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)

A number of chemicals are known to potentiate the hepatotoxicity of carbon tetrachloride. The halocarbon trichloroethylene was shown in a previous study to enhance both carbon tetrachloride-induced toxicity and lipid peroxidation in isolated hepatocytes. In this study three other chlorocarbons have been investigated in order to determine whether this interaction was peculiar to trichloroethylene or common to chlorinated solvents. Hepatocyte suspensions were exposed to carbon tetrachloride at subthreshold levels of toxicity and various concentrations of 1,1,1-trichloroethane, tetrachloroethylene, and chloroform over an eightfold concentration range. Plasma membrane preparations were exposed to tetrachloroethylene and carbon tetrachloride and effects on Mg(2+)- and Na(+)-K(+)-ATPase activities determined. None of the treatments alone caused statistically significant toxicity. Combined treatments resulted in toxicity as demonstrated by potassium ion, alanine aminotransferase, and lactate dehydrogenase leakage from the cells on coincubation of carbon tetrachloride with each of the other halocarbons studied. Only tetrachloroethylene and chloroform were found to potentiate lipid peroxidation, however. In liver plasma membranes no changes in Na(+)-K(+)-ATPase were observed with any of the treatments and only the highest dose of tetrachloroethylene was able to inhibit Mg(2+)-ATPase activity. There was no increase in this inhibition on coincubation with carbon tetrachloride, which does not support involvement of ATPases in combined halocarbon toxicity. In conclusion, the data suggest a mechanism of action common to this class of chemical although its specific nature remains to be established.
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PMID:Potentiating effects of chlorinated hydrocarbons on carbon tetrachloride toxicity in isolated rat hepatocytes and plasma membranes. 182 22

Previous studies have demonstrated that various compounds, including the common groundwater contaminants trichloroethylene (TCE) and chloroform (CHCl3), can produce a synergistic toxic response when coadministered with the model hepatotoxicant carbon tetrachloride (CCl4). This phenomenon has not, however, been demonstrated following administration of these compounds in drinking water. Initial experiments indicated that Fischer 344 (F-344) rats were significantly more sensitive to these effects than the more commonly utilized Sprague-Dawley strain. To establish the suitability of this strain as a model, a variety of indicators of hepatotoxicity was evaluated and compared to histological evidence of injury 24 hr after dosing with CCl4 or a combination of CCl4 + TCE. Plasma alanine aminotransferase (ALT) activity was the most reliable indicator of hepatic injury and was well-correlated with the histologic data. Dose-response studies utilizing simultaneous ip dosing confirm the sensitivity of the F-344 rat, demonstrating synergistic toxicity at doses as low as 0.165 mmol/kg of CCl4 and 0.6 mmol/kg of TCE. Synergism was also detected following simultaneous ip administration of 1 mmol/kg CCl4 and 0.5 mmol/kg of CHCl3. To evaluate the effects of drinking water exposure, rats were pretreated for 3 days with solutions containing TCE (0-40 mM) or CHCl3 (0-8 mM) stabilized with 1% Emulphor (EL-620P) as their only source of fluids. A single, ip dose of CCl4 (1 mmol/kg) was then administered and 24 hr later animals were killed for examination of liver histology and determination of ALT activity. Although none of the pretreatments were detectably hepatoxic, rats which drank 15 and 40 mM TCE or 8 mM CHCl3 exhibited an enhanced response to CCl4.
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PMID:Pretreatment with drinking water solutions containing trichloroethylene or chloroform enhances the hepatotoxicity of carbon tetrachloride in Fischer 344 rats. 188 17

Dimethyl-4, 4'-dimethoxy-5, 6, 5', 6'-dimethylenedioxy-biphenyl-2, 2'-dicarboxylate (biphenyldimethyldicarboxylate; BDD), a synthetic compound, has been used in the treatment of chronic hepatitis with good results in reducing s-GPT. Previous work in our laboratory studied its metabolites using 3H-labeled compound in combination with TLC and found that its main metabolic pathway is demethylation followed by conjugation with glucuronic acid. This paper reports the isolation and identification of a metabolite of BDD from rat urine using 2H-labeled compound and GC-MS. Rats fasted for 12 h were intragastrically given a mixture of 2H-labeled (consisting of monodeutero- and dideutero-BDD in the ratio about 1:1.3) and non-labeled BDD 150 mg/kg and placed in metabolism cages for urine collection. The 24 h urine was filtered and extracted three times each with 5 ml of methylenedichloride. The extracts were pooled and evaporated to dryness under reduced pressure at 35 degrees C. The residue was redissolved in chloroform and subjected to GC-MS analysis. The mass spectrum (m/z: 404, 405, 406; 373, 374, 375; 345, 346, 347; 330, 331, 332; etc) indicates that the molecular ionic and fragment peaks of the metabolite all have 14 amu less than those of BDD. This means that the metabolite isolated is mono-O-demethylated BDD. The result confirmed our findings reported previously.
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PMID:[Use of 2H-labeled compound and GC-MS in the isolation and identification of a metabolite of biphenyldimethyl-dicarboxylate in rat urine]. 209 93

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

The joint hepatotoxicity of CCl4 and CHCl3 or TCE in male CD rats following simultaneous oral administration has been investigated. Rats with chronic indwelling arterial cannulas were administered a single oral dose of CCl4 and CHCl3 or CCl4 and TCE in 5% Emulphor at doses of 0 to 700 mg/kg. Hepatotoxicity was evaluated by measuring the activity of AST, ALT, and SDH in plasma at 0, 3, 6, 12, 24, 36, 48, and 72 hr postgavage. Response data were analyzed for interaction using response surface methodology. CCl4 alone displayed dose-dependent toxicity. TCE demonstrated little evidence of hepatotoxicity. In combination, both CCl4/CHCl3 and CCl4/TCE displayed a synergistic (supraadditive) response for peak plasma enzyme activity.
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PMID:Interactions of water contaminants. I. Plasma enzyme activity and response surface methodology following gavage administration of CCl4 and CHCl3 or TCE singly and in combination in the rat. 234 Sep 78

The aim was to determine if isolated suspended hepatocytes could differentiate between the effects of four chlorinated hydrocarbons that are hepatotoxic in vivo and four that are not. Membrane integrity was assessed by measuring alanine aminotransferase (ALT) release after 30- to 180-min incubations in vitro. From the results, the chlorinated hydrocarbons fell into three groups: tetrachloroethylene and 1,1,2,2-tetrachloroethane were the most potent cytotoxicants; CCl4, 1,1,2-trichloroethane, and trichloroethylene exhibited intermediate cytotoxicity; and low cytotoxicity was observed with CHCl3, 1,1,1-trichloroethane, and 1,1-dichloroethylene. Cytotoxicity ranking correlated poorly with the reported in vivo hepatotoxicity of these agents. The effect of adding SKF-525A on the cytotoxicity of tetrachloroethylene and CCl4 was also assessed. In addition, hepatocytes from rats pretreated with 2,5-hexanedione were used to determine if they were more susceptible to the effects of CHCl3, CCl4, or tetrachloroethylene. SKF-525A decreased the cytotoxicity of both CCl4 and tetrachloroethylene, whereas pretreatment with 2,5-hexanedione enhanced their effect. The effects of both SKF-525A and 2,5-hexanedione on CCl4 in vitro are consistent with in vivo findings. However, tetrachloroethylene is not hepatotoxic in vivo, suggesting that SKF-525A might act by stabilizing plasma membranes rendering the hepatocyte more resistant to lysis. Overall, the results cast doubts on the use of ALT release from isolated hepatocytes as an appropriate in vitro model for assessing hepatotoxic properties of chlorinated hydrocarbons.
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PMID:Dose-dependent cytotoxicity of chlorinated hydrocarbons in isolated rat hepatocytes. 236 81

The hepatonecrogenic properties of chloroform (CHCl3) can be modified by the administration of various chemicals. The ability of methyl isobutyl ketone (MIBK) and its two major metabolites, 4-methyl-2-pentanol (4MPOL) and 4-hydroxymethyl isobutyl ketone (4-OHMIBK) to potentiate the liver injury induced by CHCl3 was assessed in rats. The parent compound and both metabolites significantly increased the liver damage induced by CHCl3, as demonstrated by the elevation of the plasma activity of two transferases alanine aminotransferase and ornithine carbamoyl transferase and by the severity of the morphological changes. Moreover, the minimally effective dosage needed to potentiate CHCl3-induced hepatotoxicity was approximately 5 mmol/kg for the three compounds. We also studied the inducing properties of MIBK (cytochrome P-450 liver content and the activity of aniline hydroxylase, 7-ethoxycoumarin O-deethylase, and aminopyrine N-demethylase). Cytochrome P-450 content and the oxidation of aniline and 7-ethoxycoumarin were significantly increased with either a single (7.5 mmol/kg or greater) or a multiple (5.0 and 7.5 mmol.kg-1.day-1 for 5 days) administration of MIBK. An increase in the activity of the aminopyrine demethylase was also elicited by the repetitive administration of MIBK. With gel electrophoresis, we found that MIBK significantly increased the 52.1- and 54.1-kDa proteins, corresponding most probably to P-450 isozymes.
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PMID:Potentiation of chloroform-induced hepatotoxicity by methyl isobutyl ketone and two metabolites. 239 Jul 35

Exposure to chlordecone (CD, Kepone) is known to increase the hepatotoxicity of chloroform (CHCl3) in rats. A time-course analysis was conducted relating several indices of biotransformation capacity with the ability of CD to potentiate CHCl3-induced hepatotoxicity. Male Sprague-Dawley rats were given a single administration of corn oil alone or CD (50 mg/kg, po) dissolved in corn oil. At 2, 4, 8, 16, 20, 24, or 32 days posttreatment, groups of rats were killed and their livers were analyzed for (i) cytochrome P-450, NADPH-dependent cytochrome c reductase, cytochrome b5 and glutathione content or (ii) in vitro irreversible binding of 14CHCl3-derived radiolabel to microsomal protein. Similarly treated rats were challenged (2-32 days posttreatment) with CHCl3 (0.5 mL/kg po); 24 h later, liver damage was assessed by plasma alanine aminotransferase (ALT), plasma ornithine carbamyl transferase (OCT), plasma bilirubin, and hepatic glucose-6-phosphatase. CD potentiation was maximal 2 days posttreatment; and enhanced susceptibility to CHCl3 persisted up to 20-24 days post-CD treatment. In a parallel study animals treated with chlordecone were killed 8, 16, 20, 24, or 32 days later. Blood, kidney, liver, and adipose tissue samples were taken and analyzed for chlordecone content. The results suggest that a general temporal correlation exists between biotransformation rate (microsomal 14C binding), chlordecone content, and the severity of liver injury; the other parameters monitored do not appear to relate directly to the potentiation.
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PMID:Temporal relationships between biotransformation, detoxication, and chlordecone potentiation of chloroform-induced hepatotoxicity. 242 14

The purpose of this study was to investigate whether the tissue distribution of chlordecone (CD) and mirex (M) might explain the difference in the potentiation of CHCl3 liver injury. Male Sprague-Dawley rats received either a single oral dose of CD or M (1, 2.5, 5, 10, 25, or 50 mg/kg) or three single daily doses of CD or M (0.5, 2, or 10 mg/kg). Eighteen hours following the last treatment, the animals were divided into two groups. The first group was killed and residues of CD or M in plasma, kidney, liver, and adipose tissue were measured by gas-liquid chromatography. The other group received CHCl3 (0.5 ml/kg, po) and was killed 24 hr later. Biochemical and histological indices of liver injury were evaluated. CD administered either singly or repetitively is more effective than M in potentiating the CHCl3-induced liver injury. This was exhibited by a higher increase in the plasma activities of the enzymes alanine aminotransferase and ornithine carbamoyl transferase and a greater alteration of the morphological pattern. There was a very good correlation between biochemical and histological indices. However, the severity of the liver injury did not parallel tissue concentrations. With M, a relatively poor potentiation of the liver damage was observed although adequate hepatic concentrations were present.
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PMID:Chloroform interaction with chlordecone and mirex: correlation between biochemical and histological indices of toxicity and quantitative tissue levels. 244 11


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