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)

The systemic and neurobehavioral effects of benzo[b]thiophene (routinely referred to as benzothiophene) were studied in rats following 13-wk oral exposure. Male (170 +/- 16 g) and female (146 +/- 12 g) Sprague-Dawley rats (10 animals per group) were fed diet containing 0.5, 5, 50, or 500 ppm benzothiophene for 13 wk. Control animals were given rat feed plus vehicle (corn oil) only. No clinical signs of toxicity and neurobehavioral effects were observed using screening tests that included cage-side observations, righting reflex, open field activities, and forelimb and hindlimb grip strength. Elevated serum aspartate aminotransferase activity and bilirubin level were observed in highest dose females. Except for a statistically significant decrease in hematocrit in the highest dose males, benzothiophene exerted no marked effects on hematological parameters. Benzothiophene exposure did not result in alterations in hepatic alkaline phosphatase activity, or the typical hepatic phase I (aniline hydroxylase, ethoxyresorufin O-deethylase, pentoxyresorufin O-dealkylase, aminopyrine N-demethylase) and phase II (UDP-glucuronosyltransferase, glutathione S-transferase) drug-metabolizing enzyme activities. No significant elevation in urinary ascorbic acid, protein, and N-acetylglucosaminidase activity was detected in the treated animals. Peribiliary fibrosis was the most significant histological change and occurred in the liver of females in the 50 and 500 ppm groups. Mild epithelial hyperplasia in the renal pelvis was detected in the majority of 5 and 50 ppm females, with epithelial hyperplasia in the urinary bladder observed in the 50 ppm females. In males, increased incidence and severity of mild binucleation of hepatocytes and mild thickening of the basement membrane in kidney cortex were observed at 500 ppm. Benzothiophene was not detected in the urine of high-dose animals at the termination of the experiment. Based on the kidney, hepatic, and hematocrit changes, the no-observed-adverse-effect level (NOAEL) in the diet was determined to be 0.5 ppm (0.04 mg/kg/d) for females and 50 ppm (3.51 mg/kg/d) for males.
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PMID:Subchronic toxicity of benzothiophene on rats following dietary exposure. 976 Nov 33

Two sulfotransferases (STs), designated as AST-RB1 (ST3A1) and AST-RB2 (ST2A8), with high a amine N-sulfonating activity, were purified from male rabbit liver cytosols. AST-RB1 and AST-RB2 were purified to homogeneity by the anion-exchange, affinity, and hydroxyapatite chromatography. The N-terminus of both enzymes were blocked. The subunit molecular mass of both enzymes was estimated to be 34 kDa on SDS-PAGE. AST-RB1 efficiently catalyzed N-sulfonation of alicyclic, alkyl, and arylamines such as 4-phenyl-1,2,3, 6-tetrahydropyridine, 1-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine, desipramine, and aniline, whereas its catalytic activities toward 2-naphthol and dehydroepiandrosterone (DHEA) were very low. On the other hand, AST-RB2 efficiently catalyzed sulfonation of desipramine and DHEA, but had no activity toward 2-naphthol. Amino acid sequences of peptide fragments derived from the purified AST-RB1 showed no significant homology with previously reported STs, but those from the purified AST-RB2 shared a high similarity with those of the ST2 family. Both enzymes were expressed specifically in the liver. The present results strongly suggest that the purified AST-RB1 is a novel enzyme in terms of structure and catalytic properties showing high selectivity for amine substrates, and AST-RB2 is a quite unique from among ST2A enzymes of other species in its substrate specificity.
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PMID:Purification and characterization of two amine N-sulfotransferases, AST-RB1 (ST3A1) and AST-RB2 (ST2A8), from liver cytosols of male rabbits. 998 35

Solanum alatum Moench. has been shown to have a protective effect against carbon tetrachloride (CCl4)-induced liver injury. Solanum alatum treatment (100 mg/kg, p.o.) decreased the elevation of serum alanine aminotransferase (ALT; GPT) and aspartate aminotransferase (AST; GOT) induced by acetaminophen (paracetamol) (600 mg/kg, i.p.) administration. It also decreased the extent of visible necrosis in liver tissue. In addition, Solanum alatum treatment restored hepatic glutathione (GSH) depletion induced by acetaminophen (600 mg/kg, i.p.) administration. Microsomal enzyme levels such as P-450, reductase, and aniline hydroxylation enzyme were also restored to normal levels after Solanum alatum administration. The hepatoprotective mechanism may function through direct binding with acetaminophen toxic metabolites, decreasing the attraction of acetaminophen metabolites for other cellular GSH or thiol protein. Additionally, Solanum alatum treatment increased the concentration of hepatic GSH and maintained a high level activity of GSTase, which led to acceleration of the excretion of toxic acetaminophen metabolites.
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PMID:The hepatoprotective effects of Solanum alatum Moench. on acetaminophen-induced hepatotoxicity in mice. 1079 22

The protective effects of an aqueous extract from the roots of Platycodon grandiflorum A. DC (Campanulaceae), Changkil (CK), on acetaminophen (APAP)-induced hepatotoxicities and the possible protective mechanisms involved were investigated in mice. Pretreatment with CK prior to the administration of APAP significantly prevented the increase in serum alanine aminotransferase and aspartate aminotransferase activity and hepatic lipid peroxidation in a dose-dependent manner. APAP-induced hepatotoxicity was also essentially prevented as evidenced by liver histopathology. Hepatic glutathione levels and glutathione-S-transferase activities were not affected by treatment with CK alone, but pretreatment with CK protected the APAP-induced depletion of hepatic glutathione levels. The effects of CK on cytochrome P450 (P450) 1A2 and 2E1, the major isozymes involved in APAP bioactivation, were investigated. In microsomal incubations, CK effectively inhibited P450 lA2-dependent methoxyresorufin O-deethylase activities and the P450 2E1-dependent p-nitrophenol and aniline hydroxylase. The results suggest that the protective effects of CK against the APAP-induced hepatotoxicity may, at least in part, be due to its ability to block P450-mediated APAP bioactivation.
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PMID:Hepatoprotective effects of Platycodon grandiflorum on acetaminophen-induced liver damage in mice. 1167 54

The protective effects of a Platycodi radix (Changkil: CK), the root of Platycodon grandiflorum A. DC (Campanulaceae) on carbon tetrachloride (CC14)-induced hepatotoxicity and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with CK prior to the administration of CC14 significantly prevented the increased serum enzymatic activities of alanine and aspartate aminotransferase in a dose-dependent manner. In addition, pretreatment with CK also significantly prevented the elevation of hepatic malondialdehyde formation and the depletion of reduced glutathione content in the liver of CC14-intoxicated mice. However, hepatic reduced glutathione levels and glutathione S-transferase activities were not affected by treatment with CK alone. CC14-induced hepatotoxicity was also essentially prevented, as indicated by a liver histopathologic study. The effects of CK on the cytochrome P450 (P450) 2E1, the major isozyme involved in CC14 bioactivation were also investigated. Treatment of mice with CK resulted in a significant decrease of P450 2E1-dependent p-nitrophenol and aniline hydroxylation in a dose-dependent manner. CK showed antioxidant effects in FeCl2-ascorbate-induced lipid peroxidation in mice liver homogenate and in superoxide radical scavenging activity. Our results suggest that the protective effects of CK against CC14-induced hepatotoxicity possibly involve mechanisms related to its ability to block P450-mediated CC14 bioactivation and free radical scavenging effects.
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PMID:Protective effect of Platycodi radix on carbon tetrachloride-induced hepatotoxicity. 1189 10

The protective effects of 18beta-glycyrrhetinic acid (GA), the aglycone of glycyrrhizin (GL) derived from licorice, on carbon tetrachloride-induced hepatotoxicity and the possible mechanisms involved in this protection were investigated in mice. Pretreatment with GA prior to the administration of carbon tetrachloride significantly prevented an increase in serum alanine, aspartate aminotransferase activity and hepatic lipid peroxidation in a dose-dependent manner. In addition, pretreatment with GA also significantly prevented the depletion of glutathione (GSH) content in the livers of carbon tetrachloride-intoxicated mice. However, reduced hepatic GSH levels and glutathione-S-transferase activities were unaffected by treatment with GA alone. Carbon tetrachloride-induced hepatotoxicity was also prevented, as indicated by a liver histopathologic study. The effects of GA on the cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation, were also investigated. Treatment of mice with GA resulted in a significant decrease of the P450 2E1-dependent hydroxylation of p-nitrophenol and aniline in a dose-dependent manner. Consistent with these observations, the P450 2E1 expressions were also decreased, as determined by immunoblot analysis. GA also showed antioxidant effects upon FeCl(2)-ascorbate-induced lipid peroxidation in mice liver homogenate and upon superoxide radical scavenging activity. These results show that protective effects of GA against the carbon tetrachloride-induced hepatotoxicity may be due to its ability to block the bioactivation of carbon tetrachloride, primarily by inhibiting the expression and activity of P450 2E1, and its free radical scavenging effects.
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PMID:Hepatoprotective effects of 18beta-glycyrrhetinic acid on carbon tetrachloride-induced liver injury: inhibition of cytochrome P450 2E1 expression. 1222 Sep 64

The aim of this study was to investigate the effects of trauma on alterations in cytochrome P450 (CYP 450)-dependent drug metabolizing function and to determine the role of Kupffer cells in hepatocellular dysfunction. Rats underwent closed femur fracture (FFx) with associated soft-tissue injury under anesthesia, while control animals received only anesthesia. To deplete Kupffer cells in vivo, gadolinium chloride (GdCl3) was injected intravenously via the tail vein at 7.5 mg/kg body wt., 1 and 2 days prior to FFx surgery. At 72 h after FFx, serum alanine aminotransferase (ALT) activity was increased, and this increase was attenuated by GdCl3 pretreatment. Serum aspartate aminotransferase (AST) and lipid peroxidation levels were not changed by FFx. Hepatic microsomal CYP 450 content and aniline p-hydroxylase (CYP 2E1) activity were significantly decreased; decreases that were not prevented by GdCl3. The level of CYP 2B1 activity was decreased by Kupffer cell inactivation, but not by FFx. There were no significant differences in the activities of CYP 1A1, CYP 1A2 and NADPH-CYP 450 reductase among any of the experimental groups. Our findings suggest that FFx trauma causes mild alterations of hepatic CYP 450-dependent drug metabolism, and that Kupffer cells are not essential for the initiation of such injury.
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PMID:The roles of Kupffer cells in hepatocellular dysfunction after femur fracture trauma in rats. 1256 58

This study investigated the protective effects of acteoside, a phenylethanoid glycoside, on the carbon tetrachloride-induced hepatotoxicity as well as the possible mechanisms involved in this protection in mice. Pretreatment with acteoside prior to the administration of carbon tetrachloride significantly prevented the increased serum enzymatic activities of alanine and aspartate aminotransferase in a dose-dependent manner. In addition, pretreatment with acteoside significantly prevented the increase in hepatic malondialdehyde formation and the depletion of the reduced glutathione content in the liver of carbon tetrachloride-intoxicated mice. Carbon tetrachloride-induced hepatotoxicity was also essentially prevented, as indicated by a liver histopathologic study. The effects of acteoside on cytochrome P450 (P450) 2E1, the major isozyme involved in carbon tetrachloride bioactivation were also investigated. Treatment of the mice with acteoside resulted in a significant decrease in the P450 2E1-dependent pnitrophenol and aniline hydroxylation in a dose-dependent manner. Consistent with these observations, the P450 2El protein levels were also lower. Acteoside exhibited anti-oxidant effects on FeCl2-ascorbate induced lipid peroxidation in a mouse liver homogenate, and on superoxide radical scavenging activity. These results suggest that the protective effects of acteoside against the carbon tetrachloride-induced hepatotoxicity possibly involve mechanisms related to its ability to block the P450-mediated carbon tetrachloride bioactivation and free radical scavenging effects.
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PMID:Protective effect of acteoside on carbon tetrachloride-induced hepatotoxicity. 1467 60

Hepatotoxic effect of (+)usnic acid, the active constituent of Usnea siamensis Wainio was studied in rats, isolated rat hepatocytes and isolated rat liver mitochondria. In rats, after treatment with high dose of (+)usnic acid (200 mg/kg per day, i.p.) for 5 days, there was no significant change in serum transaminase activity (serum AST, ALT) while the electron micrographs showed apparent morphological damage of mitochondria and endoplasmic reticulum. (+)Usnic acid at high dose (1 mM) as well as carbon tetrachloride (CCl4, the reference hepatotoxin) induced loss of cell membrane integrity in isolated rat hepatocytes by increasing the release of cellular transaminases (AST, ALT). Increase in lipid peroxidation, decrease in glutathione (GSH) content and increase in aniline hydroxylase activity (CYP 2E1) were also found. Combination of (+)usnic acid and CCl4 showed the additive results. (+)Usnic acid (0.15-6 microM) possessed uncoupling activity in isolated rat liver mitochondria. It stimulated respiration by mitochondria respiring with glutamate plus malate or succinate as substrates and activated ATPase activity. Increasing concentration of (+)usnic acid (>6 microM) exhibited loss of respiratory control and ATP synthesis. In conclusion, hepatotoxic effect of high dose (+)usnic acid may involve its reactive metabolite(s), causing loss of integrity of membrane like structures, resulting in destruction of mitochondrial respiration and oxidative phosphorylation.
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PMID:Hepatotoxic effect of (+)usnic acid from Usnea siamensis Wainio in rats, isolated rat hepatocytes and isolated rat liver mitochondria. 1501 5

Chemoprevention is an important alternative approach to control cancer. Chemical substances with multiple inhibitory properties would be a welcome addition to the class of chemopreventive drugs. In this study, we investigated the antioxidant, anti-inflammatory, antimutagenic and cancer preventive activities of aqueous extract of a macrofungus Phellinus rimosus (Berk) Pilat. The extract exhibited superoxide anion (O2-), hydroxyl radical (*OH), nitric oxide (NO*) scavenging and lipid peroxidation inhibiting activities. The inhibitory concentrations required by the extract to scavenge 50% (IC50) of the superoxide anion, hydroxyl radical and nitric oxide generated were 126 +/- 5.1, 71 +/- 4.7 and 31 +/- 4.5 microg/ml respectively. The concentration required to inhibit 50% of Fe2+ induced lipid peroxidation in rat liver homogenate was 318 +/- 2.4 microg/ml. The extract showed significant (P<0.05) anti-inflammatory activity in a dose dependent manner. Extract (100 mg/kg body wt, p.o) inhibited 44.5, 45.4 and 47% carrageenen, dextran and formalin induced inflammations respectively. The antimutagenic activity was determined by the Ames' Salmonella mutagenecity assay using histidine mutant Salmonella typhimurium strains. The extract at concentration of 5 mg/plate showed antimutagenecity against benzo[a]pyrene (B[a]P) and 4-nitro-o-pheneylenediamine (NPDA) induced mutations of TA98 and TA100 respectively. Anticarcinogenic activity was evaluated using N-nitrosodiethylamine (NDEA) induced hepatocellular carcinoma (HCC) in rats. Serum gamma glutamyl transpeptidase (GGT), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT) and alkaline phosphatase (ALP) activities and lipid peroxidation level (MDA) were elevated significantly (P<0.05) in the NDEA alone treated group of animals. Treatment of the extract (25 and 50 mg/kg body wt, p.o.) prior to the NDEA administration decreased the serum GGT, GOT, GPT and ALP activities and MDA level in a dose dependent manner. The NDEA alone treated animals showed altered serum albumin/globulin ratio (A:G ratio), hyperfibrinogenaemia, increased hepatic glutathione S-transferase (GST) activity, glutathione-peroxidsae (GPx) activity and reduced glutathione (GSH) level compared to the extract plus NDEA treated group. The extract also inhibited in vitro aniline hydroxylase (AH) activity of rat liver induced by phenobarbitone in a dose dependent manner. The results, thus suggest the significant chemopreventive properties of the aqueous extract of the Phellinus rimosus against NDEA induced hepatocellular carcinoma by its antioxidant, anti-inflammatory and antimutagenic activities.
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PMID:Chemopreventive activity of a macrofungus Phellinus rimosus against N-nitrosodiethylamine induced hepatocellular carcinoma in rat. 1702 71


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