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)

In previous studies using isolated perfused rat livers, we have shown that reactive oxygen species are involved in hypoxic and ischaemic liver damage. Since albumin was shown to possess strong antioxidant properties we now investigated the capacity of albumin to prevent ischaemic and hypoxic damage in isolated perfused rat livers. Both, partial ischaemia and hypoxia/reoxygenation, resulted in marked hepatic injury as evidenced by an increased release of hepatic enzymes (GPT, LDH), by a strong decline of bile flow and by a decrease in hepatic GSH levels. With partial ischaemia, hepatic ATP depletion and calcium accumulation were also observed. Bovine serum albumin, added to the perfusate at concentrations of 0.1 or 1%, provided nearly complete protection against both types of liver injury. The same level of protection was also afforded by sulfhydryl-blocked and fatty acid-free bovine albumin preparations and by human albumin. In conclusion, the protective effect of albumin in our models of oxidative liver injury is neither due to the thiol moiety nor to the presence of oxidizable fatty acids in the albumin fraction. More likely, albumin provides protection by an unspecific binding of redox-active transition metal ions capable of catalyzing reactions which yield hydroxyl or hydroxyl-like radicals. Besides, unspecific sacrifice reactions of albumin with highly reactive oxygen species or other endogenous compounds may also be implicated.
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PMID:Protection by albumin against ischaemia- and hypoxia-induced hepatic injury. 787 Jun 99

Protective effect of Fengxiang Yigankang (FXYGK) capsule against hepatotoxicity induced by CCl4 and acetaminophen (AAP) was studied. It was found that the FXYGK capsule inhibited markedly malonic aldehyde (MDA) formation of liver induced by CCl4 and AAP. It blocked also depletion of reduced form of glutathione (GSH) of damaged liver induced by AAP. In addition, FXYGK could decrease serum alanine aminotransferase levels induced by CCl4 (P < 0.05). The results of histopathological examination showed that the FXYGK capsule (0.45, 0.9 and 1.8 g/kg) could also reduce significantly fatty degeneration of liver (P < 0.05).
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PMID:[Protection against experimental hepatic injury by fengxiang yigankang capsule]. 795 Jan 88

Chemical activation of Kupffer cells in vivo by vitamin A or latex beads is associated with a worsening of hepatic injury induced by the P450-dependent hepatotoxins acetaminophen (ACET) and carbon tetrachloride (CCl4) and by the P450-independent toxin galactosamine (GLN). Immunostimulants such as Corynebacterium parvum (CP) also activate Kupffer cells, but do so while prompting release of soluble mediators which depress microsomal oxidative activities in cultured hepatocytes. Therefore, we sought to characterize the effects of CP on hepatic injury in vivo due to ACET and CCl4 while employing GLN as a control. Hepatic microsomal oxidative activity and glutathione (GSH) disposition were examined since each influences susceptibility to injury from ACET or CCl4. Rats were given CP 28 mg/kg i.v. 5 days before challenge with hepatotoxicant. Hepatic injury was assessed 24 hr after hepatotoxicant administration by measurement of serum alanine aminotransferase (ALT) activity and review of histological sections. Livers from parallel groups of rats were used to prepare microsomal and cytosolic fractions, to measure tissue GSH, or for perfusion to assess GSH efflux. Significant reductions in injury due to ACET or CCl4 were observed while injury due to GLN was potentiated. Serum ALT levels after ACET were 3000 +/- 620 in controls vs 170 +/- 45 IU/liter in the CP-treated group and ALT levels after CCl4 were 3100 +/- 500 in controls vs 1700 + 450 IU/liter in the CP-treated group. In contrast, serum ALT levels after GLN were 920 +/- 230 in controls vs 1700 +/- 370 in the CP-treated group. Patterns of hepatic injury observed on histological sections were those characteristic for each toxin and the severity of injury correlated well with alterations in serum ALT levels for each agent. Hepatic microsomal fractions from rats pretreated with CP showed significantly diminished total cytochrome P450 content as well as reduced activity for two P450IIE1 substrates, p-nitrophenol and 7-ethoxycoumarin. While sinusoidal efflux of GSH increased by 40% in rats pretreated with CP and cytosolic glutathione-S-transferase activity fell slightly, tissue GSH levels were unaffected. These data demonstrate that CP decreases microsomal cytochrome P450 content, reduces biotransformation of two P450IIE1 substrates, and diminishes ACET- and CCl4-induced hepatic injury. In contrast, hepatic injury due to the P450-independent toxin GLN was enhanced. Thus, chemical and immune stimulation of Kupffer cells may result in divergent effects on susceptibility to injury from individual hepatotoxins.
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PMID:Kupffer cell stimulation with Corynebacterium parvum reduces some cytochrome P450-dependent activities and diminishes acetaminophen and carbon tetrachloride-induced liver injury in the rat. 797 94

The changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the plasma as well as in the liver were investigated in rats with endotoxin hepatitis. Hepatitis was induced by intraperitoneal co-administration of small doses of Escherichia coli endotoxin and D-galactosamine. In the liver, the concentration of GSH decreased and that of GSSG increased 12 hr later. In the plasma taken from the right atrium, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased, as it did in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic, suprarenal inferior vena cava from those of the suprahepatic inferior vena cava. The efflux started to increase as early as 2-4 hr after the injection of the toxins. In contrast, a leakage of alanine aminotransferase, an elongation of prothrombin time, an inhibition of starvation ketosis, and an increase in serum concentration of total bilirubin were detected as late as 6-8 hr after the injection. We conclude that endotoxin/D-galactosamine hepatitis induced an increase in plasma concentrations of GSH as well as GSSG by increasing the efflux of these peptides from the liver, and that changes in plasma glutathione status might be useful and sensitive markers for liver damage.
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PMID:Increased sinusoidal efflux of reduced and oxidized glutathione in rats with endotoxin/D-galactosamine hepatitis. 802 75

To elucidate the significance of the changes in plasma glutathione concentrations associated with carbon tetrachloride (CCl4)-induced liver damage, the changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in plasma as well as in the liver were investigated in rats. In the liver, the concentration of GSH decreased, and that of GSSG increased 24 hr after the intraperitoneal administration of CCl4. In the right atrial plasma, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased as did that in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic inferior vena cava from those of the suprahepatic inferior vena cava. The net efflux of GSH and GSSG started to increase as early as 3-6 hr after CCl4 administration, and reached a plateau 6 and 24 hr after CCl4 administration, respectively. On the other hand, an elongation of prothrombin time and leakage of alanine aminotransferase reached a maximum 24 and 48 hr after CCl4 administration, respectively. Vacuolization in the centri-lobular region and inflammatory infiltration started 3 and 6 hr after CCl4 administration, respectively, and progressed for 48 hr. These results suggest that CCl4 induced an increase in plasma concentrations of GSH as well as GSSG by increasing their efflux from the liver, and that the changes in plasma glutathione status might be a useful and sensitive marker for CCl4-induced liver damage.
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PMID:Carbon tetrachloride increases sinusoidal efflux of reduced and oxidized glutathione in rats. 811 11

The hepatoprotective effects of misoprostol on acetaminophen (APAP)-induced toxicity were studied in the rat. Liver injury was evaluated at 36 hr after APAP administration by measuring serum ornithine carbamoyltransferase (OCT) and alanine aminotransferase (ALT) levels, by using tetranitroblue tetrazolium (TNBT) staining and by histological analysis. After APAP administration, peak serum levels of the drug were detected at 15 min. Liver GSH was depleted from control levels of 448 +/- 48 micrograms/g to 82 +/- 2 micrograms/g (P < 0.01) within 3 hr. Serum ALT levels increased significantly after 16 hr and H&E staining revealed significant hepatic necrosis after 12 hr. Rats treated with misoprostol before and after APAP administration showed reduced OCT and ALT levels at 36 hr of overdose (454 +/- 446 IU/liter and 2571 +/- 2944 IU/liter, respectively) compared to those without misoprostol treatment (1348 +/- 480 IU/liter and 6077 +/- 3025 IU/liter, respectively, P < 0.01). TNBT staining showed a reduced area of damage from 28.6 +/- 22.3% to 7.3 +/- 8.9% (P < 0.01), and H&E staining also showed less extensive hepatic necrosis in rats treated with misoprostol before and after the overdose. In a time sequence study, misoprostol treatment starting within 10 hr of overdose showed the same protective effect as when it was given before and after APAP ingestion. No protection was detected when the treatment was started during the development of hepatic injury. However, misoprostol given when injury was established seemed to be protective. Our results show that misoprostol protects the liver against APAP-induced injury if given within 10 hr of overdose.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Misoprostol protection against acetaminophen-induced hepatotoxicity in the rat. 820 Feb 57

Piperine, an active alkaloidal constituent of the extract obtained from Piper longum and Piper nigrum, was evaluated for its antihepatotoxic potential in order to validate its use in traditional therapeutic formulations. This plant principle exerted a significant protection against tert-butyl hydroperoxide and carbon tetrachloride hepatotoxicity by reducing both in vitro and in vivo lipid peroxidation, enzymatic leakage of GPT and AP, and by preventing the depletion of GSH and total thiols in the intoxicated mice. Silymarin, a known hepatoprotective drug was tested simultaneously for comparison. Piperine showed a lower hepatoprotective potency than silymarin.
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PMID:Evaluation of the liver protective potential of piperine, an active principle of black and long peppers. 825 33

A substantial fraction of the cysteine added to total parenteral nutrition (TPN) solutions is converted to the corresponding thiazolidine derivative, while in solution with relatively large concentrations of glucose typical of TPN (700 mM and higher). It was recently reported (Roberts et al. (1987) J. Med. Chem. 30, 1891-1896) that this thiazolidine, D-glucose-L-cysteine (DGC), offered no significant protection against the hepatic injury caused by 5 mmol/kg of acetaminophen in mice, suggesting that the cysteine present as DGC is poorly bioavailable in vivo. In the present study, fasted male ICR mice given 1.6 or 2.6 mmol/kg of acetaminophen sustained hepatic injury, estimated by elevations in plasma alanine aminotransferase (ALT) activities. Administration of 2.5 mmol/kg of N-acetylcysteine (NAC) 1 h before acetaminophen given i.p. prevented the rise in plasma ALT activities, apparently through support of glutathione (GSH) synthesis. Administration of 2.5 mmol/kg of DGC prior to acetaminophen resulted in slightly lower mean plasma ALT activities than were observed in animals given saline before acetaminophen, but the effect was not statistically significant. When DGC was given 1 h before p.o. administration of 1.6 or 2.6 mmol/kg of acetaminophen, the protective effects of DGC were statistically significant (P < 0.01, 0.025, respectively), although NAC afforded significantly greater protection than did DGC at the higher dose of acetaminophen. Given 4 h before acetaminophen, DGC attenuated acetaminophen-induced increases in plasma ALT activities significantly, whereas NAC was without effect. These results indicate that the cysteine in DGC is at least partially bioavailable in vivo and, further, that DGC may function as a slow release formulation of cysteine.
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PMID:Attenuation of acetaminophen hepatotoxicity in mice as evidence for the bioavailability of the cysteine in D-glucose-L-cysteine in vivo. 831 Apr 51

Chloroform (CHCl3) is widely used in the manufacture of drugs, cosmetics, plastics and cleaning agents. It is also found in chlorinated drinking water. This study was designed to investigate the toxic effect of CHCl3 on isolated male rat hepatocytes using several toxicity parameters. The hepatocytes were isolated by a collagenase perfusion technique and the cell viability was determined by Trypan blue exclusion. The leakage of cytosolic enzymes such as aspartate transaminase (AST) and alanine transaminase (ALT) after treatment with CHCl3 was measured. Reduced glutathione content (GSH) and its related enzymes, glutathione reductase (GSH-Rx) and glutathione peroxidase (GSH-Px), were also evaluated to study the effect of CHCl3 on hepatocytes. Exposure to 100 and 1000 ppm CHCl3 results in a significant decrease in cell after 30 min incubation. However, the effect of 1 and 10 ppm concentrations was observed at 60 min incubation. AST leakage was significantly increased in all treatment groups, while ALT was significantly increased at 100 and 1000 ppm CHCl3 after 60 and 30 min, respectively. As early as 15 min, GSH was decreased significantly at 1000 ppm, but at 100 and 10 ppm CHCl3 the decrease in GSH began after 30 and 120 min, respectively. GSH-Px activity did not changed. However, the activity of GSH-Rx was significantly decreased at 1000 ppm CHCl3 and at the same time GSH content was decreased. The data indicate that the toxic effect of CHCl3 was dose- and time-dependent. The degree of GSH depletion correlated with increased cytotoxicity and decreased GSH-Rx activity due to CHCl3.
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PMID:The mechanism of chloroform toxicity in isolated rat hepatocytes. 835 69

Mercury is the major component of dental amalgam restorative material, which typically has 50% pure elemental mercury. It is also used in some skin creams, and in the manufacturing of plastic, drugs and fungicides. The present study was designed to investigate the toxicity of methyl mercury (MeHg+) on isolated rat hepatocytes using several toxicity parameters. The hepatocytes were isolated by a collagenase perfusion technique and were incubated with different concentrations of MeHg+ (0.1-100 ppm) for 2 h. Through the incubation period the viability was determined by Trypan blue exclusion. Reduced glutathione (GSH) content and its enzymes, glutathione peroxidase (GSH-PX) and glutathione reductase (GSH-RX) were measured. Leakage of enzymes such as aspartate transaminase (AST), and alanine transaminase (ALT) were determined. The cell viability was reduced significantly after 1 h incubation when 0.1 and 1 ppm MeHg+ were applied. The decrease in the cell viability was dose- and time-dependent. A depletion of GSH content was observed with 100 ppm MeHg+ after 30 min of incubation. A significant decrease in GSH-RX was observed with 100 ppm during 15 and 30 min of incubation, while 10 ppm of MeHg+ significantly increased ALT leakage after 60 min. However, there was a significant increase in AST leakage with 100 ppm only. The present investigation indicates that the toxic effect of MeHg+ is most likely cytosolic enzyme related.
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PMID:The mechanism of methyl mercury toxicity in isolated rat hepatocytes. 835 70


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