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)

Cultures of adult rabbit hepatocytes have been used to study the early toxic effects of 2 model hepatotoxins, dimethylnitrosamine and allyl alcohol. Leakage of glutamate oxaloacetate transaminase and glutamate pyruvate transaminase into the cell culture medium was a sensitive indicator of plasma membrane damage by these compounds and a dose-response relationship was observed. By contrast, gamma-glutamyltranspeptidase and alkaline phosphatase were insensitive markers. The effects of dimethylnitrosamine were slower to develop. Dimethylnitrosamine also produced a dose-related inhibition of protein synthesis after 4 h, a decrease in NADPH diaphorase and an increase in non-specific esterase after 20 h. Dimethylnitrosamine, unlike allyl alcohol, caused extensive disruption of ribosome association with the endoplasmic reticulum.
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PMID:The effects of dimethylnitrosamine and allyl alcohol on primary maintenance cultures of adult rabbit hepatocytes. 689 38

PD 132301-2 is a substituted urea hypolipidemic and antiatherosclerotic agent that is a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). To determine its subacute toxicity, PD 132301-2 was administered orally to beagle dogs at 0, 6, 12, 25, 50, 200, 400, or 800 mg/kg/day for 2 weeks. Clinico-pathologic evaluations were completed on all dogs. Liver and adrenal total and esterified cholesterol concentrations, adrenocorticotrophic hormone (ACTH) responsiveness, and adrenal ultrastructure were determined at 0, 6, 12, and 25 mg/kg. At 12 mg/kg or greater, salivation, epiphora, conjunctivitis, emesis, anorexia or decreased food consumption, and soft to mucoid feces and/or diarrhea were noted. Suppression of ACTH response occurred by Day 6 at all doses. Adrenocortical degeneration and/or necrosis in zona fasciculata and reticularis was seen at all doses; adrenal free and esterified cholesterol were normal at 6 mg/kg and decreased at 12 and 25 mg/kg. Increases in serum alanine aminotransferase (2- to 15-fold), aspartate aminotransferase (2- to 12-fold), and alkaline phosphatase (2- to 7-fold) were noted at 50 mg/kg or greater. Periportal hepatocellular hypertrophy and hypereosinophilia occurred at 50 mg/kg or greater; hepatic cholesterol values were not significantly affected by treatment. Dose-dependent ultrastructural alterations in adrenocortical cells included decreased numbers of mitochondria and smooth endoplasmic reticulum profiles, qualitative and quantitative changes in lipid globules, and increased numbers of autolysosomes. PD 132301-2 or one of its metabolites has potent adrenocorticolytic properties and limited hepatotoxic properties by mechanism(s) that are likely independent of systemic ACAT inhibition.
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PMID:Subacute toxicity of a novel inhibitor of acyl-CoA: cholesterol acyltransferase in beagle dogs. 838 21

Clinical, pathological and ultrastructural changes in rats injected ip with extracts of Wedelia glauca are described. Macroscopic changes were congested livers with accentuated centrilobular vascular patterns. Microscopic hepatic lesions had variable degrees of degeneration and lytic necrosis of centrilobular hepatocytes. Ultrastructural liver changes were condensation of nuclear chromatin with loss of perinuclear membranes, enlargement of mitochondria with alteration of limiting membranes, disappearance of cristae and matrical rarefaction. The endoplasmic reticulum was dilated with detachment of ribosomes. Serum activities of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase were increased.
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PMID:Liver necrosis induced by Wedelia glauca in rats. A light and electron microscopy study. 882 41

The toxicity of atorvastatin (AT), an inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG), was evaluated in beagle dogs. In 4 studies [2-wk rising dose (daily increasing doses for 1 wk; maintenance for 1 wk), 12-wk rising dose (daily dosing with weekly increases in dose), 2-wk toxicity (daily dosing for 2 wk; 3 dose levels), 13-wk toxicity (daily dosing for 13 wk; 3 dose levels)], dogs received up to 400 mg/kg orally. Doses of 180 mg/kg induced moribundity, necessitating euthanasia. Weight losses up to 26% were seen at doses > or = 150 mg/kg. Decreases in cholesterol levels were dose-related. Alanine and/or aspartate aminotransferase were increased at doses > or = 80 mg/kg; alkaline phosphatase was increased at doses > or = 150 mg/kg. Histopathologic findings were seen at > or = 150 mg/kg and included hepatocellular eosinophilia related to increased smooth endoplasmic reticulum and cholangiohepatitis and cholecystitis at 150 mg/kg in the 2-wk toxicity study; hepatocellular degeneration, centrilobular bridging, cholecystitis, hemorrhage in gallbladder and brain, demyelination of optic nerve, and skeletal muscle necrosis at > or = 280 mg/kg in the 12-wk rising dose study; and erosion and hemorrhage in large intestine, hepatocellular degeneration and necrosis, and inflammation and necrosis of gallbladder epithelium at 320 mg/kg in the 2-wk rising dose study. Doses up to 80 mg/kg for 13 wk did not induce histopathologic lesions in examined organs. AT effectively lowered serum cholesterol in normal lipidemic dogs. Toxicity at AT in dogs was similar to that with other inhibitors of HMG except that lenticular changes were not seen, significant hepatic, testicular, or neurological toxicity was associated only with high doses at AT, and skeletal muscle changes similar to those described in rats and rabbits were identified.
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PMID:Subchronic toxicity of atorvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, in beagle dogs. 886 88

The cyanobacterial hepatotoxin, microcystin-LR (MCLR), is a potent protein phosphatase inhibitor that disrupts actin microfilament, cytokeratin intermediate filament, and microtubule networks in hepatocytes. To determine ultrastructural and biochemical changes that develop concurrently with microcystin-induced cytoskeletal disorganization, isolated rat livers were perfused with MCLR at 0.1 to 5.0 micrograms/ml for 5 to 40 min. Lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase changed over time, but trends for toxin-treated and control livers did not differ. The earliest toxin-induced ultrastructural changes, observed in livers perfused at 0.1 microgram/ml for 15-20 min or at 0.3 microgram/ml for 5-10 min, were loss of hepatocyte microvilli in the space of Disse, widening of sinusoidal fenestrae, disruption of sinusoidal endothelium, dilation of bile canaliculi with loss of microvilli, and widening of hepatocyte intercellular spaces. Lesions progressed with increasing toxin concentrations and exposure times. In livers perfused with MCLR at 0.5 microgram/ml for 10-20 min, hepatocytes had plasma membrane blebs and concentric whorls of rough endoplasmic reticulum, and there was marked disassociation of hepatocytes resulting in disrupted hepatic cords. At toxin concentrations of 2.0 or 5.0 micrograms/ml for 10-20 min, there was mild dilation of mitochondrial cristae, cytoplasmic vacuolization or invagination of plasma membranes, redistribution of organelles, and sometimes nuclear degenerative change. Some hepatocytes exhibited clusters of plasma membrane blebs radiating from round cytoplasmic structures, which may be composed primarily of condensed microfilaments.
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PMID:Sequential ultrastructural and biochemical changes induced by microcystin-LR in isolated perfused rat livers. 894 94

Preliminary short-term toxicity studies of sucrose acetate isobutyrate (SAIB) in the dog demonstrated that addition of this additive to the diet was associated with an increase in liver size and elevated serum alkaline phosphatase activity with no evidence of pathological change by light microscopy. To determine the basis for these changes, a 12-week oral toxicity study of SAIB was conducted in the dog and a similar study was performed in the rat. SAIB was fed in the diet to groups of six beagle dogs of each sex at 0, 0.5, 1.0, 2.0 and 4.0%. SAIB was also fed to groups of 40 Sprague-Dawley rats of each sex at levels of 0, 2.5, 5.0 and 10.0%. In the rat study, in addition to routine toxicology parameters, hepatic microsomal enzyme induction was determined using a zoxazolamine hypnotic test, urinary ascorbic acid excretion and determination of hepatic carboxylesterase activity. Sodium phenobarbital was fed to groups of 20 rats of each sex at a dose of 100 mg/kg body weight/day by gavage as a positive control for hepatic microsomal enzyme induction. In the dog study, routine toxicological tests were supplemented by tests for bromsulfophthalein (BSP) retention, histochemical staining of liver sections for glycogen, phosphorylase, succinate dehydrogenase, and acid and alkaline phosphatases. Levels of liver lipid, protein, glycogen and carboxylesterase activity were also determined. Electron microscopic examinations were made on liver sections from the dog study at the end of the 12-week SAIB feeding period and after a 2-week withdrawal period. Administration of SAIB to rats did not reveal evidence of any effect on hepatobiliary function, and there was no indication of microsomal enzyme induction. Body weight gain of male rats fed SAIB was decreased, probably as the result of decreased palatability of the diet; SAIB did not affect body weight gain in females. The changes observed in the dogs fed SAIB included increased serum alkaline phosphatase activity with no change in serum alanine aminotransferase, aspartate aminotransferase or lactic dehydrogenase activity and no change in serum electrolyte, serum protein, glucose or bilirubin levels. No haematological changes were observed. BSP retention was observed at all SAIB dose levels. There were no SAIB-related pathological changes in any organ when examined by light microscopy. Examination by electron microscope revealed dilatation of bile canaliculi and an increase in smooth endoplasmic reticulum compared with controls. Histochemical studies also indicated increased enzyme activity of the bile canaliculi. The electron-microscope-revealed changes were completely reversed during a 2-week treatment withdrawal period. The dog study did not establish a no-effect level for changes in hepatobiliary function induced by feeding SAIB.
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PMID:Subchronic toxicity studies of sucrose acetate isobutyrate (SAIB) in the rat and dog. 951 48

Acute aflatoxin B1 (AFB1)-induced hepatotoxicity was assessed in vivo in male Sprague-Dawley rats (150-300 g) using magnetic resonance imaging (MRI). MRI results were compared to serum enzyme levels, histology and electron microscopy. Twenty-four hours following intraperitoneal delivery of AFB1 (3 mg/kg body weight in a saline/dimethyl sulfoxide (DMSO; 0.03 ml/kg body weight) solution), regions of damage, characterised by increased proton signal intensities in T2-weighted images, were observed in the vicinity of the hepatic portal vein (HPV) and in the right medial regions of the liver. Image analysis of regions of apparent damage around the HPV and right medial regions, following 24 h of AFB1 exposure, indicated statistically significant (P<0.05) increases in proton image signal intensities, when compared to saline/DMSO-treated rats. No significant difference in proton image signal intensities were observed 1-2 h following AFB1 exposure. Twenty-four hours following AFB1 exposure, histopathological assessment was characterised by portal/central vein/artery congestion, sinusoid congestion, nuclear pyknosis and karyolysis, and hepatocyte vacuolation; electron microscopy (EM) examination indicated nuclear debris, swollen cytoplasmic compartments, vacuolation, and the disappearance of the smooth endoplasmic reticulum, and elevated levels of serum aspartate aminotransferase and alanine aminotransferase were found to be significantly different (P<0.01) than controls.
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PMID:Non-invasive in vivo magnetic resonance imaging assessment of acute aflatoxin B1 hepatotoxicity in rats. 1091 31

Activities of hexokinase (HK), glucose-6-phosphate dehydrogenase (G6PDH), fructose-6-phosphate kinase (F6PK), glutamate dehydrogenase (GlutDH), aspartate aminotransferase (AAT), malate dehydrogenase (MDH) and glycerol-3-phosphate dehydrogenase (GPDH) were determined in tissue extracts of testes and ovaries of adult Dipetalogaster maximus (Uhler) and Triatoma infestans (Klug) (Hemiptera: Reduviidae), insect vectors of Chagas disease. The fine structure organization of the same organs were studied by electron microscopy. Results allow the following inferences: in testes from both species, most of the glucose would be utilized through the glycolytic pathway. Amino acid catabolism for energy purposes appears to be unimportant. The number of mitochondria and the development of the rough endoplasmic reticulum in cells of the spermatogenic line indicate the occurrence of active oxidative metabolism and protein synthesis; in ovaries, levels of G6PDH indicate the existence of an active pentose pathway which would supply the NADPH required for fat and ecdysteroid synthesis. Amino acid catabolism appears to be relatively more important in ovary than in testis. Fat and glycogen are stored in follicular cells of D. maximus; oocytes of both species contain numerous fat droplets. Abundant mitocondria are present in follicular cells and oocytes. A well developed rough endoplasmic reticulum and free ribosomes are also conspicuous in these cells. The malate/aspartate H-transfer system seemed to be relatively more important than the glycerophosphate shuttle in ovaries as well in testes.
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PMID:Comparative study of enzymes in testes and ovaries from adult Dipetalogaster maximus (Uhler) and triatoma infestans (Klug) (Hemiptera: Reduviidae). correlation with fine structural organization. 1175 15

In this study, the effect of a combination of vitamin C (ascorbic acid), vitamin E (dl-alpha-tocopherol acetate), and selenium (sodium selenate) on ethanol-induced liver damage in rats was investigated, morphologically and biochemically. The ethanol-induced injury was produced by the administration of 1 mL of absolute ethanol to each rat. Animals received vitamin C (250 mg/kg), vitamin E (250 mg/kg), and selenium (0.5 mg/kg) (ViCESe) for 3 d 1 h prior to the administration of absolute ethanol. In the liver of the animals given ethanol, the degenerative changes such as extreme hyperemia, vacuolization in cells of portal areas, a dilation in sinusoids, mononuclear cell infiltration, a swelling in cisternae of granular endoplasmic reticulum and in mitochondrial cristae, an increase in smooth endoplasmic reticulum, many lipid vacuoles were observed both light and electron microscopically. A similar structure was usually distinguished when compared with control animals, in rats given ethanol + ViCESe. In this group, the findings indicating cellular damage were either not observed at all or were decreased. In the group administered ethanol, a reduction of the blood glutathione (GSH) level and increases in serum values of alanine aminotranserase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activities were observed, whereas in the control group, the reverse was found to occur. On the other hand, in the group in which ethanol + ViCESe was administered, it was observed that the blood GSH value and serum ALP and ALT activities increased and serum AST, LDH, and GGT activities decreased. As a result, the present study indicates that ViCESe because of their antioxidant activity against ethanol damage have a protective effect on the liver.
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PMID:Protective effects of ascorbic acid, dl-alpha-tocopherol acetate, and sodium selenate on ethanol-induced liver damage of rats. 1498 25

Rabbit haemorrhagic disease (RHD) is caused by a calicivirus infection that kills most adult rabbits 24-72 h after viral inoculation. Two liver enzymes (AST, aspartate aminotransferase, and ALT, alanine aminotransferase) were monitored in blood samples of calicivirus-infected rabbits during the short course of RHD. Values of AST were used to differentiate three stages of hepatocellular degeneration in RHD: mild (up to 20-fold increase in AST), moderate (150-200-fold elevation of AST) and severe (more than 1000-fold elevation in AST). Liver samples of rabbits from these three biochemical stages of hepatocellular degeneration of RHD were studied by transmission electron microscopy to define the fine structure of the hepatocytes. In the mild hepatocellular degeneration there was proliferation (microvesiculation) of the smooth endoplasmic reticulum and swelling of mitochondria into spheroid bodies with loss of cristae. In moderate hepatocellular degeneration, vacuolization of cytoplasm and mitochondrial damage continued to be present, and there was also formation of autophagic vesicles. In the severe hepatocellular degeneration of RHD, the altered mitochondria also showed loss of density of their matrix; rupture of cytoplasmic vacuoles led to the formation of large vesicles. Marked depletion of liver glycogen was also found in this late stage of RHD. These data offer a correlation between biochemical and cytological features of the liver during the hepatocellular degeneration of RHD.
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PMID:Liver enzymes and ultrastructure in rabbit haemorrhagic disease (RHD). 1650 7


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