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)

Male Swiss Webster mice (25-30 g) maintained on powdered control diet, or on diets containing chlordecone (CD, 10 ppm), mirex (M, 10 ppm), or phenobarbital (PB, 225 ppm) were used in this study. At these low levels, chlorinated hydrocarbon pesticides are not toxic, they neither affect food or water consumption, nor the body weight of mice. After a 15-day dietary protocol, a single challenge dose of CHCl3 (0.1 ml/kg) was administered intraperitoneally in corn oil vehicle. Liver damage was assessed 24 hours later using serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, histopathology, and lethality. For comparison, serum enzymes were measured in a separate group of mice receiving a high dose of CHCl3 (1.0 ml/kg) alone. None of the dietary treatments alone affected any of the serum transaminases. The serum enzymes were remarkably elevated in the mice treated with CD and CHCl3. A high dose of CHCl3 (1.0 ml/kg) elevated the serum enzymes more than 10-fold over those in the mice fed normal diet receiving only the corn oil vehicle. The histopathology of the liver indicated midzonal necrosis typical of liver injury from CHCl3 and depletion of PAS positive glycogen deposits. These effects were not evident in mice treated with 0.1 ml/kg CHCl3 alone. Additional histological alterations in the livers of the CD + CHCl3 group include the degenerated cells, loss of basophilic staining characteristics, and an increased degree of cytoplasmic vacuolation. The amplification of CHCl3 hepatotoxicity by CD was also reflected by a 4.2-fold increase in lethality determined by 48-hour LD50.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Amplification of chloroform hepatotoxicity and lethality by dietary chlordecone (kepone) in mice. 245 13

Three chlorinated methanes, carbon tetrachloride, chloroform, and methylene chloride, known to cause liver tumors in rodents, were given by oral gavage to adult female rats both 21 h and 4 h before sacrifice. Then hepatic DNA damage, ornithine decarboxylase (ODC), cytochrome P-450, glutathione content, and serum alanine aminotransferase (SGPT) activity assays were performed. Carbon tetrachloride increased rat hepatic ODC activity and decreased cytochrome P-450 content at doses both below and above cytotoxicity (as measured by increased SGPT activity). At 54 and 160 mg/kg, chloroform increased hepatic ODC activity with minimal or no elevation in SGPT activity. At 480 mg/kg chloroform increased hepatic ODC and SGPT activity. A dose of 1,275 mg/kg methylene chloride caused a small, but significant amount of hepatic DNA damage. When these three compounds are compared on either an equimolar or equitoxic (1/5 LD50) basis, their ability to induce hepatic ODC or increase SGPT activity was carbon tetrachloride greater than chloroform greater than methylene chloride. The results of this biochemical study are interpreted with respect to the ability of chemicals to cause hepatic cancer by either genetic or epigenetic mechanisms.
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PMID:Biochemical effects of three carcinogenic chlorinated methanes in rat liver. 256 70

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 hepatotoxicity of chloroform (CHCl3) is thought to require biotransformation, by the polysubstrate monooxygenase system (P-450), to a reactive intermediate(s). Therefore, the potentiation of CHCl3-induced hepatotoxicity, which occurs following exposure to certain ketones, may hypothetically be explained by a reduced capacity of the cell to form glutathione conjugates (detoxicate the intermediate) and (or) by an increased rate of reactive intermediate(s) generation secondary to a modification of the P-450 system. To test these hypotheses, liver damage, as indicated by elevation in plasma alanine aminotransferase and ornithine carbamyl transferase activities, was modulated in male Sprague-Dawley rats by varying the time interval (10, 18, 24, 48, 72, 96 h) between acetone, 2-butanone, or 2-hexanone (15 mmol/kg, p.o.) pretreatment and CHCl3 (0.5 mL/kg, p.o.) administration. These data were compared with hepatic glutathione and with various parameters of the polysubstrate monooxygenase system: cytochrome P-450, cytochrome c reductase, cytochrome b5, and microsomal binding of 14CHCl3-derived radiolabel. Reduced detoxication capacity does not appear to be involved as hepatic glutathione levels were not reduced. Globally, a relationship between modifications to the polysubstrate monooxygenase system and potentiation of CHCl3-induced hepatotoxicity appears to exist. The rank order of each ketone's ability to modify P-450 parameters was the same in most instances as that based on peak ability to potentiate CHCl3-induced hepatotoxicity: 2-hexanone greater than 2-butanone greater than or equal to acetone. Therefore, these results suggest that a general relationship exists between the ketone-induced potentiation of CHCl3-induced hepatotoxicity and increased CHCl3 reactive metabolite generation. However, other factors may also contribute to the phenomenon.
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PMID:The role of biotransformation-detoxication in acetone-, 2-butanone-, and 2-hexanone-potentiated chloroform-induced hepatotoxicity. 344 91

Studies were made with male Wistar rats on the effects of 50% food restriction on the metabolism of eight organic solvents (chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethylene, trichloroethylene, benzene, toluene and styrene) and on the hepatotoxicity induced by carbon tetrachloride inhalation at 400 ppm for 4 h. The activities of liver drug-metabolizing enzymes for these solvents were enhanced almost equally without exception by one-day food restriction, although the restriction produced no significant increase in the microsomal protein and cytochrome P-450 contents. Carbon tetrachloride hepatotoxicity was enhanced by the food restriction, as evidenced by a marked increase of serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) activities in the food-restricted rats. Histological findings of the liver also supported this finding. Thus, food restriction enhances metabolism of organic solvents in the liver, and can modify toxicity of some chemicals such as carbon tetrachloride, which need metabolic activation to become cytotoxic.
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PMID:[Effects of one-day food restriction on the metabolism and toxicity of organic solvents in rats]. 376 20

Protective effect of malotilate on the liver injuries induced by several hepatotoxins was studied in mice and rats. Malotilate suppressed the elevation of plasma glutamate pyruvate transaminase (p-GPT) activity induced by chloroform (CHCl3) in rats when the animals were treated with 25 mg/kg or more dose of malotilate at 6 hours prior to the treatment with CHCl3. The effect was observed even in the rats treated with malotilate 24 or 48 hours prior to the treatment with CHCl3. Malotilate, when orally administered 6 hours prior to treatment with hepatotoxins such as CHCl3, allyl alcohol, bromobenzene, dimethylnitrosamine or thioacetamide, suppressed the elevation of p-GPT activity, liver triglyceride content and/or the decrease of bromosulphalein clearance induced by these hepatotoxins in mice. Anethole trithione, which was used as a possible protective agent against chemical-induced hepatotoxicity, tended to normalize changes in the parameters induced by the most of these hepatotoxins, but enhanced the elevation of p-GPT activity induced by CHCl3. In a case of CHCl3-induced liver injury, the protective effect of malotilate was histopathologically confirmed. Malotilate and anethole trithione reduced p-nitroanisole 0-demethylation activity in rat liver 6 hours after the administration but increased or tended to increase the activity 48 hours after the administration. Malotilate showed a protective effect on the liver injury induced by CHCl3 even when the activity of drug metabolizing enzymes in the liver was increased, although anethole trithione enhanced the CHCl3-induced liver injury regardless of the activity of drug metabolizing enzymes.
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PMID:[Protective effect of malotilate (diisopropyl 1,3-dithiol-2-ylidenemalonate) on chemical-induced hepatotoxicity]. 379

H2 receptor antagonist-hepatotoxicant interactions were evaluated in male Fischer-344 rats. The H2 receptor antagonists, cimetidine, ranitidine, oxmetidine, and 2-[2-(2-dimethyl-aminomethyl-5-furanylmethyl-thio)-ethylamino]-5-( 6-methyl- 3-picolyl)-4-pyrimidine trihydrohydrochloride (SK&F 93479) were administered (p.o.) at a dose of 0.143 mMoles/kg 30 minutes prior to hepatotoxicant treatment. Submaximal hepatotoxic doses (p.o.) of carbon tetrachloride (795 mg/kg), bromobenzene (748 mg/kg), chloroform (1,190 mg/kg), allyl alcohol (60 mg/kg), galactosamine (200 mg/kg, i.p.), and acetaminophen (1000 mg/kg) were employed. Hepatotoxicity was evaluated by determining serum alanine aminotransferase activity (ALT). Pretreatment with the H2 receptor antagonists did not significantly alter carbon tetrachloride or allyl alcohol hepatotoxicity. Bromobenzene and chloroform toxicities were unaffected by cimetidine, ranitidine, and oxmetidine pretreatment but were potentiated by SK&F 93479. Cimetidine and ranitidine decreased galactosamine mediated hepatotoxicity. Acetaminophen hepatotoxicity was markedly potentiated by ranitidine pretreatment but was unaltered by the other three H2 receptor antagonists. The mechanisms of hepatotoxicity potentiation or protection have not been determined, however, the lack of consistent H2 receptor antagonists effects indicates that it is unlikely that alterations in G.I. pH account for the effects observed. H2 receptor antagonist mediated changes in hepatotoxicant metabolism provide a more plausible mechanism of action, particularly in the cases of SK&F 93479 potentiation of bromobenzene and chloroform and ranitidine potentiation of acetaminophen hepatotoxicity.
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PMID:Effects of H2 receptor antagonists on the hepatotoxicity of various chemicals. 614 1

Our previous studies indicated that the toxicity of chloro- or bromo-methanes is potentiated by chlordecone (CD). The present work was conducted to study the effect of prior dietary exposure to CD on toxicity of bromoform. Male S-D rats (175-200 g) were fed 0 or 10 ppm CD in the powdered ration for 15 days. Bromoform (25 to 300 microliters/kg) was given i.p. on day 15. 24 h later, hepatotoxicity was assessed by functional, biochemical and histopathological parameters. Excretion of phenolphthalein glucuronide in bile and the rate of bile flow were unaltered by either bromoform or CD-bromoform combination. Serum enzymes (GPT, GOT and isocitric dehydrogenase (ICD) were also not significantly elevated by any treatment. The results suggest that, unlike chloroform, CHBr3 does not act as a potent hepatotoxin and that its effects are not potentiated by CD to any significant extent.
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PMID:Absence of potentiation of bromoform hepatotoxicity and lethality by chlordecone. 618 8

A semiquantitative morphologic procedure has been applied to chlordecone potentiation of CHCl3-induced liver injury in male Sprague-Dawley rats. The distance of the injured area from the terminal hepatic venule (THV) to the portal area was measured and the damaged cells were classified by type. The results were plotted graphically, along with elevations in plasma enzyme activities (GPT and OCT), to depict the pattern of damage. Chlordecone pretreatment enhanced the severity of the CHCl3-induced cellular changes and increased the number of cells affected. Dosages of 5 mg/kg of chlordecone did not potentiate CHCl3 toxicity, but higher dosages (10-50 mg/kg) enhanced the toxic response in a dose-dependent manner.
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PMID:A semiquantitative morphologic assessment of chlordecone-potentiated chloroform hepatotoxicity. 619 77

Diethyldithiocarbamate (DTC) and carbon disulfide (CS2), at nearly equimolar oral dose levels, protected mice against liver damage induced by carbon tetrachloride, chloroform, bromotrichloromethane, thioacetamide, bromobenzene, furosemide, acetaminophen, dimethylnitrosamine and trichloroethylene, as evidenced by the suppression of elevations in plasma GPT activity and liver calcium content, and of histopathological alterations. Both agents also prolonged hexobarbital sleeping time and zoxazolamine paralysis time in mice. DTC and SC, alone, given orally, decreased microsomal metabolism of several substrates (aniline, p-nitroanisole, hexobarbital, zoxazolamine, aminopyrine and 3,4-benzopyrene), CC14-induced lipid peroxidation, and cytochrome P-450 content. The loss of microsomal drug-metabolizing enzyme activity was also observed in the experiments in vitro using liver slices and isolated microsomes. Since a characteristic common to such diverse hepatotoxins is that they require metabolic activation before exhibiting hepatotoxicity, the protective mechanisms of DTC and CS2 may involve their interference with the process of metabolic activation of these hepatotoxins. The protective action of DTC may be mediated almost entirely through CS2 when administered orally and at least partly with parenteral administration, since, in CCl4-induced liver injury, DTC was most effective when given orally, while the action of CS2 was less dependent on the route of administration. Thus CS2 and CS2-producing agents in vivo such as dithiocarbamate derivatives and disulfiram may modify toxicological and pharmacological effects of foreign compounds by inhibiting microsomal drug-metabolizing enzyme activity in the liver.
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PMID:Protective effect of diethyldithiocarbamate and carbon disulfide against liver injury induced by various hepatotoxic agents. 629 43


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