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)

Administration of carbon tetrachloride to normal rats increased activities of hepatic 5(1)-nucleotidase, acid phosphatase, acid ribonuclease while the activities of succinate dehydrogenase, glucose 6-phosphatase, superoxide dismutase and cytochrome P450 were decreased. Levels of lipid peroxides, total lipids and cholesterol of liver were also increased. The activities of serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and alkaline phosphatase were increased. Other serum parameters showing changes after carbon tetrachloride were: bilirubin, proteins, cholesterol, triglycerides and lipoprotein-X. Picroliv (from the plant Picrorhiza kurroa) in doses of 6 and 12 mg/kg provided a significant protection against most of the biochemical alterations produced by carbon tetrachloride. The degree of protection afforded by picroliv, when administered simultaneously or as a pretreatment was almost equal.
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PMID:Hepatoprotective activity of picroliv against carbon tetrachloride-induced liver damage in rats. 240 41

The biphasic behaviour observed in endotoxin-induced shock attributed to a direct interaction of bacterial lipopolysaccharides with the cell membrane and an indirect activation of multiple homeostatic regulatory mechanisms, cannot be completely elucidated with in vivo studies. In primary cultures of adult rat hepatocytes, lipopolysaccharide from Escherichia coli 0111:B4 affects the cytochrome P450 levels directly; however, albumin and aspartate aminotransferase secretion are induced by some mediators present in the sera of animals in acute-phase shock.
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PMID:Direct and mediated Escherichia coli lipopolysaccharide action in primary hepatocyte cultures. 329 5

To study the influence of hepatic metallothionein (MT) on the hepatotoxic response to carbon tetrachloride (CCl4), adult male rats were pretreated with a 10 mg X kg-1 dose of zinc (Zn) 24 h prior to CCl4 (i.p., l mL X kg-1) treatment. Zn pretreatment increased the hepatic MT concentrations markedly and reduced the magnitudes of the CCl4-induced reduction of cytochrome P450 concentration as well as elevation of serum alanine aminotransferase and aspartate aminotransferase activities when determined at 4 or 24 h following CCl4 treatment. Treatment of Zn-exposed animals with CCl4 also resulted in significant reduction of the concentrations of hepatic MT (as determined by the cadmium-saturation method) as well as cytosolic Zn. Sephadex G-75 chromatographic study of hepatic cytosols showed that MT-bound Zn was selectively depleted by CCl4 exposure. Moreover, it was demonstrated that CCl4, after metabolic activation, reduced the cadmium binding capacity of Zn-induced hepatic MT in vitro. To examine the possible protective effect of Zn independent of induction of MT synthesis, CCl4 was administered 2 h following Zn pretreatment and the hepatotoxic response was examined 4 h later. This study revealed limited protection by Zn prior to the induction of MT synthesis. These data further support a role of MT in the modulation of CCl4 hepatotoxicity.
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PMID:Interaction of metallothionein and carbon tetrachloride on the protective effect of zinc on hepatotoxicity. 379 Oct 46

A variety of hematologic, serum chemistry, and cytochrome P450 variables from 20 F344/N rats were measured and analyzed statistically to determine the effects of shipping stress on clinicopathologic indicators. Additionally, whole body, liver, and total kidney weights were recorded and compared. Ten rats were assayed upon receipt (stressed group), and 10 additional rats were held on a wire substrate for 12 days (poststress group) and assayed. Significant differences were detected between the 2 groups in ratio of total kidney weight to body weight, segmented neutrophil count, monocyte count, eosinophil count, and serum cholesterol, serum potassium, serum aspartate transaminase, and serum lactate dehydrogenase values.
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PMID:Effect of shipping stress on clincopathologic indicators in F344/N rats. 382 73

The carcinogenic water disinfection byproduct, bromodichloromethane (BDCM), produces renal and hepatic toxicity in rodents in acute and subchronic studies. In the present investigation, female rats and mice (n = 6) were dosed daily for 5 consecutive days with BDCM (dissolved in an aqueous, 10% Emulphor solution) by gavage. Rats received 75, 150 and 300 mg BDCM/kg body weight/day and mice received 75 and 150 mg BDCM/kg body weight/day. Two rats in the 300 mg/kg/day treatment group died on day 5. On day 6, the animals were sacrificed and serum samples were taken for analysis of indicators of hepatic and renal toxicity. Livers and kidneys were excised and samples taken for histopathological evaluation. Portions of the livers were also utilized to produce microsomes for analysis of cytochrome P450 enzyme activities and total P450 content. Total hepatic cytochrome P450 was decreased in rats dosed with 150 and 300 mg BDCM/kg body weight/day, but was not significantly affected in BDCM-treated mice. Serum lactate (LDH) and sorbitol (SDH) dehydrogenase, aspartate aminotransferase (AST), creatinine and blood urea nitrogen were increased above those of controls in rats dosed with 300 mg BDCM/kg/day. These data suggested that hepatic and renal damage had occurred in this treatment group. This was confirmed by histopathological analyses which revealed that lesions occurred in both hepatic and renal tissues from rats dosed with 150 and 300 mg BDCM/kg/day. The hepatic lesions were centrilobular and primarily consisted of vacuolar degeneration. The hepatotoxicity indicators alanine aminotransferase (ALT) and SDH were increased in mice dosed with 150 mg BDCM/kg/day. However, no histopathological lesions were observed in these animals. This study shows that BDCM is both hepatotoxic and nephrotoxic to female rats after repeated dosing, but is only weakly hepatotoxic to female mice at the administered doses. Also, reduced activities of hepatic cytochrome P450 were observed in rats, but not mice. These species differences in toxicity and xenobiotic metabolizing enzyme inhibition caused by BDCM suggest that an understanding of the mechanism of toxicity of this compound will be critical when extrapolating rodent toxicity data to humans for this environmental pollutant.
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PMID:Toxicity of bromodichloromethane in female rats and mice after repeated oral dosing. 780 27

Changes in different microsomal membrane functions were measured in the liver of rats 3, 6, or 9 weeks following an oral infection with 20 metacercariae of Fasciola hepatica. The parasitic pathology noted at autopsy was accompanied by increased levels in both plasma aspartate aminotransferase (EC 2.6.1.1) and microsomal gamma-glutamyltransferase (EC 2.3.2.2). Heme oxygenase activity of microsomes was significantly decreased by Weeks 3 and 6 postinfection and this decrease correlates with those of total microsomal cytochrome P450 and certain P450-dependent monooxygenase activities, namely, benzphetamine demethylation, ethoxycoumarin deethylation, and benzopyrene hydroxylation. Microsomal epoxide hydrolase (EC 3.3.2.3) was only altered 6 weeks after the infection. During the early stages of the parasitism, there were decreases in both microsomal calcium uptake and calcium ATPphosphohydrolase activity (EC 2.6.1.1), whereas membrane fluidity, estimated by the order parameter S, was lower in the infected rats than that in the controls. These alterations could be related to the already described increase in liver cytosolic calcium or lipid peroxidation which occurs in experimental fascioliasis.
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PMID:Fasciola hepatica: liver microsomal membrane functions in host rat. 790 29

Earlier studies showed that hepatotoxicant-treated experimental animals were more susceptible than controls to the lethal effects of bacterial endotoxin. The exact mechanisms of this effect were not understood. In this paper we showed that nitric oxide (.NO) was produced in whole blood and in liver tissues of rats that had been treated with a nonlethal dose of CCl4 (1.3 g/kg) followed by a low dose of lipopolysaccharide (LPS) (100 micrograms/kg). EPR spectroscopy was used in this study to detect nitrosyl-protein complexes. Hemoglobin-nitrosyl complexes were detected in both whole blood and liver. By performing analyses of EPR spectra obtained from hepatocytes exposed to .NO, we were able to identify EPR signals attributable to nitrosyl-cytochrome P420 in rat liver. We found that nitrosyl complex formation in red blood cells and liver was inhibited by treatment with NG-mono-methyl-L-arginine, suggesting enzymatic biosynthesis of .NO. A small but significant inhibition of nitrosyl complex formation by gadolinium trichloride pretreatment was found in the liver, suggesting that Kupffer cells were also involved in .NO biosynthesis, because this treatment decreased Kupffer cells. There was a synergistic effect of CCl4 and LPS on the serum levels of the hepatic enzymes aspartate aminotransferase, alanine amino-transferase, lactate dehydrogenase, and sorbitol dehydrogenase, which are indices of parenchymal cell damage. NG-Mono-methyl-L-arginine treatment increased these hepatic enzyme activities, suggesting a protective role for .NO. EPR resonances at g approximately 2.48, 2.29, and 1.91, due to low-spin cytochromes P450/P420 (FE3+), were decreased in the livers of LPS-induced rats that had been previously treated with CCl4, indicating cytochrome P450/P420 destruction or at least a change in the valence state of the cytochrome P450/P420 heme groups to Fe2+ in the presence of .NO. Because nitrosyl-cytochrome P450 is not stable, the concomitant detection of nitrosyl-cytochrome P420 (Fe2+) could account, at least in part, for the decrease of the ferric low-spin heme groups. Our novel observations of hepatic nitrosyl species suggest that .NO plays an important role during hepatic injury caused by CCl4 in hosts exposed to endotoxin.
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PMID:Nitric oxide production during endotoxic shock in carbon tetrachloride-treated rats. 807 2

Carbon tetrachloride (CCl4) is a classical pericentral hepatotoxicant; however, precise details of its mechanism of action remain unknown. One possibility is that Kupffer cells participant in this mechanism since CCl4 elevates calcium, and the release of toxic eicosanoids and cytokines by Kupffer cells is calcium-dependent. Therefore, these studies were designed to evaluate the role of Kupffer cells in CCl4 toxicity in the rat in vivo. Kupffer cells were destroyed selectively with gadolinium chloride treatment (10 mg/kg GdCl3 iv) 1 day prior to administration of CCl4 (4 g/kg ig). Twenty-four hours after CCl4 treatment, rats were anesthetized, blood samples were drawn for aspartate aminotransferase (AST) determination, which is indicative of parenchymal cell damage, and trypan blue was infused into the liver to stain the nuclei of dead hepatocytes. AST levels were in the normal range and trypan blue staining was negligible in livers from vehicle- or GdCl3-treated rats. As expected, CCl4 treatment alone elevated AST levels to values over 4000 U/liter and caused massive cell death (60-90 trypan blue-positive cells/pericentral field). In dramatic contrast, the elevation in AST and cell death due to CCl4 were almost completely prevented by GdCl3 treatment. In attempts to understand this phenomenon, metabolic and detoxification pathways were assessed. CCl4 is metabolized via cytochrome P450 II.E.1; however, GdCl3 treatment did not alter this pathway as assessed from p-nitrocatechol formation from the selective substrate, p-nitrophenol. GdCl3 treatment also had no effect on hepatic glutathione levels. On the other hand, GdCl3 treatment significantly reduced infiltration of neutrophils resulting from exposure to CCl4. These data clearly support the hypothesis that Kupffer cells participate in the mechanism of toxicity of CCl4 in vivo, possibly by release of chemoattractants for neutrophils.
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PMID:The involvement of Kupffer cells in carbon tetrachloride toxicity. 848 Mar 36

Milacemide or 2-n-pentylaminoacetamide hydrochloride, a new glycine derivative, was found to cause elevations of plasma transaminases in patients suffering from severe depression and Alzheimer's disease. However, no signs of liver toxicity were observed during the course of earlier conducted subchronic and chronic in vivo studies in rodents and cynomolgus monkeys. In this study an in vivo/in vitro approach has been proposed to detect early alterations in key metabolic and functional liver capacities. Milacemide was administered by continuous i.v. infusion for 7 days to male Sprague-Dawley rats using subcutaneously implanted osmotic pumps. Doses were given of 0, 250 and 500 mg/kg per day. Body weight and food intake were recorded and at day 7 of exposure, Milacemide concentration, glucose, urea, triglycerides and cholesterol levels and alanine (ALT) and aspartate aminotransferase (AST) activities were measured in plasma. Non-esterified fatty acids were determined in serum. On day 8, after overnight fasting, hepatocytes were isolated. A portion of the cells derived from untreated animals (no osmotic pumps) were cultured in a primary monolayer and exposed in vitro to different Milacemide concentrations. The xenobiotic biotransformation capacity of the isolated hepatocytes was studied by measuring the cytochrome P450 content, ethoxycoumarin-O-deethylase (ECOD), pentoxyresorufin-O-deethylase (PROD), ethoxyresorufin-O-deethylase (EROD), aldrin epoxidase (AE), epoxide hydrolase (EH) and glutathione S-transferase (GST) enzyme activities. Triglycerides, cholesterol and phospholipid contents were measured on the isolated cells. At plasma concentrations of 43 and 130 microM Milacemide, the ALT activity was unchanged or significantly decreased, whereas the AST activity was increased in both cases. Other clinical chemistry parameters remained unchanged. Weight gain was significantly lower in rats treated with the high Milacemide dose. In addition, decreased food consumption was observed in all treated animals leading to significantly lower food efficiency factors for the rats treated with the high dose. Milacemide had a specific inhibitory effect on xenobiotic biotransformation: ECOD activity decreased to 60% of the control value for both Milacemide doses, PROD activity remained unaffected whereas EROD activity decreased to 65% of the control value. A decrease was also observed at the highest drug concentration for AE (to 41%), EH (to 65%), cytochrome P450 content (to 80%) and GST (to 85%). At 500 mg Milacemide kg/day, hepatocyte triglycerides levels increased 3.1-fold while cholesterol and phospholipid levels remained unaffected. Electron and light microscopy on total liver and isolated hepatocytes indicated a concentration-dependent accumulation of lipid droplets, the occurrence of numerous vacuoles in the cytoplasm and other structural abnormalities. When the cultured hepatocytes of control animals (without osmotic pumps) were exposed to Milacemide, the appearance of vacuoles and myeloid bodies could be confirmed in vitro. The results of this study using an in vivo/in vitro approach clearly show potential hepatotoxic properties of Milacemide, an effect not observed in conventional toxicity studies.
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PMID:Observation of hepatotoxic effects of 2-n-pentylaminoacetamide (Milacemide) in rat liver by a combined in vivo/in vitro approach. 913 5

The present study reports on the effects of horminone on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, on hepatic cytochrome P450 (P450) and cytochrome b5 (cyt b5) contents and on the activities of NADPH-cytochrome P450 reductase (NR), mixed function mono-oxygenases (MFO), glutathione-S-transferase (GST) and glutathione reductase (GR) of Wistar male rat. Horminone is a diterpenoid quinone (7,12-dihydroxyabiet-8,12-diene-11,14-dione) present in several species of the Labiatae family and used as medicinal plants in folk medicine. In this study, horminone was administered by the intraperitoneal route (i.p.) at a concentration of 1 or 10 mg/kg to each group of six mice, using water as a vehicle. On the one hand, results showed that horminone increased serum ALT and AST levels and cyt b5 content and induced the activities of ethylmorphine N-demethylase (EMD). On the other hand, horminone decreased P450 content and inhibited the activities of 7-ethoxyresorufin O-deethylase (ERD), 7-ethoxycoumarin O-deethylase (ECD), aniline 4-hydroxylase (AH) and NR. Based on these results, the possibility of toxic effects occurring after administration of plant extracts containing horminone must be considered.
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PMID:Effects of horminone on liver mixed function mono-oxygenases and glutathione enzyme activities of Wistar rat. 932 1


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