Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present investigation was undertaken to test our hypothesis that the slow responses of hepatocellular regeneration and tissue repair after CCl4-induced liver injury are responsible for the high sensitivity of gerbils to the hepatotoxic and lethal effects of CCl4. These studies were conducted in normal and actively regenerating livers using male gerbils 5 or 15 days after partial (2/3) hepatectomy (PH5 and PH15, respectively), or those undergoing sham operation (SH). An LD50 dose of CCl4 (80 microL/kg, i.p.) resulted in a mortality (21%) significantly (P less than 0.05) less than 50% in PH5 gerbils 48 hr after CCl4 administration, whereas the mortality observed in PH15 or SH gerbils was not significantly different from 50%. The elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly (P less than 0.05) less in PH5 gerbils than in PH15 or SH groups after the administration of either the LD50 dose or a low dose (15 microL/kg) of CCl4. Histopathological and histomorphometric examinations also indicated that CCl4-induced liver injury was less severe in PH5 gerbils than in the PH15 and SH groups. The hepatic microsomal cytochrome P450 content measured before CCl4 administration in the PH5 gerbils was decreased (26%) significantly (P less than 0.05) as compared with the SH group, but was not significantly different from that of PH15 gerbils. In vivo metabolism of 14CCl4 and lipid peroxidation in liver tissue were not significantly different among the various groups. Therefore, the protection against CCl4 toxicity observed in PH5 gerbils is unlikely to be due to decreased bioactivation of CCl4 or lipid peroxidation in that group. [3H]Thymidine incorporation into hepatocellular nuclear DNA was 4- to 5-fold higher in PH5 gerbils than in the PH15 and SH groups, indicating active hepatocellular proliferation in PH5 gerbils. [3H]Thymidine incorporation was further increased significantly (P less than 0.05) 24 hr after challenge with a low dose of CCl4 in PH5 gerbils, whereas it remained low until 48 hr after the CCl4 injection in the PH15 or SH group. The protection against CCl4 toxicity afforded by partial hepatectomy was closely associated with active hepatocellular regeneration. The overall results confirm the concept that the high sensitivity of gerbils to CCl4 is due to very sluggish hepatocellular regeneration and tissue repair response to the CCl4-induced liver injury.
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PMID:Protection from CCl4 toxicity by prestimulation of hepatocellular regeneration in partially hepatectomized gerbils. 185 67

The destruction of liver microsomal cytochromes P450 by a previously administered low dose of CCl4 has been widely accepted as the mechanism of CCl4 autoprotection. However, circumstantial evidence suggests that this mechanism cannot completely explain the phenomenon of autoprotection. The protective effect of a low dose of CCl4 (0.3 ml/kg, po) on the lethal effect of a subsequently administered high dose (5 ml/kg, po) was established in male Sprague Dawley rats. The protective dose permitted 100% survival, whereas only 15% survival was observed without it. Hepatotoxicity, measured by serum enzyme elevations (aspartate transaminase, alanine transaminase, and sorbitol dehydrogenase) and histopathological changes 24 hr after the treatment with high dose, was similar in both the groups, even though the protective dose had significantly decreased liver microsomal cytochromes P450 (to 62% of normal) and associated enzymes, aminopyrine demethylase and aniline hydroxylase. Rats pretreated with CoCl2 to decrease hepatic microsomal cytochrome P450 to 44% of normal levels did not show a significant protection from the hepatotoxicity of high dose of CCl4. Previous studies have established that hepatocellular regeneration is stimulated within 6 hr after the administration of a low dose of CCl4. Based on this observation, a premise that autoprotection results from augmented recovery from injury rather than decreased injury appears likely. Hence, the role of hepatocellular regeneration was evaluated by following 3H-thymidine incorporation in hepatocellular nuclear DNA, labelling index by autoradiography, and by morphometric estimation of mitotic index. After administration of the protective dose of CCl4, stimulated nuclear DNA synthesis measured by 3H-thymidine incorporation into nuclear DNA was increased and this remained high even after subsequent administration of high dose of CCl4. Forty-eight hr after the administration of a lethal dose of CCl4 alone (5 ml/kg, po), labelling index was slightly increased, but mitotic index was not increased. In the surviving rats (15%), both labelling index and mitotic index were significantly elevated after an additional 24 hr. In rats receiving the protective dose, a significantly greater elevation of labelling index as well as mitotic index occurred 48 hr after the administration of the same lethal dose of CCl4. These results suggest that hepatocellular regeneration stimulated by the protective dose, as a biological response recruited to overcome the accompanying limited injury, may augment and sustain tissue repair processes to permit tissue restoration even after the massive liver injury elicited by the subsequent large dose of CC14.
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PMID:Role of hepatocellular regeneration in CCl4 autoprotection. 204 7

Liver necrosis was produced in rats by administering 3 doses of a mixture of carbon tetrachloride + olive oil, 2 ml/kg, ip. The liver damage was evidenced by the elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (gamma-GT) and by histopathological observations of liver sections. Aspartate and glutamate administration (100 mg/kg, ip) significantly reduced these elevated levels of AST, ALT, and gamma-GT. Carbon tetrachloride induced liver necrosis was also found to be significantly reduced in aspartate and glutamate pretreated animals as observed macroscopically and histologically.
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PMID:Effect of aspartate and glutamate on carbon tetrachloride induced liver damage in rats. 209 35

beta-Hexosaminidase (Hex) activity has been shown to be increased in the sera of patients with chronic liver diseases as well as in rats with CCl4-induced liver cirrhosis. In this study, serum and liver Hex activity was determined in rats during the acute phase of CCl4 poisoning, a widely used animal model of acute necrotic liver damage. The results showed a statistically significant decrease of Hex activity in the sera of rats 36 h after CCl4 poisoning (5.84 +/- 2.90 U/l), as compared to controls (11.58 +/- 1.35 U/l; p less than 0.001). No significant change was observed in liver tissue of CCl4-treated animals and controls. A significant correlation between the decrease in Hex and the increase in serum aspartate aminotransferase in serum was found. The results are consistent with the hypothesis that this lysosomal enzyme could be released by non-parenchymal liver cells, such as activated macrophages; its increased activity could be the expression of macrophage activation, as demonstrated in patients with chronic liver diseases.
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PMID:beta-Hexosaminidase activity in the acute phase of CCl4 poisoning in the rat. 215 17

Various aliphatic alcohols potentiate the toxicity of a wide range of xenobiotics including several haloalkanes. The present series of experiments were designed to test: (i) whether a single subtoxic dose of alcohol can potentiate CCl4 and CHCl3 hepatoxicity, and (ii) whether this potentiation leads to greater animal lethality. Selected members of a homologous series of straight chain alcohols were chosen for this study. Methanol, ethanol, isopropanol, t-butanol, pentanol, hexanol, octanol, decanol, and eicosanol at equimolar doses (10 mmol/kg) were tested in the present investigation. Each alcohol was administered orally to male Sprague-Dawley rats (175-250 g) 18 hr prior to a single oral administration of CCl4 or CHCl3. Liver injury was assessed by plasma transaminases (alanine aminotransferase, ALT; aspartate aminotransferase, AST) and histopathological examination of liver sections 24 hr after the halomethane treatment. None of these alcohols alone increased plasma ALT or AST significantly, whereas CCl4 or CHCl3 administration to alcohol-treated animals resulted in significant elevation of plasma transaminases. Eicosanol (20-carbon alcohol) did not potentiate the toxicity of either halomethane. Methanol, ethanol, isopropanol, and decanol in combination with CCl4 caused massive liver damage but failed to augment CCl4 lethality. t-Butanol, pentanol, hexanol, and octanol significantly decreased the LD50 of CCl4. The hepatotoxic effects of CHCl3 were potentiated by all of the alcohols and the LD50s were also decreased significantly. On a comparative basis, alcohol-potentiated CHCl3 toxicity was greater than the toxicity of CCl4. These findings indicate that even though halomethane liver injury might be potentiated by alcohols, the underlying mechanisms differ among alcohols since not all alcohols potentiate the lethal effects of these halomethanes.
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PMID:Potentiation of CCl4 and CHCl3 hepatotoxicity and lethality by various alcohols. 225 8

To determine the course of hepatic recovery from subchronic oral administration of carbon tetrachloride (CCl4), male F-344 rats were gavaged with 0, 20, or 40 mg CCl4/kg, 5 days/week, for 12 weeks. Exposure to CCl4 caused dosage-dependent increases in relative liver weight and the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, and cholesterol as well as a dosage-dependent decrease in hepatic cytochrome P450. Centrilobular hepatocellular vacuolar degeneration, necrosis, and cirrhosis occurred at both 20 and 40 mg/kg, with dosage-dependent severity. Reversibility of these reported effects varied with parameter. By Day 8 postexposure, necrosis had disappeared and all serum indicators and cytochrome P450 had returned to control levels. By Day 15 postexposure, the severity of the vacuolar degeneration had decreased. Reversibility of cirrhosis was dosage dependent; complete recovery occurred in the low- but not the high-dose group by Day 15. The disappearance of the increase in relative liver weight was also dependent on dosage; the low- but not the high-dose group had returned to the control level by Day 22. In an attempt to measure persistent hepatic damage, liver uptake relative to the spleen was determined for a sulfur colloid labeled with technetium-99m and for tritiated 2-deoxyglucose. Neither method consistently measured hepatic damage in cirrhotic livers due, in part, to the high degree of variability in the tracer uptake data.
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PMID:Assessment of hepatic indicators of subchronic carbon tetrachloride injury and recovery in rats. 225 19

We evaluated plasma amino acid (AA) concentrations associated with a histologically defined lesion caused by bile duct ligation (BDL) in developing rats. Nineteen rats that underwent BDL at 14 days of age had marked bile duct proliferation with bridging fibrosis, multifocal lobular necrosis, and minimal polymorphonuclear periportal infiltrate in their livers at sacrifice (11-31 days after ligation). These were compared to two age-matched control groups: 21 nonoperated rats and 22 sham-operated rats; and eight rats with cirrhosis caused by carbon tetrachloride. Signs of liver damage including jaundice, growth failure, bleeding, and ascites were accompanied by elevated bilirubin, ammonia, aspartate aminotransferase (AST), and alkaline phosphatase levels in BDL rats compared to controls. They had higher concentrations of total AAs, phenylalanine, tyrosine, and cyst(c)ine when compared to controls and to CCl4-treated rats. Micronodular cirrhosis was present in CCL4-treated rats with elevated AST and alkaline phosphatase levels. Glutamine and glutamate levels were higher in them than in BDL rats or controls, and branched chain AA levels were lower. These two chronic lesions, one obstructive and one hepatotoxic, both result in fibrotic change, but their metabolic abnormalities as reflected in plasma AA levels are distinct. We found that BDL is an appropriate model with which to study metabolic changes and growth failure due to chronic biliary stasis during its progression to frank cirrhosis.
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PMID:Plasma amino acids in long-term models for obstructive versus toxic liver injury in developing rats. 232 99

The potentiation of CCl4 toxicity by pre-exposure to chlordecone (CD) is well established. Chlordecone-induced metabolism of CCl4 and suppressed hepatocellular repair have been offered as possible mechanisms for this potentiation. Recent work using the partially hepatectomized (PH) rat as a model for an actively regenerating liver has provided supportive evidence for the latter hypothesis. The present study was initiated to determine if metabolism and disposition of 14CC14 is altered in the PH rat, and if this is a contributing factor to the reported protective effect afforded by the PH procedure. Male Sprague-Dawley rats (150-175 g) maintained on dietary CD (10 ppm) for 15 days were partially hepatectomized or sham-operated (SH) on day 15. Another group of CD-pretreated rats received 0.9% CoCl2 (60 mg/kg, sc, qd for 2 days) in lieu of the surgical procedure. On day 16 the rats were challenged with a single dose of CCl4 (100 microL/kg, ip) containing 20 muCi 14CCl4. A radiolabel inventory consisting of exhaled 14CCl4, 14CO2 production, total hepatic 14C, free 14CCl4 and covalently bound 14C was taken over a 6-hr time period. Lipid peroxidation and serum enzyme activities [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] were measured in indices of toxicity. Neither CD pretreatment alone nor CoCl2 treatment alone produced significant alterations in metabolism of low dose (100 microliters/kg) CCl4. No significant difference in 14CCl4 recovery or 14CO2 production was detected for PH versus SH rats. Hepatic 14CCl4-derived 14C (per gram tissue) was greater in PH rats. Values for free 14CCl4, covalently bound 14C, and lipid peroxidation were similar for SH and PH rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Carbon tetrachloride metabolism in partially hepatectomized and sham-operated rats pre-exposed to chlordecone (Kepone). 248 48

The authors studied the pharmacotherapeutic efficacy of antioxidants vitamin E, sodium selenite, and their combination in damage to rat liver by CCl4 and the anthelmintic agent chloxyl. Changes of the intensity of peroxidation of biological membrane lipids, the activity of enzymes-markers of hepatocyte cytolysis--alanine aminotransferase and aspartate aminotransferase--in blood serum, and changes in the structure of the liver were studied. Antioxidants and their combination blocked lipid peroxidation, reduced the activity of alanine aminotransferase and aspartate aminotransferase in blood serum considerably, and caused a protective effect on the structure of rat liver in its damage by CCl4 and chloxyl.
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PMID:[Experimental antioxidant therapy in toxic liver damage from CCl4 and chloxyl]. 255 82

The effect of vitamin A on experimental hepatic fibrosis in rats induced by administration of carbon tetrachloride (CCl4) and pig serum was studied. Vitamin A content in the CCl4-induced cirrhotic liver decreased significantly. Administration of pig serum caused hepatic fibrosis without hepatocytic damage. Vitamin A suppressed induction of experimental hepatic fibrosis by CCl4 and pig serum. Neither hepatocytic injury nor increased activities of serum aspartate aminotransferase and glutamic pyruvic transaminase induced by CCl4 was diminished by vitamin A. These data provide evidence that vitamin A inhibits hepatic fibrogenesis and that this effect may be mediated by an action on stellate cells rather than hepatocytes.
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PMID:Suppression of experimental hepatic fibrosis by administration of vitamin A. 257 84


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