly assigned to receive subcutaneous injection of either conventional heparin sodium (1000IU kg(-1)), three already marketed low molecular weight heparin (LMWH) preparations: nadroparin (1000 anti-Xa IU kg(-1)), tinzaparin (1000 anti-Xa IU kg(-1)), enoxaparin (180 anti-Xa IU kg(-1)) or saline. Drugs were administered once a day, starting 7 days after surgery and continued for 3 weeks. At the end of the treatment period, rats were killed and analyzed for blood biochemistry and liver pathology. Liver fibrosis was assessed by image analysis. Data indicated that treatment with nadroparin decreased plasma total bilirubin, serum alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) levels by 80.3, 70.7 and 42%, compared with bile duct ligated (BDL) control values. The reduction in plasma total protein observed in BDL controls was prevented by nadroparin. Enoxaparin-treated rats showed significant reduction in plasma total bilirubin and alanine aminotransferase levels by 32.5 and 38.4% versus BDL controls. Liver necrosis evaluated histologically was significantly reduced in the nadroparin- and enoxaparin-treated rats. Morphometric analysis showed significant reduction in fibrosis on nadroparin and enoxaparin treatment: area of fibrosis: 1.66 +/- 0.17% and 14.03 +/- 1.1% versus 18.94 +/- 2.4% (P<0.05); nadroparin and enoxaparin versus BDL control. By contrast, neither conventional heparin nor tinzaparin prevented the bile duct ligation-induced liver damage as indicated by increased plasma aminotransferases, ALP and GGT concentrations and the histological evidence of necrosis. Total serum bilirubin was increased by 27.5% in rats treated with conventional heparin, while ALP and GGT levels were 38.6 and 31.4% higher after tinzaparin treatment versus BDL controls. Significant increase in the area of fibrosis was observed after tinzaparin treatment compared to BDL control group. Results suggest a beneficial effect for nadroparin and enoxaparin in the therapy of patients with obstructive jaundice or cholestatic liver disorders. The present data from bile duct ligated rats suggest an antifibrotic effect for nadroparin and enoxaparin.
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PMID:A study of unfractionated and low molecular weight heparins in a model of cholestatic liver injury in the rat. 1551 36


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