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)

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

Differences in sensitivities of chloroquine-sensitive and chloroquine-resistant strains of Plasmodium berghei were observed following irradiation of the parasites. A dose of 15 kilorads from a cobalt-60 source killed the erythrocytic stages of the chloroquine-sensitive strain and no parasitemias were observed when mice were injected with these irradiated parasites. In contrast, when the chloroquine-resistant strain was irradiated with the same dose of cobalt-60 and injected into mice, an infection rate of 12.5% was observed, indicating that the latter strain was more resistant to inactivation by irradiation. Following injection of these irradiated strains of P. berghei into mice, significant decreases in mouse hepatic cytochrome P450 and benzo(a)pyrene hydroxylase activity, with no significant effect on N-demethylase activity, were observed. Serum glutamic-oxaloacetic transaminase (SGOT) and glutamic-pyruvic transaminase (SGPT) levels of mice injected with the irradiated parasites fell within the range of the serum enzyme levels in normal laboratory mice.
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PMID:Plasmodium berghei: sensitivity of chloroquine-resistant and chloroquine-sensitive strains to irradiation and the effect of irradiated malaria parasites on cytochrome P450-dependent monooxygenases. 858 51

We describe a 76-year-old male patient who developed a life-threatening acute hepatotoxicity possibly caused by flutamide, an antiandrogen drug given during the previous 10 months, in the scenario of a brief moderate hypotension secondary to atrial flutter. There was a sudden increase of liver enzyme levels AST = 4.521 IU/L, ALT = 1.716 IU/L (normal values 0-37 and 0-40 respectively), prothrombin activity decreased to 16%, and also felt the platelet count, with significant haemorrhages. We hypothesize this was triggered as a consequence of the transient diminished supply of oxygen to the subclinically flutamide-damaged hepatocytes by the well-known mechanism of the cytochrome P450 (3A and 1A)-mediated formation of electrophilic metabolites, and the inhibitory effect of flutamide on mitochondrial respiration and ATP formation.
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PMID:[Hepatoxicity caused by flutamide increased by hypotensive situation?]. 901 17

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

CYP2E is considered the only form of cytochrome P450 responsible for ethanol-mediated increases in acetaminophen hepatotoxicity. However, in experimental systems used for investigating ethanol-mediated increases in acetaminophen hepatotoxicity, animals are withdrawn from ethanol for 16 to 24 hr before the administration of acetaminophen to ensure the clearance of ethanol from the circulation. In rats, CYP2E has been shown to decrease to control levels after this time period of withdrawal from ethanol. We have previously shown in cultured human and rat hepatocytes, and in intact rats, that ethanol induces CYP3A in addition to CYP2E. To determine if there might be a role for CYP3A in ethanol-mediated APAP hepatotoxicity in addition to the recognized role for CYP2E, we investigated the effect of triacetyloleandomycin (TAO) on acetaminophen hepatotoxicity in ethanol-pretreated rats, as well as the effect of 11 hr withdrawal from ethanol on hepatic levels of CYP3A and CYP2E. TAO was dissolved in saline instead of dimethylsulfoxide, the solvent most usually employed, since dimethylsulfoxide inhibits CYP2E. Rats were administered 6.3% ethanol as part of the Lieber-DeCarli diet for 7 days, followed by replacement of the liquid diet with water for 11 hr. This 11-hr withdrawal from ethanol resulted in a decrease in hepatic levels of ethanol-induced CYP2E; however, considerable induction was still evident. There was no significant decrease in CYP3A. TAO completely prevented the histologically observed liver damage from acetaminophen in ethanol-pretreated rats, but did not prevent the increase in serum levels of AST. In ethanol-pretreated rats, exposure to APAP in the absence of TAO was associated with a 75% decrease in CYP3A, compared to animals exposed to APAP in the presence of TAO. These results suggest that CYP3A may have been suicidally inactivated by acetaminophen in the absence of TAO. Our findings suggest that CYP3A has a major role in ethanol-mediated increases in acetaminophen hepatotoxicity.
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PMID:Role of CYP3A in ethanol-mediated increases in acetaminophen hepatotoxicity. 914 48

The association between an in vivo oxidative stress condition of the liver and hepatic porphyria during HCB intoxication is postulated. After 30 days of treatment, HCB (25 mg/kg b.w.) promotes an induction of microsomal cytochrome P450 system, increase in microsomal superoxide anion generation accompanied by increased levels of liver lipid peroxidation, as measured by the production of thiobarbituric acid reactants and by spontaneous visible chemiluminescence. Concomitantly, liver antioxidant defenses are slightly modified, with decreased activity of glutathione peroxidase, superoxide dismutase and glucose-6-phosphate dehydrogenase contributing to an oxidative stress condition of the liver. These liver biochemical alterations are closely related to increased levels of urinary coproporphyrin, plasma AST and ALT activities and to the onset of liver morphological lesions.
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PMID:Pro- and anti-oxidant parameters in rat liver after short-term exposure to hexachlorobenzene. 919 4

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

The relationship was investigated between biochemical and morphological changes in chloroform (CHCl3)- and carbon tetrachloride (CCl4)-induced liver damage. The time courses of hepatic microsomal cytochrome P450 (CYP) content, hepatic microsomal CYP2E1 activity, hepatic reduced glutathione (GSH) content, plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were examined in relation to the liver morphology in rats orally treated with CHCl3 or CCl4 (3.35 mmol/kg). The CYP content and the activity of CYP2E1 markedly decreased in the CCl4-treated rats 3 h after treatment compared to much lower decreases in the CHCl3-treated rats. The hepatic GSH content was decreased to a similar extent in both groups of rats at 3 h after treatment; in the CCl4-treated rats, the GSH content continued to decrease, reaching a minimum at 24 h and without attaining the normal level at 72 h after treatment. By contrast, hepatic GSH content in the CHCl3-treated rats began to increase from 6 h, attaining complete recovery 48 h after treatment. Plasma ALT and AST activities were significantly elevated by CCl4 as early as 3 h after treatment, while the activities in the CHCl3-treated rats did not increase until 6 h after treatment. In both groups of rats, ALT and AST activities reached a maximum at 24 h, and gradually decreased, remaining at abnormal levels at 72 h. Hepatic cells in the CCl4-treated rats were found to be necrotic as early as 3 h post-treatment, whereas few or no morphological changes appeared in the liver of CHCl3-treated rats. The extent of necrosis was at a maximum 24 h after treatment in both CHCl3- and CCl4-treated rats. In addition, some necrotic cells remained in the liver of CCl4-treated rats 72 h after treatment, while the necrosis in the CHCl3-treated rats was almost negligible. The present results indicate that almost the same time-courses of biochemical and morphological changes were followed in rats of both the CHCl3- and CCl4-treated groups.
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PMID:Time courses of hepatic injuries induced by chloroform and by carbon tetrachloride: comparison of biochemical and histopathological changes. 933 1

Although numerous studies report hepatic drug metabolizing enzyme alterations during aflatoxicosis, the mechanisms involved in P450 decreases remain to be established. The purpose of this work is to investigate whether increased oxidative damage revealed by the detection of malondialdehyde (MDA), lipofuscin substances, and conjugated dienes in microsomes, could explain the decreased P450 content. Studies were conducted with two different doses of aflatoxin B1 (AFB1), both in vivo in rabbits and ex vivo in primary cultures of rabbit hepatocytes, in the presence or absence of beta-naphthoflavone or rifampicin used as respective P450 inducers. Strong negative correlations were observed between MDA and P450 contents, both in vivo and ex vivo, whereas rifampicin appears to protect the hepatocytes from oxidative damage but not AFB1 toxicity. Positive correlation were also obtained between MDA formation and lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT) or alanine amino-transferase (ALAT) releases, used as non-specific markers of AFB1 toxicity. Taken together these results suggest that the dramatic decreases of cytochrome P450 observed in vivo during aflatoxicosis could be linked, at least in part, to microsomal oxidative damage.
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PMID:Cytochrome P450 decreases are correlated to increased microsomal oxidative damage in rabbit liver and primary cultures of rabbit hepatocytes exposed to AFB1. 1004 57


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