Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pretreatment with Zn is known to produce tolerance to several toxic effects of Cd. This study was designed to determine if zinc pretreatment decreased Cd-induced lethality and hepatotoxicity. Rats given 4.0 mg Cd/kg, iv, died within 10 to 20 hr while there was no mortality in rats pretreated with Zn (12 mg Zn/kg, sc, 48 and 24 hr prior to Cd challenge). Ten hr after Cd, plasma aspartate aminotransferase and sorbitol dehydrogenase activities were markedly elevated and extensive histopathologic lesions of the liver were evident in control rats while such injury was not evident in Zn-pretreated rats. To examine the mechanism of this tolerance, distribution of Cd to 14 organs and the subcellular distribution in 6 organs (liver, kidneys, intestines, heart, spleen, and testes) was determined in control and Zn-pretreated rats. Two hours after challenge (3.5 mg Cd/kg, iv, 7 microCi 109Cd/mg Cd), the distribution of Cd to the liver markedly increased after Zn pretreatment without concomitant decreases in other tissues. Zn pretreatment resulted in distribution of more Cd to hepatic cytosol and less associated with endoplasmic reticulum. Gel filtration chromatography indicated that most cytosolic Cd was bound to metallothionein. These data suggest that Zn pretreatment reduces Cd-induced hepatotoxicity which prevents the lethal effects of Cd possibly by altering the hepatic subcellular distribution of Cd.
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PMID:Zinc-induced tolerance to cadmium hepatotoxicity. 674 Jun 79

Tolerance to several toxic effects of Cd, including lethality, has been shown following pretreatment with Cd. This study was designed to determine if tolerance also develops to Cd-induced hepatotoxicity. Rats were challenged with Cd (2.0, 3.0, 4.0, or 5.0 mg/kg, iv) 24 hr after pretreatment with saline (2 ml/kg, sc) or Cd (2.0 mg/kg, sc). Ten hours following challenge, plasma enzyme activities were dramatically elevated in control rats (sorbitol dehydrogenase 30- to 300-fold and aspartate aminotransferase 3- to 40-fold). In addition, histologic examination revealed moderate to severe hepatic injury, evidenced by cell swelling, cytoplasmic eosinophilia, pyknosis, karyorrhexis, and necrosis. In Cd-pretreated rats, plasma enzyme levels were similar to control values and only slight morphologic changes were evident. This tolerance to Cd-induced hepatotoxicity is probably due to the increase in hepatic metallothionein induced by Cd pretreatment, which has been shown to alter the hepatic subcellular distribution of Cd such that less binds to subcellular organelles and more binds to metallothionein located in the cytosol.
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PMID:Tolerance to cadmium-induced hepatotoxicity following cadmium pretreatment. 674 Jun 80

Because the concentration of metallothionein (MT) in perinatal rat liver is 10 to 20 times higher than levels present in liver of untreated adult rats, it was of interest to determine if immature rats are less susceptible to the hepatotoxic effects of cadmium (Cd) seen in adults. Male Sprague-Dawley adult rats received a hepatotoxic dose of 4.0 mg Cd/kg, iv, and 10-day-old rats received 4.0, 5.0, 6.0 mg Cd/kg, iv. Ten hours following Cd injection, plasma enzyme activities in adults were elevated (aspartate aminotransferase, 50-fold; sorbitol dehydrogenase, 87-fold) and histologic examination showed extensive hepatic injury; however, no damage was evident in 10-day-old rats, even at the 6 mg Cd/kg dose. Two hours after injection of 3.5 mg Cd/kg, iv (7 microCi 109Cd/mg Cd), the concentration of Cd was higher in liver, heart, and brain and lower in kidneys of 10-day-old rats compared to adults. An age comparison of the hepatic subcellular distribution of Cd revealed a higher amount of Cd in cytosol and less in the particulate fraction of 10-day-old rats. Furthermore, cytosolic Cd was predominantly bound to MT. These data support the hypothesis that presynthesized levels of MT are important in producing tolerance to acute Cd toxicity and that tolerance results from an altered hepatic subcellular distribution of Cd.
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PMID:Resistance to cadmium-induced hepatotoxicity in immature rats. 674 Jun 82

In order to test the possibility of metallothionein (MT) transfer from liver to kidney, experimental hepatic disorders produced by hepatotoxins were examined to study the release of MT from liver. 109Cd exposed rats were treated with carbon tetrachloride (CCl4) and the distribution of cadmium (Cd) in the body was studied. Hepatic Cd was significantly decreased corresponding to the dose of CCl4. Cd in plasma, kidney, and urine was increased remarkably in contrast with the decrease of hepatic Cd. No remarkable changes in Cd of other tissues and feces were observed. These phenomena were produced by other hepatotoxins like galactosamine and ethionine, and long-term administration of Cd, too. In every case that plasma Cd increased markedly, plasma levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and lactate dehydrogenase (LDH) rose simultaneously, and a significant, positive correlation between Cd concentration and each of enzyme activities in plasma was observed. Cd in hepatic supernatant of CCl4 treated rats was bound mostly to MT fraction, and in kidney, plasma or urine, Cd was also in the form of MT. These results suggest that hepatic MT can be released into blood in the same manner as hepatic enzymes and transported to kidney and urine in some types of hepatic disorders.
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PMID:Effects of hepatic disorder on the fate of cadmium in rats. 705 69

To explore the relationship between mitochondrial aspartate aminotransferase (mAspAT; EC 2.6.1.1) and plasma membrane fatty acid-binding protein (FABPpm) and their role in cellular fatty acid uptake, 3T3 fibroblasts were cotransfected with plasmid pMAAT2, containing a full-length mAspAT cDNA downstream of a Zn(2+)-inducible metallothionein promoter, and pFR400, which conveys methotrexate resistance. Transfectants were selected in methotrexate, cloned, and exposed to increasing methotrexate concentrations to induce gene amplification. Stably transfected clones were characterized by Southern blotting; those with highest copy numbers of pFR400 alone (pFR400) or pFR400 and pMAAT2 (pFR400/pMAAT2) were expanded for further study. [3H]Oleate uptake was measured in medium containing 500 microM bovine serum albumin and 125-1000 microM total oleate (unbound oleate, 18-420 nM) and consisted of saturable and nonsaturable components. pFR400/pMAAT2 cells exhibited no increase in the rate constant for nonsaturable oleate uptake or in the uptake rate of [14C]octanoate under any conditions. By contrast, Vmax (fmol/sec per 50,000 cells) of the saturable oleate uptake component increased 3.5-fold in pFR400/pMAAT2 cells compared to pFR400, with a further 3.2-fold increase in the presence of Zn2+. Zn2+ had no effect in pFR400 controls (P > 0.5). The overall increase in Vmax between pFR400 and pFR400/pMAAT2 in the presence of Zn2+ was 10.4-fold (P < 0.01) and was highly correlated (r = 0.99) with expression of FABPpm in plasma membranes as determined by Western blotting. Neither untransfected 3T3 nor pFR400 cells expressed cell surface FABPpm detectable by immunofluorescence. By contrast, plasma membrane immunofluorescence was detected in pFR400/pMAAT2 cells, especially if cultured in 100 microM Zn2+. The data support the dual hypotheses that mAspAT and FABPpm are identical and mediate saturable long-chain free fatty acid uptake.
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PMID:3T3 fibroblasts transfected with a cDNA for mitochondrial aspartate aminotransferase express plasma membrane fatty acid-binding protein and saturable fatty acid uptake. 756 34

The ability of chromium (Cr) salts to increase metallothionein (MT) levels in rat liver, kidney and pancreas, and its relationship with the presence of toxic effects are reported here. Rats were injected subcutaneously with 0, 10, 20, 30, 40, or 50 mg K2Cr2O7/kg and sacrificed 24 h later. Total Cr accumulation followed a dose-dependent pattern, levels in kidney being higher than those in liver or pancreas, suggesting different tissue bioavailabilities and accumulation patterns. Cr(IV) administration resulted in a tissue-specific MT induction: pancreas and liver showed five- and 3.5-fold MT increases, respectively; no increase was observed in the kidney. A positive correlation was observed between zinc and MT concentrations in liver, and between total Cr and MT concentrations in pancreas. Serum alpha-amylase activity showed a dose-dependent increase starting from 20 mg/kg, whereas serum glucose levels increased at doses higher than 30 mg/kg. Serum aspartate aminotransferase and alanine aminotransferase activities were increased in a dose-dependent manner, from 20 and 30 mg/kg, respectively. Our results showed that treatment with Cr(VI) can induce MT synthesis in pancreas and suggests a subsequent binding of Cr to MT. Also, pancreas is a target organ for Cr toxicity, and the usefulness of alpha-amylase activity as a sensitive biomarker of Cr toxicity in human exposed populations merits further study.
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PMID:Chromium increases pancreatic metallothionein in the rat. 1068 10

Several compounds have been shown to cause acute toxicity to cadmium (Cd). The mechanism of tolerance to Cd toxicity induced by glucocorticoids or by inflammation involves induction of metallothionein (MT) synthesis via glucocorticoid response elements or by inflammatory cytokines. We have demonstrated previously that the synthetic glucocorticoid dexamethasone suppresses inflammation-mediated induction of hepatic MT synthesis. Here we investigated the effect of glucocorticoid on tolerance to Cd induced by inflammation in mice. The LD50 of Cd for mice with induced inflammation by injection with turpentine oil (Tur-mice) was higher than the LD50 in control mice. Pretreatment of Tur-mice with dexamethasone to the Tur-mice (Dex+Tur-mice) resulted in a decrease in LD50 after Cd treatment. A significant increase in plasma alanine aminotransferase and aspartate aminotransferase levels in the Dex+Tur-mice was observed at lower doses of Cd than in the Tur-mice and at higher doses of Cd than in control mice. Dexamethasone did not suppress tolerance to cadmium toxicity in the testes of the Tur-mice. Pretreatment of Tur-mice with dexamethasone resulted in suppression of both plasma interleukin (IL)-6 elevation and in suppression of hepatic MT levels when induced by inflammation but not when induced by Cd. These data suggest that suppression of tolerance to Cd toxicity induced by glucocorticoid may involve hepatic MT synthesis mediated by inflammatory cytokines, such as IL-6. We suggest that the inflammatory response can modulate Cd toxicity by induction of MT by inflammatory cytokines.
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PMID:Glucocorticoids suppress the inflammation-mediated tolerance to acute toxicity of cadmium in mice. 1178 Oct 73

The efficacy of Emblica officinalis in modifying the acute cytotoxicity of cadmium in male rats was evaluated. Oral administration of Emblica fruit juice (500 mg/kg, b.w.) for 8 days followed by a single toxic dose of Cd as CdCl2 (3 mg/kg,b.w. ip), considerably reduced the mortality in rats as well as prevented to some extent the cadmium induced histopathological damage in testis, liver and kidneys. Biochemical investigation also revealed reduced levels of Cd induced serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and gamma glutamyltranspeptidase. The enhanced levels of Cd and lipid peroxidation in liver, kidney, and testes and metallothionein and total sulphydryl in liver and kidney by Cd were significantly reduced by Emblica pretreatment. These results suggest cytoprotective potential of Emblica fruit in acute cadmium toxicity which could be due to its multiple role in biological system.
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PMID:Modulation of acute cadmium toxicity by Emblica officinalis fruit in rat. 1262 3

Mercury is a highly toxic metal which induces oxidative stress. Metallothionein and heat shock protein 70 (HSP70) are stress proteins involved in response to different stimuli. In the present study rats were administered per oral application by gavage, a single daily dose (0.1 mg/kg) of HgCl(2) for 3 consecutive days. To find a relation between these two stress proteins and mercury, parameters of liver injury, redox state of the cells, and the expression and protein levels of HSP70 and metallothionein by Northern and Western blot analysis were assayed either in blood or in liver. HgCl(2) at the doses of 0.1 mg/kg induced liver injury detected by a slight increase in serum aspartate aminotransferase and alkaline phosphatase activities and by the enhanced levels of bilirubin. Oxidative stress was detected by a significant decrease in protein-SH and an increase in thiobarbituric acid reactive substances in liver following one dose of mercury. mRNA and protein levels of both metallothionein and HSP70 increased progressively from first to third doses of mercury. We conclude that against low doses of mercury that produce a slight liver injury and oxidative stress, the liver rapidly responds by inducing the expression of metallothionein and HSP70. We suggest that metallothionein induction attenuates the decrease in protein-SH induced by the first dose of mercury, since metallothionein increases the pool of thiol groups in the cytosol eliminating oxygen radicals and inhibiting lipid peroxidation. From these results we can suggest that the changes observed in these stress proteins by the effect of mercury appear to be a response rapidly induced at transcriptional and at translational levels.
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PMID:Relationship between expression of HSP70 and metallothionein and oxidative stress during mercury chloride induced acute liver injury in rats. 1281 12

The influence of oral administration of rare earth element cerium (Ce) was studied in relation to metallothionein (MT) and glutathione (GSH) content in the organs of ICR mice, which were administered heavy metal cadmium (Cd) for comparison. Male ICR mice were divided into 9 groups: 1 control group, 4 cerium groups and 4 cadmium groups, each with 4 mice, for a total of 36 mice. Ce groups included a 20 ppm CeCl3 diet (Ce-low) group and a 200 ppm CeCl3 diet (Ce-high) group, as did Cd groups, i.e., a 20 ppm CdCl2 diet (Cd-low) group and a 200 ppm CdCl2 diet (Cd-high) group. Each group was subdivided in 2 groups except a control group: 6-week administration group and 12-week administration group. The level of plasma aspartate aminotransferase(AST) activity, plasma alanine aminotransferase(ALT) activity, plasma cholesterol and plasma triglyceride in the Ce-low, Cd-low, Ce-high, and Cd-high group were higher than that of control group, although there were no significant differences (p > 0.05). By contrast, both Ce and Cd groups had higher levels of MT and GSH in hepatic cells compared to the control group (p < 0.05) and decreased liver tissue level of lipoperoxide (p < 0.05). These groups also had decreased plasma superoxide dismutase (SOD) activity (p < 0.05), and increased plasma level of lipoperoxide (p > 0.05). In conclusion, it is suggested that orally administered Ce increases MT and GSH as an antioxidant in the mouse liver, and these reaction are probably caused by increases in the oxidative stress with Ce.
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PMID:Orally administrated rare earth element cerium induces metallothionein synthesis and increases glutathione in the mouse liver. 1596 10


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