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)

The interaction of ethanol and aflatoxin B1 (AFB1)-induced hepatotoxicity was studied in male Wistar rats using the activity of plasma GOT and GPT, liver triglyceride and histopathologic changes of liver necrosis as indices. Pretreatment of four oral doses of ethanol (4.0 g/kg BW each) at 48, 45, 24 and 21 hrs prior to AFB1 (0.5 to 2.0 mg/kg BW) single i.p. administration caused a significant increase in the activity of PGOT (6 folds) and PGPT (5 folds), liver triglycerides (2 folds) and severity of liver necrosis at 48 hrs after AFB1 administration. Ethanol pretreatment potentiated AFB1-induced hepatotoxicity by increasing MFO enzymes, aniline hydroxylase and p-nitroanisole-O-demethylase activity and lipid peroxidation, and decreasing in cytochrome b5, epoxide hydrolase activity and hepatic glutathione content. However, it did not cause any significant change in the activity of NADPH-cytochrome c reductase and glutathione-S-transferase and cytochrome P-450. These results suggest that potentiation of ethanol pretreatment on AFB1-induced hepatotoxicity may be due to an increase in the metabolic formation of AFB1-2, 3-oxide and subsequent binding to DNA.
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PMID:Potentiation of aflatoxin B1 induced hepatotoxicity in male Wistar rats with ethanol pretreatment. 308 65

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

Acetaminophen (ACAP) was fed to adult Swiss-Webster mice for 4 weeks to examine the effect of prolonged ACAP ingestion on hepatic reduced glutathione (GSH) concentrations. In the first experiment, male and female mice were pair-fed diets containing ACAP at levels of 0.0 (control), 0.3, 0.6, and 1.0% of diet on a dry weight basis with the total sulfur-amino acids provided at 0.5% of the diet. Hepatic GSH was depleted, and the percentage of dose excreted as the urinary ACAP-GSH-derived conjugate increased in a dose-dependent manner with increasing ACAP. Serum glutamic-pyruvic transaminase activity, relative liver weight, and hepatic microsomal protein content increased in the group given 1.0% ACAP, but microsomal aniline hydroxylation decreased. In the second experiment, adult male mice were fed ad libitum diets containing 0.0 or 0.6% ACAP with total L-methionine provided at 0.25, 0.5 (requirement level), or 1.0%. Hepatic GSH was markedly depleted 1 week after initiation of ACAP treatment in all groups except those receiving 1.0% methionine. This reduction persisted throughout the 4-week treatment period. After 4 weeks, liver cysteine was also reduced as a result of ACAP ingestion and methionine deficiency, whereas serum inorganic sulfate concentration was not changed. Reduction in hepatic cysteine levels was also prevented by 1.0% dietary methionine. The dose-dependent depletion of GSH, the trend toward an increase in ACAP-GSH-derived conjugate excretion, and the prevention of GSH depletion by providing dietary methionine in excess of requirement indicate that prolonged ingestion of ACAP may increase the requirement for sulfur-containing amino acids and limit the availability of methionine and cysteine for protein synthesis, methylation reactions, and drug detoxification.
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PMID:Effects of prolonged acetaminophen ingestion and dietary methionine on mouse liver glutathione. 324 Jul 15

No significant increases in serum SDH, ALT and AST activities were observed in goats and rats receiving oral sulfadimethoxine at 5 times the therapeutic dose. The quail showed significantly higher activities of SDH and ALT when compared to control values. Moderate increases in liver microsomal cytochrome P-450 and aniline hydroxylase activity were observed in goats and quail but no appreciable change in benzphetamine N-demethylase activity was detected in any species. These results suggest a lack of hepatic toxicity of sulfadimethoxine to these species under the reported experimental conditions.
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PMID:Studies on possible sulfadimethoxine toxicity to liver and liver drug metabolizing enzyme system of goats, quail and rats. 327 41

The acute toxicity of helenalin, a sesquiterpene lactone isolated from Helenium microcephalum, was examined in male BDF1 mice. The 14-day LD50 for a single ip dose of helenalin in male mice was 43 mg/kg. A single ip injection of 25 mg helenalin/kg increased serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), urea nitrogen (BUN), and sorbitol dehydrogenase within 6 hr of treatment. Multiple helenalin exposures, ip injection of 25 mg helenalin/kg for 3 days, increased differential polymorphonuclear leukocyte counts and decreased lymphocyte counts. Serum ALT, BUN, and cholesterol levels were also increased by multiple helenalin exposures at 25 mg helenalin/kg/day. Helenalin significantly reduced liver, thymus, and spleen relative weights and histologic evaluation revealed substantial effects of multiple helenalin exposures on lymphocytes of the thymus, spleen, and mesenteric lymph nodes. No helenalin-induced histologic changes were observed in the liver or kidney. Multiple helenalin exposures (25 mg/kg/day) significantly inhibited hepatic microsomal enzyme activities (aminopyrine demethylase and aniline hydroxylase) and decreased microsomal cytochromes P-450 and b5 contents. Three concurrent days of diethyl maleate (DEM) pretreatment (3.7 mmol DEM/kg, 0.5 hr before helenalin treatment) significantly increased the toxicity of helenalin exposure. The present studies indicate that the hepatic microsomal drug metabolizing system and lymphoid organs are particularly vulnerable to the effects of helenalin. In addition, helenalin toxicity is increased by DEM pretreatments which have been shown to decrease glutathione concentrations.
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PMID:Acute toxicity of helenalin in BDF1 mice. 335 17

Weanling, male Sprague-Dawley rats given 10% ethanol in the drinking water and food ad lib. for up to 8 weeks consumed 17% of their calories as ethanol. The alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver histology by light microscopy were unaffected by this treatment. Similarly, hepatic microsomal NADPH-cytochrome c reductase, ethylmorphine N-demethylase and benzphetamine N-demethylase activities were also not affected by ethanol consumption. On the other hand, cytochrome P-450 content, aniline hydroxylase activity and acetaminophen metabolism as measured by both the cysteine conjugate and the [3H]acetaminophen covalently-bound to microsomal protein were increased significantly by ethanol consumption. The maximal effect was seen by 6 weeks. The 2- to 3-fold increase in aniline and acetaminophen metabolism, the absence of liver damage, and the similarity in weight gains and caloric intakes for controls and treated animals suggest that the rat on 10% ethanol in the drinking water is a reasonable model for studies of the effect of moderate alcohol consumption on specific biochemical pathways.
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PMID:Studies on the effect of chronic consumption of moderate amounts of ethanol on male rat hepatic microsomal drug-metabolizing activity. 393 44

Experiments were conducted to examine the role of zinc in the prevention of bromobenzene hepatoxicity in male rats. Bromobenzene (BB) (7.5 mmol/kg, ip) produced a marked hepatotoxicity as evidenced by increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and a marked depression in hepatic glutathione (GSH) content 24 hr after administration. The administration of zinc (92 mumol Zn/kg, ip, at 48 and 24 hr prior to the bromobenzene) ameliorated the bromobenzene elevations in plasma AST (25%) and plasma ALT (50%) but did not alter the decreases in hepatic GSH. Following administration of [14C]BB, the radioactive label was distributed primarily in the cytosolic and lipid fractions derived from liver homogenates. Furthermore, the subcellular distribution of [14C]BB was not altered by zinc pretreatment. The extent of covalent binding of [14C]BB metabolites to hepatic tissue was significantly depressed in zinc-treated rats. Zinc induced the hepatic levels of metallothionein but [14C]BB did not bind to this sulfhydryl rich protein. Further experiments showed that zinc treatment depressed cytochrome P-450 content, the activity of NADPH cytochrome c reductase, and the metabolism of aniline, but not that of ethylmorphine. These studies suggest that the hepatoprotective effect of zinc against bromobenzene toxicity does not involve altered binding of the reactive toxic metabolite to glutathione or metallothionein, but it may be mediated by the inhibitory effect of zinc on the microsomal cytochrome P-450-dependent drug metabolizing system.
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PMID:Amelioration of bromobenzene hepatotoxicity in the male rat by zinc. 398

When male Sprague-Dawley rats were treated with sodium selenite (1 mg/kg, sc) 24 hr prior to or simultaneously with bromobenzene (2.5 mmol/kg, ip) and sacrificed 48 hr after the bromobenzene dose, increased levels of the activities of serum transaminases (serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT) induced in the bromobenzene-treated rats were significantly reduced in the presence of selenium. However, no such reduction in the transaminases activities were observed when rats were either pretreated with selenite for 48 hr or pretreated with 0.1, 0.2, or 0.5 mg/kg of selenite. Although selenium alone had no effect on the hepatic microsomal drug metabolism, simultaneous treatment of selenite (1 mg/kg) with bromobenzene resulted only an increase in the activity of aniline hydroxylase after 48 hr as compared to that in the bromobenzene-treated group. When rats were given 2.5, 10, and 20 ppm of selenite in drinking water daily for 4 weeks prior to an ip injection of 2.5 mmol/kg of bromobenzene and were sacrificed 48 hr after bromobenzene administration, a reduction in the SGOT activities in all the pretreated groups and a reduction of SGPT activity in 20 ppm selenite-treated group were observed when compared with those in the bromobenzene-treated groups. A dose-dependent increase in hepatic GSH concentrations were observed due to such chronic selenium treatment. Treatment with selenite (1 mg/kg) 24 hr prior to bromobenzene injection (2.5 mmol/kg) increased initially both o and p-bromophenols in the rat urine at 0-7.5 hr without affecting urinary thioethers. On the contrary, the ratio of thioethers to p-bromophenol was significantly higher in both 2.5 and 10 ppm selenite-pretreated (4 weeks) rats as well as a significant increase in the ratio of thioethers to total phenolic metabolites in 10 ppm and an increase close to significant in 2.5 ppm selenite-treated rats were observed initially at 0-7.5 hr urine samples. These results indicate that acute selenium pretreatment under certain conditions, favors increased hydroxylation of the intermediate bromobenzene epoxides, whereas higher detoxification of the epoxides involving hepatic glutathione (GSH)/GSH transferases pathway is more favored due to increased biosynthesis of GSH in certain chronic selenium treated rats.
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PMID:Influence of selenium on the metabolism of bromobenzene and a possible relationship to its hepatotoxicity. 401 88

Carbon tetrachloride (CCl4)-induced hepatotoxicity was potentiated by pretreatment with beta-phenethyl alcohol, abundantly present in sake. The injury was determined by serum GPT levels and histological examination. Similar results were observed in ethanol- and phenobarbital-pretreated rats. Acetaminophen-induced hepatotoxicity was not accentuated by beta-phenethyl alcohol or ethanol pretreatment. The activities of liver microsomal enzymes, such as cytochrome P-450, cytochrome b5 reductase, aniline hydroxylase and aminopyrine demethylase, were not altered in beta-phenethyl alcohol-pretreated rats. Thus, CCl4-induced hepatotoxicity potentiation by beta-phenethyl alcohol administration is postulated to be due to a mechanism other than increased free radical generation.
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PMID:Potentiation of carbon tetrachloride hepatotoxicity by beta-phenethyl alcohol. 608 1

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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