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)

There are too few reliable markers by which one can predict future function of a liver before implantation. Consequently, the purpose of this study was to test the hypothesis that amino acids in rinse-effluents could predict transplant outcome in marginal fatty livers from rats. Amino acids were measured in the rinse effluent from the livers immediately after harvest and graft preparation or cold storage. Amino acids in the effluent were twice as high in ethanol-treated animals compared to those in nonfatty controls. Ethanol-treated fatty livers survived for no longer than 7 days after transplantation while 83% of nonfatty controls survived (P < 0.05). In subsequent studies, the cold-storage time was decreased to 6 h to determine whether failing fatty livers released more amino acid than grafts that would function normally. There was a significant increase in amino acids in the effluent of fatty grafts compared to controls. Moreover, the sum of the four selected amino acids (alanine, valine, histidine, leucine) was lower than 23 nmol/g liver in functional livers, whereas failing grafts had totals significantly higher than 25 nmol/g liver. The sum of the four amino acids correlated well with 24 h post-transplant serum AST levels (r = 0.78, P < 0.0001). So we can conclude that amino acid release can serve as a useful marker of graft viability and reliably predicts survival.
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PMID:Amino acids in rinse effluents as a predictor of graft function after transplantation of fatty livers in rats. 1042 53

Enflurane is a fluorinated volatile anesthetic, mostly eliminated unchanged in exhaled air. About 10% of inhaled enflurane undergoes oxidative metabolism in liver via mixed function oxidase. We examined the influence of ethanol and subchronical exposition (6 hours a day, during five consecutive days) to subanesthetic and anesthetic concentrations of enflurane on liver function in BALB/c mice. Specially designed chamber for inhalatory application of anesthetics was constructed for this study. Animals were divided in six groups of twenty. The ethanol treated group was injected with ethanol intraperitoneally (1 g/kg). Two enflurane treated groups were intraperitoneally injected with 0.9% solution of sodium chloride (10 ml/kg) and one of them exposed to subanesthetic (0.5 Vol%) and the other one to anesthetic (2.75 Vol%) concentrations of enflurane. Following two groups received ethanol (1 g/kg) and each of them inhaled enflurane at previously mentioned doses. The control group was intraperitoneally injected with 0.9 % solution of sodium chloride (10 ml/kg) and did not receive any anesthetic. On the day following the last day of exposure half of the animals from each group were sacrificed for determination of glucose levels, erythrocyte glutathion levels, haematocrit, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), liver protein and glutathion levels, and total cytochrome P-450 (CYP P-450). The other half of animals from each group were injected intraperitoneally with caffeine (20 mg/kg). Caffeine and its metabolites in 8 hour urine were analyzed by high performance liquid chromatography (HPLC) method. Excretion of caffeine and its metabolites was different among the groups. We followed two caffeine metabolic ratios - 1,3-dimethyl uric acid and 3,7-xanthine (1,3-U/3,7-X) and 3,7-dimethyl xanthine + 7-xanthine and 1-xanthine + 1,7-dimethyl uric acid (3,7-X + 7-X/1-X + 1,7-U). The difference in caffeine metabolites ratios suggests that enflurane changes oxidative metabolism in liver via certain subtypes of mixed function oxidase, probably via CYP-4502E1. This effect is more expressed when ethanol and enflurane are applied together. Ethanol is well known inductor of CYP-4502E1 and the registrated enzyme induction could be explained by both influences - of ethanol and enflurane.
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PMID:The influence of anesthetic concentrations of enflurane and ethanol on caffeine metabolism in mice. 1044 95

L-2-oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. Here, its effect on alcohol-induced liver injury in an enteral alcohol feeding model was investigated. Male Wistar rats were given control high-fat or ethanol containing diets enterally for 4 weeks. Treated rats received 500 mg/kg/d of dietary OTC. Ethanol delivery, weight gain, and the cyclic pattern of ethanol in the urine were not different between the OTC-ethanol and ethanol groups. After 4 weeks, serum aspartate transaminase (AST), necrosis and inflammation were elevated significantly by ethanol compared with appropriate high-fat controls, effects blocked by OTC. Moreover, ethanol elevated hepatic tumor necrosis factor alpha (TNF-alpha) messenger RNA (mRNA) and the nuclear transcription factor nuclear factor kappaB (NFkappaB) 2-3 fold. NFkappaB in isolated Kupffer cells was also increased by ethanol. These effects were all blocked by OTC treatment. Additionally, superoxide production was higher in Kupffer cells isolated from ethanol-treated rats, an effect blunted by OTC. OTC also increased circulating glutathione (GSH) levels about 2-fold; however, GSH levels were not affected by ethanol or OTC in livers from the groups studied. Surprisingly, GSH was elevated by ethanol and OTC treatment in isolated Kupffer cells about 2-fold. Moreover, GSH (Ki-10 micromol/L) and cysteinyl-glycine, but not oxidized glutathione (GSSG) or OTC, blunted the LPS-induced increase in calcium in isolated Kupffer cells, possibly by activating a glycine-gated chloride channel due to their structural similarity with glycine. Collectively, it is concluded that GSH is protective, in part, by increasing circulating GSH, which blunts activation of Kupffer cells via the glycine-gated chloride channel.
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PMID:The glutathione precursor L-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat. 1065 62

Free radical formation caused by chronic ethanol administration could activate transcription factors such as nuclear factor-kappaB (NF-kappaB), which regulates production of inflammatory cytokines. Xanthine oxidase is one potential source of reactive oxygen species. Therefore, the purpose of this study is to determine whether allopurinol, a xanthine oxidase inhibitor and scavenger of free radicals, would affect free radical formation, NF-kappaB activation, and early alcohol-induced liver injury in rats. Male Wistar rats were fed a high-fat diet with or without ethanol (10-16 g/kg/day) continuously for up to 4 weeks with the Tsukamoto-French enteral protocol. Either allopurinol or saline vehicle was administered daily. Allopurinol had no effect on body weight or the cyclic pattern of ethanol in urine. Mean urine ethanol concentrations were 271 +/- 38 and 252 +/- 33 mg/dl in ethanol- and ethanol + allopurinol-treated rats, respectively. In the control group, serum aspartate aminotransferase and alanine aminotransferase levels were approximately 40 I.U./l and 25 U/l, respectively. Administration of enteral ethanol for 4 weeks increased serum transaminases approximately 5-fold. Allopurinol blunted these increases significantly by approximately 50%. Ethanol treatment also caused severe fatty infiltration, mild inflammation, and necrosis. These pathological changes also were blunted significantly by allopurinol. Furthermore, enteral ethanol caused free radical adduct formation, values that were reduced by approximately 40% by allopurinol. NF-kappaB binding was minimal in the control group but was increased significantly nearly 2.5-fold by ethanol. This increase was blunted to similar values as control by allopurinol. These results indicate that allopurinol prevents early alcohol-induced liver injury, most likely by preventing oxidant-dependent activation of NF-kappaB.
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PMID:Allopurinol prevents early alcohol-induced liver injury in rats. 1073 82

The purpose of this study was to determine whether early alcohol-induced liver injury (ALI) in females is associated with changes in CD14 on Kupffer cells, activation of hepatic nuclear factor (NF)-kappaB, and expression of tumor necrosis factor (TNF)-alpha mRNA. Male and female rats were given high-fat control or ethanol-containing diets for 4 wk using the intragastric enteral protocol. Physiological parameters were similar in both genders. Ethanol was increased as tolerance developed with higher blood levels than previously observed, resulting in a fourfold increase in aspartate aminotransferase (males 389 +/- 47 IU/l vs. females 727 +/- 66 IU/l). Hepatic pathology developed more rapidly and was nearly twofold greater and endotoxin levels were significantly higher in females after ethanol. Also, expression of CD14 on Kupffer cells was 1.5-fold greater and binding of transcription factor NF-kappaB in hepatic nuclear extracts and TNF-alpha mRNA expression were threefold greater in females. These data are consistent with the hypothesis that elevated endotoxin after ethanol triggers more activation of Kupffer cells via enhanced CD14 expression in females. NF-kappaB is activated in this process, leading to increases in TNF-alpha mRNA expression in the liver and more severe liver injury in females. It is concluded that gender differences in ALI are dependent on endotoxin and a signaling cascade leading to TNF-alpha.
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PMID:Gender differences in early alcohol-induced liver injury: role of CD14, NF-kappaB, and TNF-alpha. 1076 20

Ursolic acid is the active material isolated from the leaves of the Eucalyptus hybrid E. tereticornis. In the present study, it has shown a significant preventive effect in vitro against ethanol-induced toxicity in isolated rat hepatocytes. Compared with the incubation of isolated hepatocytes with ethanol only, the simultaneous presence of ursolic acid in the cell suspension preserved the viability of hepatocytes and reversed the ethanol-induced loss in the level of all the marker enzymes (AST, ALT and AP) studied. Ethanol alone resulted in a 48%-54% decrease in the viability and a 42%-54% reduction in the biochemical parameters of the hepatocytes. Ursolic acid showed a concentration dependent (1-100 microg/mL) preventive effect (12%-76%) on alcohol-induced hepatocyte toxicity by restoring the altered parameters. The results thus suggest the effective use of an in vitro test system as an alternative for in vivo assessment of hepatoprotective activity of purified material.
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PMID:Ursolic acid isolated from Eucalyptus tereticornis protects against ethanol toxicity in isolated rat hepatocytes. 1081 8

Experiments were performed to address some outstanding issues and investigate possible mechanisms relating to the acute comparative effects of ethanol on liver and skeletal muscle protein metabolism. Ethanol (EtOH)-treated rats were injected (i.p.) with a bolus of EtOH (75 mmol/kg body weight) and sacrificed at 20 min, 1-, 2.5-, 6-, and 24-hr time points. Control rats were injected with saline (Con-Sal; 0.15 mmol/L NaCl). All 24-hr ethanol-treated animals were compared with saline-injected rats subjected to controlled feeding (i.e. pair-fed controls for 24 hr EtOH). At 24 hr, there was no measurable alcohol in the plasma, whereas high levels were seen from 20 min to 6 hr (up to 448 mg/dL). Plasma levels of albumin were reduced at initial time points, and activities of aspartate aminotransferase increased, but there was no histological evidence of overt tissue damage either in muscle or liver. Hepatic protein and RNA contents and indices of tissue (C(s) and k(s)) and whole-body (V(s)) protein synthesis were significantly increased in ethanol-dosed rats relative to saline-injected pair-fed controls at 24 hr. In the liver, four of the seven cytoplasmic proteases investigated (alanyl-, arginyl-, and pyroglutamyl-aminopeptidases and proline-endopeptidase) showed significant increases in activity at 24 hr relative to pair-fed controls; four of the six lysosomal proteases showed significant decreases in activity (dipeptidyl-aminopeptidase II and cathepsins B, L, and H). In skeletal muscle, k(s) fell progressively between 1 and 24 hr (-25 to -69%; P < 0.001), but no significant changes in skeletal muscle protease activities were seen at 24 hr. At 24 hr after ethanol dosage in vivo, there were no significant increases in protein carbonyl content in liver or skeletal muscle compared to pair-fed controls (muscle levels actually decreased slightly). However, using either rat or human tissue, both liver and muscle carbonyl increased in vitro in response to superoxide and hydroxyl radicals: muscle was more susceptible to carbonyl formation than liver and both tissues were more sensitive to hydroxyl compared to superoxide radicals. These results show divergent effects of acute ethanol treatment on liver and skeletal muscle protein metabolism, which may not be linked to in vivo free radical-mediated protein damage (as indicated by carbonyl formation), at least in the short term.
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PMID:Comparative effects of acute ethanol dosage on liver and muscle protein metabolism. 1110 92

Biochemical assessment of liver damage during ethanol-induced stress was done by measuring the activities of serum enzymes, viz., aspartate transaminase (AST) and alkaline phosphatase (ALP), which were significantly elevated in rats fed ethanol. Ethanol administration for a period of 60 days modifies the fatty acid composition, and the analysis of fatty acids showed that there was a significant increase in the concentrations of palmitic acid (16:0), stearic acid (18:0), and oleic acid (18:1) in liver, kidney, and brain, whereas the concentrations of palmitoleic (16:1) and arachidonic acid (20:4) were significantly decreased. The breakdown products of arachidonic acids (20:4), prostaglandins, were elevated. The antioxidants curcumin and N-acetylcysteine (NAC) decreased the activities of serum AST and ALP. Curcumin and NAC decreased the concentrations of fatty acids, viz., palmitic, stearic, and oleic acid, whereas arachidonic acid and palmitoleic acid were elevated. The prostaglandin concentrations were also decreased after curcumin and N-acetylcysteine treatment. Thus the present investigation shows that curcumin and N-acetylcysteine prevent the fatty acid changes produced by ethanol and also reduce the inflammatory response of ethanol by reducing the level of prostaglandins.
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PMID:Potential role of antioxidants during ethanol-induced changes in the fatty acid composition and arachidonic acid metabolites in male Wistar rats. 1150 46

Hepatic steatosis and steatohepatitis are encountered with great frequency in people who consume large amounts of ethanol (more than 6 drinks per day). Ethanol causes steatosis by altering several steps in the hepatic processing of fatty acids, including their uptake from plasma, their use as fuel substrates, and their export as triglyceride. When clinically mild, alcoholic steatosis and steatohepatitis can be difficult to distinguish from nonalcoholic fatty liver disease. This is particularly true among individuals at high risk of accelerated alcoholic liver injury, such as women, the obese, and those with hepatitis C. In the outpatient setting, history and aspartate aminotransferase:alanine aminotransferase ratio offer the best clues to diagnosis. Liver biopsy cannot determine the cause of steatohepatitis, but can show the extent of disease. The etiology of disease is important to prognosis, as alcoholic fatty liver carries a much higher risk of progression and mortality than nonalcoholic fatty liver disease. Patients with moderate to severe alcoholic steatohepatitis are typically hospitalized. Derangements in white blood cell count, prothrombin time, and bilirubin identify those with the highest early mortality. Survival in this severely ill subgroup is improved with the short-term use of corticosteroids; patients who have contraindications to steroids may benefit from other forms of therapy, either pharmacologic, nutritional, or both.
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PMID:Alcoholic steatosis and steatohepatitis. 1194 32

Alcoholic liver disease is associated with abnormal hepatic methionine metabolism and folate deficiency. Because folate is integral to the methionine cycle, its deficiency could promote alcoholic liver disease by enhancing ethanol-induced perturbations of hepatic methionine metabolism and DNA damage. We grouped 24 juvenile micropigs to receive folate-sufficient (FS) or folate-depleted (FD) diets or the same diets containing 40% of energy as ethanol (FSE and FDE) for 14 wk, and the significance of differences among the groups was determined by ANOVA. Plasma homocysteine levels were increased in all experimental groups from 6 wk onward and were greatest in FDE. Ethanol feeding reduced liver methionine synthase activity, S-adenosylmethionine (SAM), and glutathione, and elevated plasma malondialdehyde (MDA) and alanine transaminase. Folate deficiency decreased liver folate levels and increased global DNA hypomethylation. Ethanol feeding and folate deficiency acted together to decrease the liver SAM/S-adenosylhomocysteine (SAH) ratio and to increase liver SAH, DNA strand breaks, urinary 8-oxo-2'-deoxyguanosine [oxo(8)dG]/mg of creatinine, plasma homocysteine, and aspartate transaminase by more than 8-fold. Liver SAM correlated positively with glutathione, which correlated negatively with plasma MDA and urinary oxo(8)dG. Liver SAM/SAH correlated negatively with DNA strand breaks, which correlated with urinary oxo(8)dG. Livers from ethanol-fed animals showed increased centrilobular CYP2E1 and protein adducts with acetaldehyde and MDA. Steatohepatitis occurred in five of six pigs in FDE but not in the other groups. In summary, folate deficiency enhances perturbations in hepatic methionine metabolism and DNA damage while promoting alcoholic liver injury.
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PMID:Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. 1212 4


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