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:2.6.1.2 (alanine aminotransferase)
26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various aliphatic alcohols potentiate the toxicity of a wide range of xenobiotics including several haloalkanes. The present series of experiments were designed to test: (i) whether a single subtoxic dose of alcohol can potentiate CCl4 and CHCl3 hepatoxicity, and (ii) whether this potentiation leads to greater animal lethality. Selected members of a homologous series of straight chain alcohols were chosen for this study. Methanol, ethanol, isopropanol, t-butanol, pentanol, hexanol, octanol, decanol, and eicosanol at equimolar doses (10 mmol/kg) were tested in the present investigation. Each alcohol was administered orally to male Sprague-Dawley rats (175-250 g) 18 hr prior to a single oral administration of CCl4 or CHCl3. Liver injury was assessed by plasma transaminases (alanine aminotransferase, ALT; aspartate aminotransferase, AST) and histopathological examination of liver sections 24 hr after the halomethane treatment. None of these alcohols alone increased plasma ALT or AST significantly, whereas CCl4 or CHCl3 administration to alcohol-treated animals resulted in significant elevation of plasma transaminases. Eicosanol (20-carbon alcohol) did not potentiate the toxicity of either halomethane. Methanol, ethanol, isopropanol, and decanol in combination with CCl4 caused massive liver damage but failed to augment CCl4 lethality. t-Butanol, pentanol, hexanol, and octanol significantly decreased the LD50 of CCl4. The hepatotoxic effects of CHCl3 were potentiated by all of the alcohols and the LD50s were also decreased significantly. On a comparative basis, alcohol-potentiated CHCl3 toxicity was greater than the toxicity of CCl4. These findings indicate that even though halomethane liver injury might be potentiated by alcohols, the underlying mechanisms differ among alcohols since not all alcohols potentiate the lethal effects of these halomethanes.
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PMID:Potentiation of CCl4 and CHCl3 hepatotoxicity and lethality by various alcohols. 225 8

Fusarium moniliforme has been associated with several diseases including equine leukoencephalomalacia, human esophageal cancer and hepatotoxicity/hepatocarcinogenicity in laboratory animals. The potential health risks to animals and humans posed by F. moniliforme contaminated grains cannot be assessed until the toxins are identified and toxicologically evaluated. As part of a systematic approach to identifying the hepatotoxins produced by F. moniliforme, diets containing aqueous and chloroform/methanol (1:1) extracts of F. moniliforme strain MRC 826 culture material (CM) and/or the extracted CM residues were fed to male Sprague-Dawley rats for four weeks. Serum alanine aminotransferase, aspartate amino-transferase and alkaline phosphatase activities were increased after two and four weeks and microscopic liver lesions were found in those animals fed aqueous CM extract and the CM residue after chloroform/methanol extraction. Fumonisins B1 and B2 were extracted from the CM by water, but not chloroform/methanol, and were present in the toxic diets at concentrations of 93-139 and 82-147 ppm, respectively. Nontoxic diets contained less than or equal to 22 ppm fumonisin B1 and less than or equal to 65 ppm fumonisin B2.
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PMID:Comparative studies of hepatotoxicity and fumonisin B1 and B2 content of water and chloroform/methanol extracts of Fusarium moniliforme strain MRC 826 culture material. 229 36

In isolated, hemoglobin-free perfused livers of fasted rats, formaldehyde at an initial concentration of 10 mmol/l produced toxicity as evidenced by a release of enzymes (GPT, SDH) and of glutathione (mainly GSSG) into the perfusate, an accumulation of calcium in the liver, and a depletion of hepatic glutathione. Formaldehyde also led to an enhanced release of malondialdehyde into the perfusate, indicating peroxidative processes and decreased hepatic oxygen consumption by about 50-70%. The electron microscopic investigation of formaldehyde-exposed livers showed a destruction of the mitochondria (ruptured membranes, loss of the cristae) and some damage of the rough endoplasmic reticulum. Feeding the rats prior to surgery attenuated the hepatotoxic effects of 10 mmol/l formaldehyde. At an initial concentration of 3 mmol/l, formaldehyde did not release enzymes from livers of fed or fasted rats but only from those whose glutathione content had been depleted by treatment with phorone (250 mg/kg ip 2 h earlier). Formaldehyde liberated glucose and lactate from the livers of fed but not from those of fasted rats, indicating anaerobic energy supply in the fed state. The hepatotoxic action of formaldehyde is not due to its metabolism to formate or to the 10% methanol added as a stabilizing agent to the commercially available 37% solution named formalin. In conclusion, by destruction of mitochondria, formaldehyde inhibits aerobic energy supply and thereby presumably produces hepatocellular damage.
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PMID:Mechanistic study on formaldehyde-induced hepatotoxicity. 275 59

Acute treatment with ethanol and other alcohols has been shown to potentiate the hepatotoxicity of certain xenobiotics, in part via induction of the mixed-function oxidase (MFO) system. Carbon disulfide (CS2)-induced hepatotoxicity and inhibition of the MFO system have been shown to be a consequence of MFO metabolism. In the present study, the ability of several different alcohols to induce the hepatic MFO metabolism of CS2 and the effects of this induction on CS2 distribution and hepatotoxicity were examined in rats. Eighteen hours after alcohol administration (1/2 LD50 dose, po), CS2 microsomal MFO metabolism was significantly enhanced, in order of descending potency, by isopropanol, methanol, and ethanol pretreatments, but not by isobutanol pretreatment. The degree of enhancement of CS2 metabolism by different alcohols paralleled the enhancement of nitroanisole O-demethylation and aniline hydroxylation, MFO activities associated with the ethanol-inducible isozyme of cytochrome P450. CS2 (1 mg/kg, ip, 3 hr) inhibited only the cytochrome P450-mediated activities enhanced by alcohol pretreatment. These results suggest that CS2 metabolism is catalyzed by the ethanol-inducible isozyme. Alcohol-induced rats had significantly more 14CS2-derived radioactivity in the liver than control and isobutanol-pretreated rats 3 hr after dosing (1 mg/kg, ip). However, only methanol pretreatment resulted in an increased retention of 14CS2-derived radioactivity in plasma, brain, and kidney. Unlike other alcohol pretreatments, methanol decreased the total 14C expired during the 3-hr period after CS2 dosing and caused a significant (twofold) increase in plasma glutamic-pyruvic transaminase, measured 24 hr after CS2 exposure (625 mg/kg). These data indicate that alcohol induction of MFO-dependent CS2 metabolism per se is not sufficient to result in CS2-induced hepatic damage although it does lead to loss of specific cytochrome P450 function.
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PMID:The possible role of the ethanol-inducible isozyme of cytochrome P450 in the metabolism and distribution of carbon disulfide. 312 44

Methanol, ethanol and isopropanol were tested for the ability to change effects of chlorinated hydrocarbons on the alanine aminotransferase (ALAT = GPT; EC 2.6.1.2.) activity in serum of rats. The alcohols were given once orally or repeatedly together with drinking water. After additional i.p. administration of chloroform we found a significant increase of ALAT activities in the order: isopropanol greater than or equal to methanol greater than ethanol, both after single and repeated application of the alcohols. Together with trichloroethene and 1.1.2.2-tetrachloroethane no such elevations were found. The results suggest that different mechanisms of action could be underlying.
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PMID:Influence of alcohol pretreatment on effects of chloroform in rats. 317 85

The Authors have studied AST and ALT enzymatic activities in the workers of two firms, the former of which (tannery) with a high and the latter (boot and shoe factory) with a low level of hepatic-toxic risk. The influence of various trouble factors such as age, sex and seniority was eliminated through appropriate statistical techniques. A significant difference was evidenced between AST and ALT levels in two firms, chiefly attributable to the quantity and quality of the substances utilized in the two technological cycles: trichloroethylene, chromium, sulphuric acid, mineral oils, ammonia, N-hexane, pentanes acetone, ciclo hexane, methanol, ethyl acetate, isopropyl acetate, toluene, methylene chloride.
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PMID:[Levels of aspartate aminotransferase and alanine aminotransferase in two factories with various hepato-toxic risks]. 734 21

Increases in the use of methanol (MeOH) as a transportation fuel would result in greater potential for inhalation exposure. Because oral exposure to MeOH potentiates the hepatotoxicity of carbon tetrachloride (CCl4), we examined the ability of inhaled MeOH to potentiate CCl4 hepatotoxicity and the time course of injury and recovery. Adult male F-344 rats were exposed to 0 or to 10,000 ppm MeOH by inhalation for 6 h and gavaged with 0.075 ml CCl4/kg 24 h later. Hepatotoxicity was assessed 0.5, 1, 1.5, 2, 3, 7, 15, 30, and 61 d after CCl4 exposure. For CCl4 alone, hepatotoxicity was most severe at 0.5 and 1 d, when minimal centrilobular hepatocellular necrosis and predominately mild centrilobular hepatocellular vacuolar degeneration occurred. By d 3, the livers from the CCl4 rats were histologically normal. For MeOH+CCl4, peak severity of hepatic injury was at 1 and 1.5 d, when moderate centrilobular necrosis and moderate/marked centrilobular degeneration occurred. MeOH+CCl4 resulted in serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) that were increased, relative to CCl4 alone, 171- and 113-fold, respectively, on d 1, and 166- and 140-fold, respectively, on d 1.5. Significant serum elevations in MeOH+CCl4 rats, relative to CCl4 alone rats, were present until d 7 and d 15 for AST and ALT, respectively. By d 3 and d 7, degeneration and necrosis, respectively, due to MeOH+CCl4 were essentially resolved. On d 7, the MeOH+CCl4 hepatic injury consisted mainly of chronic inflammation and centrilobular fibrosis. By d 30, the livers of MeOH+CCl4 rats were histologically normal. These data demonstrate that inhaled MeOH potentiates the hepatotoxicity of orally ingested CCl4, increasing the severity of CCl4 hepatotoxicity as well as the time required for recovery.
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PMID:Potentiation of carbon tetrachloride hepatotoxicity by inhaled methanol: time course of injury and recovery. 756 18

A single 6-hr exposure to inhaled methanol (MeOH) has been shown to enhance carbon tetrachloride (CCl4) hepatotoxicity. The objective of the present study was to use gas uptake data and the development of a physiologically based pharmacokinetic model (PBPK) to determine in vivo changes in CCl4 metabolism resulting from MeOH pretreatment. Adult male F344 rats (167-197 g) were exposed to 10,000 ppm MeOH (constant concentration) via inhalation for 6 hr. Individual rats were exposed using gas uptake techniques to CCl4 alone or to CCl4 either 24 or 48 hr after initiation of MeOH pretreatment. The following initial concentrations were used for CCl4: 0, 25, 100, 250, and 1000 ppm with exposures lasting 6 hr. Vmax (metabolic rate) was estimated from gas uptake data and Km (Michaelis constant) was assumed constant after methanol pretreatment. For CCl4 alone, Vmax was 0.11 mg/hr (Vmaxc = 0.37 mg/hr/kg) and Km was 1.3 mg/liter. Vmax was 0.48 mg/hr (Vmaxc = 1.6 mg/hr/kg) for the 24-hr MeOH + CCl4 group and Vmax was 0.18 mg/hr (Vmaxc = 0.6 mg/hr/kg) for the 48-hr MeOH + CCl4 group. For CCl4 alone, serum markers of hepatotoxicity alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) were increased significantly only at 1000 ppm CCl4. Both serum markers of hepatotoxicity in the 24-hr MeOH + CCl4 group increased as a function of CCl4 concentration when compared with 0 ppm CCl4 controls. The maximum increase occurred at 1000 ppm CCl4, where ALT and SDH increased by 392- and 286-fold, respectively. At 100, 250, and 1000 ppm CCl4, ALT and SDH values for the 24-hr MeOH + CCl4 groups were significantly increased relative to control (0 ppm CCl4), CCl4 alone, and 48-hr MeOH + CCl4. ALT and SDH levels in the 48-hr MeOH + CCl4 groups were not statistically different from the respective CCl4 alone groups.
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PMID:Physiologically based pharmacokinetic estimated metabolic constants and hepatotoxicity of carbon tetrachloride after methanol pretreatment in rats. 888 40

Acute methanol intoxication causes metabolic and structural disturbances of liver cells. The aim of this paper, therefore, was to evaluate the ultrastructure of liver cells membrane and the amount of lipid peroxidation products, as well as the concentration of marker enzymes of liver damage (ALT and AST) in blood serum. The experiment was done on Wistar rats which once received intragastrically 6,0 g methanol/kg b.w. as a 50% solution. The animals were decapitated 6, 12 and 24 h and 2, 5 and 7 days after the methanol administration. The liver was evaluated under transmission electron microscope and lipid peroxidation products were determined in the liver homogenate. The serum ALT and AST activity were also assayed. The biochemical results indicate the increase in lipid peroxidation products. The consequence of this is probably the membrane liver cell damage visible in the electron microscope.
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PMID:Ultrastructural evaluation of hepatocytes membranes and changes in cytosolic enzymes distribution in methanol intoxication. 964 81

We investigated the acute toxic and metabolic effects of 23-aliphatic alcohols (16 saturated and 7 unsaturated) in the isolated perfused rat liver at a concentration of 65.1 mmol/l (approximately 0.3% ethanol). The capacity of the straight chain primary alcohols (methanol, ethanol, 1-propanol, 1-butanol and 1-pentanol) to release the enzymes glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH) and glutamate dehydrogenase (GLDH) into the perfusate was strongly correlated with their carbon chain length. The secondary alcohols were less active in this respect whereas branching of the carbon chain did not consistently change alcohol toxicity. Unsaturation in the straight chain but not in the branched chain alcohols was accompanied by an increase in toxicity. An increased enzyme release was in general accompanied by, and correlated to, reductions in oxygen consumption, bile secretion, and perfusion flow of the isolated livers. Statistically significant correlations exist between parameters of alcohol-induced hepatotoxicity and the membrane/buffer partition coefficents of the alcohols. With the exception of methanol, all alcohols tested increased the lactate/pyruvate ratio of the perfusate, although this effect was not correlated to the degree of hepatic injury. Hepatic ATP concentrations decreased in most cases in line with hepatic injury and were particularly correlated with changes in oxygen consumption. Hepatic concentrations of reduced glutathione (GSH) were only diminished by the unsaturated alcohols, whereas an increase in hepatic oxidized glutathione (GSSG) occurred only with some of the saturated alcohols. Hepatic concentrations of malondialdehyde (MDA) increased after two saturated and three unsaturated alcohols but did not correlate with other parameters of hepatotoxicity. In conclusion, alcohol-induced hepatotoxicity is primarily due to membrane damage induced by the direct solvent properties of the alcohols. The consequences and relative contributions of alcohol metabolization to the overall hepatotoxicity of higher alcohols requires further study.
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PMID:The toxic and metabolic effects of 23 aliphatic alcohols in the isolated perfused rat liver. 1036 51


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