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 Sprague-Dawley rats received an intraperitoneal injection of 0.25-, 0.5-, 1.0-, 2.5-, and 5.0-mmol/kg dose of bromobenzene in corn oil. The metabolic fate of bromobenzene was studied by measuring its various urinary metabolites 24 h following bromobenzene administration. The hepatotoxicity of bromobenzene was estimated by determination of the serum glutamic-oxaloacetic and glutamic-pyruvic transaminase activities (SGOT and SGPT) 24 h after dosing. Treatment of rats with bromobenzene at up to 0.5 mmol/kg did not influence the transaminase activities, but significant increases in such activities began to manifest at a dose of 1 mmol/kg. However, no further increase in hepatotoxic response was induced on exposure to higher doses (2.5 and 5.0 mmol/kg) of bromobenzene. The urinary excretion of toxic doses of bromobenzene was nonlinear, based on the quantitative composition of various urinary metabolites. Furthermore, the fraction of the dose converted to thioethers, p-bromophenol, m-bromophenol, and total phenolic metabolites decreased with increasing toxic dose, suggesting their formation to be capacity-limited. The ratios of thioethers to total phenolic metabolites, of thioethers to p-bromophenol, and of thioethers to o-bromophenol decreased with increasing dose of bromobenzene. The correlation of the dose-dependent fate of metabolic excretion of bromobenzene with the results of the dose-hepatotoxic response curves supports the conclusion that there exists an apparent threshold dose (approximately 1-2.5 mmol/kg) for the toxic effects of bromobenzene that coincides with saturation of the metabolic pathways involving both glutathione/glutathione S-transferase(s) and formation of certain phenolic derivatives for its detoxification. All these results further suggest a role of a saturable, metabolic activation process involving 3,4-epoxide rather than 2,3-epoxide of bromobenzene in the development of its hepatotoxicity.
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PMID:Dose-dependent metabolic excretion of bromobenzene and its possible relationship to hepatotoxicity in rats. 650 40

Sodium stibogluconate is the mainstay of treatment for all forms of leishmaniasis. Therapy is associated with an increase in serum aminotransferases. In this study liver damage was assessed during treatment of American cutaneous leishmaniasis with sodium stibogluconate and also in a control group given aminosidine. In addition to standard liver function tests, acute hepatocellular damage was assessed by measuring plasma glutathione S-transferase B1 (GST), and hepatic metabolic capacity was assessed by a caffeine clearance (CCL) test, before, during and after treatment. Thirteen patients were treated; 5 received sodium stibogluconate, 6 received aminosidine and a further 2 patients received aminosidine followed by sodium stibogluconate. Treatment with sodium stibogluconate was associated with an increase in both alanine aminotransferase (ALT) and GST and a fall in the CCL, indicating both hepatocellular damage and functional impairment. Six weeks after treatment had stopped ALT and GST had returned to pre-treatment levels and the CCL remained depressed in only one patient. Patients given aminosidine did not show any evidence of liver damage. Sodium stibogluconate is associated with significant hepatocellular damage and hepatic functional impairment. However, this is rapidly reversible on drug withdrawal. We suggest that liver function is monitored throughout treatment and that patients with pre-existing liver disease receive alternative treatment.
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PMID:Hepatotoxicity of sodium stibogluconate therapy for American cutaneous leishmaniasis. 757 Aug 43

Paracetamol (acetaminophen) 90-150 mg.kg-1 increased the activity of serum glutathione S-transferase (GST) and yet reduced the activities of liver microsomal and homogenate GST in mice. The GST activity was dose- and time-related to paracetamol. A negative correlation was found between serum GST and liver homogenate GST, as well as between serum GST and liver microsomal GST. A good positive correlation between serum GST and serum alanine aminotransferase (AAT) was also seen. In addition, butylated hydroxyanisole (BHA) and sodium ferulate (SF) remarkably reversed the changes of serum GST and serum AAT activities in paracetamol-treated mice. These results suggested that the conjugation level in liver was decreased in paracetamol-induced hepatotoxicity in mice.
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PMID:[Effects of paracetamol on glutathione S-transferase activity in mice]. 801 73

Sodium ferulate (SF) is one of the effective components of Angelica sinensis Diels. Pretreatment with SF (100 mg.kg-1 ig, qd x 10 d) inhibited the activity of serum alanine aminotransferase, prevented the depletion of liver glycogen and glutathione, increased the liver homogenate and microsomal glutathione S-transferase activities, and reduced the malondialdehyde content, the membrane fluidity of liver microsome and the mitochondria in paracetamol (130 mg.kg-1, ip)-induced liver toxicity in mice. These results demonstrated the hepato-protective action of SF in mice.
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PMID:[Sodium ferulate alleviated paracetamol-induced liver toxicity in mice]. 801 94

Inducers of Phase II enzymes, already consumed by humans as food additives, medicines or as constituents of vegetables, can prevent experimental carcinogenesis. Since protection is neither carcinogen- nor organ-specific, clinical trials are already underway to establish the efficacy of 'anticarcinogenic enzyme inducers' (i.e. oltipraz). However, efficient and cost-effective assays to establish the dose wherein a putative anticarcinogen can raise Phase II enzyme levels are lacking. We tested the proposal that serum Phase II enzyme activities would be dependent on relative tissue levels by measuring quinone reductase and glutathione S-transferase activities in sera of mice treated with dietary 2(3)-tert-butyl-4-hydroxyanisole (BHA) or dimethyl fumarate. Serum activities were significantly elevated in animals with increased tissue specific activities of these Phase II enzymes. Increasing concentrations of BHA in the diet from 0.05-0.5% increased hepatic specific activities of both QR and GST from two to six-fold, and increases in serum activities were well correlated to increases observed in the liver (r2 > or = 0.95). There was no evidence for an elevation of serum alanine aminotransferase levels. Thus, in the absence of serological evidence for hepatocellular damage, increased serum Phase II enzyme activities can be correlated to tissue levels. Our results suggest that similar assays tailored to human sera will not only be useful in the execution of chemoprevention trials, but also to assess the role that Phase II enzyme induction plays in the prevention of cancer by fruits and vegetables.
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PMID:Elevation of serum phase II enzymes by anticarcinogenic enzyme inducers: markers for a chemoprotected state? 826 10

Tyrosine aminotransferase purified from epimastigotes of Trypanosoma cruzi displays an additional activity of alanine aminotransferase, absent in all other tyrosine aminotransferases characterized so far. Since the parasite's genome contains a high number of copies of the tyrosine aminotransferase gene, we could not rule out the possibility that two very similar proteins, with changed specificity due to a few amino acid substitutions, might be responsible for the two activities. We have now expressed in Escherichia coli a recombinant tyrosine aminotransferase as a fusion protein with glutathione S-transferase. The purified fusion protein, intact or after thrombin cleavage, displays tyrosine aminotransferase and alanine aminotransferase activities with apparent Km values similar to those for the natural enzyme, thus proving that they belong to the same protein.
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PMID:A recombinant tyrosine aminotransferase from Trypanosoma cruzi has both tyrosine aminotransferase and alanine aminotransferase activities. 856 4

A choline deficient L-amino acid defined (CDAA) diet led to the development of liver cirrhosis in male Wistar rats after 16 weeks. A new prolyl 4-hydroxylase inhibitor, 2,4-pyridine dicarboxylic acid bis [(2-methoxyethyl amide)] (HOE 077), prevented liver fibrosis in a dose-dependent manner without a reduction in increased serum alanine aminotransferase and aspartate aminotransferase in parallel with a reduction in preneoplastic enzyme-altered lesions stained with anti-glutathione S-transferase placental form antibody. HOE 077 reduced the increase in serum procollagen III peptide (PIIIP) in a dose-dependent manner and in proportion to the reduction in mRNA expression of type III procollagen in the liver of rats fed a CDAA diet.
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PMID:New prolyl 4-hydroxylase inhibitor reduces procollagen gene expression and enzyme-altered lesions in rat liver cirrhosis. 858 46

The modulation of CCl4-induced hepatotoxicity in response to alkyl sulfides and alkyl ethers including allyl disulfide (ADS), allyl sulfide (AS), allyl ether (AE), propyl disulfide (PDS), propyl sulfide (PS), propyl ether (PE) and butyl sulfide (BS) was studied. Whereas pretreatment of rats with either ADS or AS (50 mg/kg, 7 days) blocked a CCl4-induced increase in plasma alanine aminotransferase (ALT) activity by 91 and 56%, respectively, AE, PDS, PS, PE or BS treatment enhanced CCl4-induced ALT activity by 52, 55, 238, 25 or 86%, respectively. Histochemical examinations supported the results of plasma ALT activity. Injection of GdCl3 to PS-pretreated rats failed to block the potentiated ALT increase, whereas GdCl3 completely prevented vitamin A-enhanced elevation of ALT activity. AS treatment completely blocked PS-potentiated CCl4 intoxication. Concomitant treatment of animals with both PS and vitamin A followed by a CCl4 insult resulted in super-potentiation of CCl4-induced hepatotoxicity, suggesting that the mechanism of PS-enhanced hepatotoxicity differs from that caused by vitamin A. Pyridine or phenobarbital potentiation of CCl4-induced increases in ALT activity implys that cytochrome P450 2E1 (P450 2E1) and P450 2B expression may be associated with the increased toxicity. P450 2E1 expression appeared to be associated with the alkyl sulfide-modulated hepatotoxicity, as evidenced by both immunoblot analyses and metabolic activity. P450 2B immunoblot analysis revealed that either AS or PS substantially induced hepatic P450 2B1/2 levels. Thus, PS-enhanced CCL4 hepatotoxicity may be related in part with P450 2B induction. ADS, AS or PS treatment caused increases in the glutathione S-transferase (GST) conjugating activity toward 1-chloro-2,4-dinitro-benzene. ADS, AS or PS induced Ya and Yb1 subunits by 2- to 3-fold. ADS or AS treatment also significantly elevated the levels of Yc subunits. PS failed to induce Yc expression, although this agent effectively increased Yb2 expression. Northern blot analyses revealed that ADS and AS concomitantly stimulated GST Ya, Yb1 and Yc2 gene expression, whereas PS increased the levels of Ya, Yb1, and Yb2 mRNA, but not Yc2 mRNA levels. The expression of GST subunit Yc2 in response to these compounds might be associated with hepatoprotective effects. These results demonstrate that ADS and AS have distinct capability of blocking CCl4-induced hepatotoxicity, whereas certain saturated alkyl sulfides rather potentiate CCl4-induced hepatotoxicity and that the underlying mechanism is associated with P450 2E1 and P450 2B expression, and possibly with certain GST expression.
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PMID:Molecular mechanism for alkyl sulfide-modulated carbon tetrachloride-induced hepatotoxicity: the role of cytochrome P450 2E1, P450 2B and glutathione S-transferase expression. 862 17

Hepatic levels of GSH and Phase II detoxication enzymes were compared to biochemical and histological indices of hepatic damage in 4- to 76-week-old nontransgenic mice and their transgenic littermates that overexpress the hepatitis B virus large envelope protein. The mice were fed a low-sucrose AIN-76A diet ad libitum. Hepatic-specific activities of quinone reductase (QR) and glutathione S-transferase (GST) were increased 2- to 10-fold beginning at 12 weeks of age in transgenic mice and correlated with increases in serum alanine aminotransferase (ALT) (r = 0.84 and 0.59, respectively). Quantitative histological analysis demonstrated that apoptosis was the predominant feature in 4- to 12-week-old transgenic mice, whereas necrosis and inflammation predominated at later time points. Surprisingly, 3-fold elevations in ALT were observed beginning at 52 weeks of age in nontransgenic mice, and hepatic-specific activities of QR and GST were also modestly increased in elderly nontransgenic animals. In contrast to transgenic mice, apoptosis was not a prominent feature. The strongest histological correlates to ALT in 4- to 76-week-old nontransgenic mice were necrosis and inflammation (r > 0.96), which in turn may have been evoked by hepatic fat accumulation. Profiles of specific GST isoforms were quantitated chromatographically and identified by sequencing tryptic digests. The Ya1 subunit of alpha-class GST was markedly increased from undetectable levels in transgenic mice, while more modest increases were observed in nontransgenic mice more than 1 year old. Fivefold elevations of the Yb1 subunit, a constitutively expressed mu-class GST, were found in transgenic mice older than 4 weeks of age, while 2-fold increases were observed in nontransgenic animals that were more than 1 year old. These studies demonstrate that selected increases in Phase II detoxication enzymes are a stereotyped response to chronic hepatitis that is strikingly reminiscent of the treatment of mice with anticarcinogenic enzyme inducers.
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PMID:Elevations of hepatic quinone reductase, glutathione, and alpha- and mu-class glutathione S-transferase isoforms in mice with chronic hepatitis: a compensatory response to injury. 866 Jun 89

We found that NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) in rat liver cytosol reduces ubiquinone (UQ) to ubiquinol (UQH2) in lipid membranes and consequently inhibits lipid peroxidation [Takahashi T., et al., Biochem. J., 309, 883-890 (1995)]. Here we examined whether or not this UQH2-regenerating system functions as a cellular antioxidant defense in animals. Rats were given UQ-10 for 2 weeks, and were then exposed to carbon tetrachloride (CCl4). The UQ-10 supplement increased only in the NADPH-UQ reductase and the UQH2-10 pool of rat liver without any appreciable change in the levels of other antioxidant factors. On the other hand, CCl4 markedly increased plasma aspartate aminotransferase and alanine aminotransferase, liver weight and thiobarbituric acid reacting substances formation, which are indicators of CCl4-hepatitis, and it decreased the liver levels of L-ascorbic acid, reduced form of glutathione (GSH), alpha-tocopherol, NADPH-UQ reductase and glutathione S-transferase. However, all the above indicators of CCl4-induced hepatitis were significantly improved in rats given UQ-10. Furthermore, alpha-tocopherol, but neither L-ascorbic acid nor GSH, was significantly saved. UQ-10 supplement also was recovered glutathione S-transferase and NADPH-UQ reductase activities slightly. These results indicated that UQ-10 given to rats increased the cellular UQH2-10 pool and cytosolic NADPH-UQ reductase activity in their livers, resulting in the inhibition of lipid peroxidation in the biomembranes, and consequently protected the rats from the CCl4-hepatotoxicity.
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PMID:Cellular antioxidant defense by a ubiquinol-regenerating system coupled with cytosolic NADPH-dependent ubiquinone reductase: protective effect against carbon tetrachloride-induced hepatotoxicity in the rat. 887 5


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