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)

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

Carbon tetrachloride (CCl4) added to isolated rat hepatocytes produces toxic effects which were assessed by monitoring the release of aspartate aminotransferase (ASAT). CBrCl3 was equitoxic with CCl4, while CHCl3 was inactive, suggesting solvent properties not to be involved. The CCl4-mediated toxicity was markedly decreased by carbon monoxide, indicating possible activation by cytochrome P 450. 55 flavonoid compounds were tested for their ability to interfere with CCl4-induced release of ASAT. The compounds are cianidanol, 3-ethers and 3-esters thereof, flavanones, flavanolols, flavones and flavanols. The more hydrophilic compounds inhibit the CCl4-induced toxicity, while the lipophilic derivatives are potentiators. No other structure-activity relationships are apparent. The results are discussed in terms of the mechanisms of action of the compounds and of the validity of the technique as a screening test for hepatotropic agents.
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PMID:Inhibiting or potentiating effects of flavonoids on carbon tetrachloride-induced toxicity in isolated rat hepatocytes. 377 62

The effects of the cyclodiene pesticide, endrin, and its aldehyde and ketone metabolites on hepatobiliary function and CCl4-induced hepatotoxicity were investigated in Sprague-Dawley rats. The rats were given control diet or diets containing 5 or 10 ppm endrin, 10 ppm endrin aldehyde or 5 ppm endrin ketone for 15 days. Three to six rats from each treatment group were given a single ip dose (100 microliter/kg body weight) of CCl4 in corn oil (1 ml/kg) on day 15. Levels of serum glutamic-oxalacetic transaminase (SGOT), glutamic-pyruvic transaminase (SGPT), isocitrate dehydrogenase and ornithine-carbamyl transferase, bile flow and biliary excretion of an anionic model compound, phenolphthalein glucuronide (PG), were measured on day 16. Dietary treatment with endrin at either dose level did not significantly elevate serum enzyme levels, while endrin aldehyde produced a slight increase in SGOT and SGPT and endrin ketone produced a small elevation in SGPT levels. Treatment with endrin aldehyde or endrin ketone did not result in significant alterations of bile flow or biliary PG excretion. Treatment with 5 ppm endrin produced a significant reduction in bile flow and a corresponding reduction in PG excretion by male rats, whereas treatment with 10 ppm endrin reduced only the PG excretion by male rats. Female rats treated with 5 or 10 ppm endrin showed a dose-dependent choleretic effect with a commensurate increase in PG excretion. With the exception of a further slight reduction in PG excretion by male rats, treatment with the endrin or endrin derivative did not potentiate CCl4-induced alterations in hepatobiliary functions. Although the levels of some serum enzymes of rats given endrin or endrin derivatives plus CCl4 were elevated over those of rats given CCl4 alone, the increases were not of the magnitude of those that have been reported previously for chlordecone. Generally, female rats challenged with CCl4 or endrin/CCl4 exhibited greater increases in serum enzyme levels than did male rats given corresponding treatments.
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PMID:Effect of endrin and endrin derivatives on hepatobiliary function and carbon tetrachloride-induced hepatotoxicity in male and female rats. 378 35

To study the influence of hepatic metallothionein (MT) on the hepatotoxic response to carbon tetrachloride (CCl4), adult male rats were pretreated with a 10 mg X kg-1 dose of zinc (Zn) 24 h prior to CCl4 (i.p., l mL X kg-1) treatment. Zn pretreatment increased the hepatic MT concentrations markedly and reduced the magnitudes of the CCl4-induced reduction of cytochrome P450 concentration as well as elevation of serum alanine aminotransferase and aspartate aminotransferase activities when determined at 4 or 24 h following CCl4 treatment. Treatment of Zn-exposed animals with CCl4 also resulted in significant reduction of the concentrations of hepatic MT (as determined by the cadmium-saturation method) as well as cytosolic Zn. Sephadex G-75 chromatographic study of hepatic cytosols showed that MT-bound Zn was selectively depleted by CCl4 exposure. Moreover, it was demonstrated that CCl4, after metabolic activation, reduced the cadmium binding capacity of Zn-induced hepatic MT in vitro. To examine the possible protective effect of Zn independent of induction of MT synthesis, CCl4 was administered 2 h following Zn pretreatment and the hepatotoxic response was examined 4 h later. This study revealed limited protection by Zn prior to the induction of MT synthesis. These data further support a role of MT in the modulation of CCl4 hepatotoxicity.
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PMID:Interaction of metallothionein and carbon tetrachloride on the protective effect of zinc on hepatotoxicity. 379 Oct 46

An attempt was made to establish a concentration-time-response relationship for a single inhalation of CCl4 in rats. Rats were exposed to CCl4 under conditions of various combinations of concentration (C = 1350, 2500, 3400, and 6900 ppm) and time (t = 1, 2, 3, and 6 hr). As a parameter of toxicity, glutamic-oxaloacetic transaminase (GOT) activity was measured. The concentration-time-response relationship obtained by graphic analysis of the data could be described by the equation: log g = nCmlog t + gamma C + log delta, where g is the GOT activity 24 hr after the end of exposure, and n, m, gamma, and delta are empirical parameters. It was found from this relationship that concentration has more influence on toxic effect than time does. The concentration-time relationship, furthermore, suggested that the time-weighted average of the concentration of CCl4 (and presumably also other atmospheric contaminants), which can be applied only under the condition of C X t = constant, does not correctly reflect the "toxicity value" of exposures. Quantitative expression of the concentration-time-response relationship makes it possible to predict the "no observable effect level" (NOEL) of CCl4 for various exposure times.
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PMID:Concentration-time-response relationship under conditions of single inhalation of carbon tetrachloride. 397 98

Both cytosolic (c-AAT) and mitochondrial (m-AAT) isozymes of aspartate aminotransferase (EC 2.6.1.1) appear in serum in some diseases including hepatobiliary dysfunction. The present study aimed at elucidation of the mechanism by which AAT isozymes are cleared from blood. Intravenous injection into rats of m-AAT and c-AAT purified from rat liver exhibited a biphasic clearance curve with an overall half-life of 42 min and 4.7 hr, respectively. The tissue distribution of the radioactivity following intravenous administration of 125I-labeled isozymes revealed that the liver is a major organ involved in plasma clearance of these isozymes. This conclusion was also supported by the significant retardation in plasma clearance of m-AAT in hepatectomized as well as CCl4-intoxicated rats. Furthermore, clearance rate of each AAT isozyme in an isolated perfused liver exhibited a single exponential process with the uptake rate for m-AAT being much faster than that for c-AAT. Separation of hepatocytes and sinusoidal liver cells from the rat intravenously injected with 125I-labeled AAT isozymes revealed that sinusoidal cells were responsible for the plasma clearances. In vitro uptake study showed that both isozymes were exclusively taken up by sinusoidal liver cells. The uptake rate for m-AAT was considerably greater than that for c-AAT. Endocytotic index for uptake by sinusoidal cells was 16 times with c-AAT and 34 times with m-AAT as compared with that for inulin or dextran which are taken up by fluid-phase endocytosis, suggesting involvement of adsorptive endocytosis in the uptake of the isozymes.
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PMID:Plasma clearance of intravenously injected aspartate aminotransferase isozymes: evidence for preferential uptake by sinusoidal liver cells. 399 68

The effects of the administration of tryptophan and/or cysteine on carbon tetrachloride (CCl4)-induced hepatic injury were investigated. Rats received CCl4 (1 ml/kg ip) followed 6 hr later by tryptophan (300 mg/kg) and/or cysteine (950 mg/kg) via stomach tube and rats were killed after 24 hr. Treatment with tryptophan, cysteine, or both reduced the degree of hepatic necrosis observed histologically. While CCl4 caused polyribosomal disaggregation and decreased [14C]leucine incorporation into liver proteins in vitro and in vivo, treatment with tryptophan, cysteine, or both caused a shift in polyribosomes toward heavier aggregation and protein synthesis was increased. Serum activities of lactic dehydrogenase (LDH), glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and gamma-glutamyl-transpeptidase were markedly increased after CCl4 alone but after subsequent treatment with cysteine or with tryptophan and cysteine appreciable decreases occurred. Glutathione concentration decreased but total amount remained constant in the livers of CCl4-treated rats while subsequent treatment with cysteine alone or together with tryptophan elevated both levels of glutathione. Using isolated hepatocytes, CCl4 caused decreases in cell viability, in release of LDH, and in [14C]leucine incorporation into protein. Treatment with CCl4 and tryptophan and/or cysteine revealed that cysteine alone or with tryptophan improved cell viability and decreased LDH release of the cells, while tryptophan alone or with cysteine improved protein synthesis. Upon cytologic evaluation, the isolated hepatocytes revealed membrane distortions after CCl4 alone but these were less marked after CCl4 plus tryptophan, cysteine, or both (most improvement). Thus, tryptophan and cysteine act in a beneficial manner against CCl4-induced hepatic injury in the rat.
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PMID:Protective effect of tryptophan and cysteine against carbon tetrachloride-induced liver injury. 406 14

The present study, conducted over a time course of 36 hr after CCl4 administration, describes sequential morphometric and biochemical changes which occur in livers of rats exposed to a combination of low levels of chlordecone (10 ppm for 15 days) and a single ip injection of CCl4 (0.1 ml/kg). Those changes were compared to hepatic alterations which occur in rats that received the same dose of chlordecone or CCl4 alone. Biochemical studies showed only trivial increases in levels of glutamic-pyruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT), and moderate but temporary increases in isocitrate dehydrogenase (ICD) after CCl4 alone. The combination of chlordecone and CCl4 resulted in significantly greater elevations of all three serum enzymes at all time intervals examined. Morphometric data showed no difference between normal diet controls and animals exposed to chlordecone alone as far as numerical density of hepatocytes or volume densities of hepatocytes with glycogen, lipid, dilated rough endoplasmic reticulum (RER), pyknosis, or mitoses. Morphometric analysis of livers from animals that received CCl4 alone showed decreases in numerical density, temporary decrease in percentage of hepatocytes containing glycogen, an increase in hepatocytes containing lipid, temporary increase in hepatocytes with dilated RER, and temporary increases in pyknotic nuclei. Soon after the initial hepatic injury was histologically evident between 4 and 6 hr, the number of mitoses increased dramatically and this progressed until complete recovery from CCl4 damage. From all indices of damage, complete recovery was evident by 36 hr after CCl4 administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Chlordecone-induced potentiation of carbon tetrachloride hepatotoxicity: a morphometric and biochemical study. 619 13

Hyperbaric oxygen (HPO) was administered to rats (100% O2 at 2.8 atm for 90 min) immediately or 1 hr after severe carbon tetrachloride (CCl4) intoxication in order to study the mechanisms of protection against hepatocellular injury by hyperoxia. Slight to moderate hepatocellular injury was observed, particularly by morphologic criteria, 4 hr after CCl4 intoxication. Little cell death was observed; 24 hr after CCl4, 20% of the untreated animals died. In the survivors, the following typical changes occurred in the liver: extensive hepatocellular swelling, vacuolization and necrosis; severe ultrastructural alterations; binding of CCl4 to microsomal lipids; elevation of lipid peroxidation products (conjugated dienes); little decrease in cytochrome b5 and severe decrease in cytochrome P-450 levels. Serum transaminase (alanine aminotransferase and aspartate aminotransferase) levels were elevated. Immediate treatment with HPO prevented the mortality and markedly decreased the hepatocellular necrosis 24 hr after intoxication. Immediate HPO treatment did not lower the levels of free CCl4 in the liver. However, the rise in lipid peroxidation products caused by CCl4 intoxication at 4 hr was reduced. Delayed treatment with HPO (1 hr after CCl4) prevented the mortality but was less effective in preventing necrosis. Some hepatocellular protection was still demonstrable. In particular, the rise in lipid peroxidation products was reduced. Hyperoxia protects hepatocytes against CCl4 toxicity. The rapid decline in protective effect within 60 min of intoxication suggests that hyperoxia inhibits CCl4 activation and/or damage from molecular intermediates. Hyperoxia has little effect on the progression of sublethal injury to cell death in the livers of CCl4-intoxicated rats.
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PMID:Protection of hepatocytes with hyperoxia against carbon tetrachloride-induced injury. 653 53

The previously reported increases in liver and serum aspartate aminotransferase (ASAT) activities and liver protein content 24 hours after the administration of carbon tetrachloride (CCl4) were reduced by administering multiple doses of the protein synthesis inhibitor cycloheximide (CH). Liver ASAT and protein content were reduced to saline-injected control levels, and the serum ASAT increase was reduced by 45.0 percent in rats given CH. Although there are morphological features of severe hepatotoxicity in the cycloheximide-carbon tetrachloride-injected rats, cycloheximide does reduce the severity of these lesions and the regenerative response. These findings lend some support to the hypotheses that (1) the increase in liver ASAT activity and protein content after CCl4 is due to increased synthesis and (2) the increase in serum ASAT after CCl4 is most likely due to a combination of increased synthesis and leakage from necrotic and damaged cells.
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PMID:Effect of cycloheximide on increased aspartate aminotransferase in carbon tetrachloride hepatotoxicity. 669 88


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