Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New biologically active compounds (BAC) created on the basis of nicotinic acid possess hepatoprotective action. The preparations were introduced preventively in doses of 10 mg/kg during 14 days. Litonit and nicogamol increased survival of experimental animals by 36.8% and nicotinic acid by 26.8%. ALT, AST, GGT activity in the blood serum was reduced. The activity of the main antioxidant enzymes (SOD and catalase) grew in the rat liver tissue in parallel with inhibition of DK and MDA activity. Morphological picture of the rat liver, most evident after application of litonit improved. Hepatoprotective action of these BAC are attributed to their membrano stabilizing effects.
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PMID:[Mechanisms of hepatoprotective action of new nicotinic acid derivatives in experimental CCL4-induced liver injury]. 142 11

Fed and fasted rats were injected with L-tryptophan (12.5 mg/100 g body weight) and the specific activities of L-glutamic: NAD oxidoreductase (deaminating) (EC 1.4.1.2) (GDH), L-aspartic-2-ketoglutaric aminotransferase (EC 2.6.1.1) (GOT) and L-alanine-2-ketoglutaric aminotransferase (EC 2.6.1.2) (GPT) from hepatic mitochondria and cytosol were compared. L-tryptophan results in a decrease of mitochondrial GDH activity by 22% and of cytosolic GPT and GOT by 42% and 38% respectively in the liver of fasted rats. Xanthurenate is a potent inhibitor of purified extramitochondrial GPT, whereas anthranilate and quinolinate are less potent inhibitors. L-tryptophan, 5-OH-tryptophan and indole exert a slight inhibition. Kynurenine, 5-OH-tryptamine, tryptamine, picolinic acid, nicotinic acid and indoloacetic acid do not show any inhibition of GPT. It is suggested that L-tryptophan injection inhibits extramitochondrial GPT by its transformation to xanthurenate and anthranilate.
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PMID:Effect of L-tryptophan injection in rats on some enzymes of amino acid metabolism in liver. I. In vitro studies of the effect of L-tryptophan and its metabolites on the extramitochondrial L-alanine: 2-ketoglutaric aminotransferase. 722 74

The author carried out a dynamic study on the metabolic changes in liver under the influence of nicotinic acid, administered singly by intramuscular injection in a dose of 2mM/kg of body weight. She examined at the 1th, 3th, 6th and 24th hour the changes in the levels of nicotine-amide coenzymes (NAD, NAD-H and NADP), adenine nucleotides (ATP, ADP and AMP), the metabolic lactate and pyruvate and the enzymes LDH, MDH, GOT and GPT. The obtained data were compared with those of the control groups, treated with saline and killed at the same intervals as the experimental animals. Furthermore she made also a comparison with an intact group, presented as O group, whose values served as basal. The obtained data showed that after application of the nicotinic acid (NA) complex metabolic changes occurred in liver, due to its basic effects-stimulation of biosynthesis of nicotinamide coenzymes and inhibition of lipolysis in the fatty tissue. Most probably the effect on the biosynthesis of NAD was primary, which showed later substantial regulatory influence both on lipolysis in the fatty acid and on the metabolization of mobilizing lipids on behalf of the liver. Parallel occurring metabolic processes in the aorta and in the vascular wall in general, stimulation of the biological oxidation and bioenergetics formed the whole antilipolytic and antiarteriogenic action of nicotinic acid.
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PMID:[Metabolic changes in the liver as affected by nicotinic acid]. 730 22

1. The effects of racemic thalidomide (D[+]/L[-] alpha-phthalimido-glutarimide) on acetaminophen (AAP)-induced hepatitis were tested in male NMRI mice (n = 133) and quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). 2. A 2.1-fold increase of GOT and a 1.9-fold increase of GPT activities (P < 0.001) were observed in mice treated perorally with 500 mg/kg of AAP plus 150 mg/kg of thalidomide (Thal). In the absence of AAP, Thal did not display any detectable hepatotoxic effects. 3. The Thal-induced exacerbation of AAP hepatotoxicity was completely inhibited by nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP) (P < 0.0001), suggesting a possible influence of Thal on the hepatic metabolism of NAD-adenoribosylation. 4. We see the main application of nicotinic acid amide as for the combinational use in pharmaceutical preparations of AAP in order to avoid hepatic damage in patients treated with AAP and Thal.
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PMID:Exacerbation of acetaminophen hepatotoxicity by thalidomide and protection by nicotinic acid amide. 759 Jan 13

In a comparative study, 158 patients with type IIa or IIb primary hypercholesterolemia received either placebo, nicotinic acid extended-release capsules (0.5 to 1.0 g twice daily), pravastatin (40 mg at bedtime), or the combination for a short-term, 8-week period. A long-term, 88-week phase followed in which the addition of other lipid-lowering agents was permitted. During the short-term phase, low-density lipoprotein cholesterol levels were lower, in relation to baseline, with nicotinic acid treatment (-21%) than with placebo (P < or = 0.05), with pravastatin (-33%) than with either placebo (p < or = 0.001) or nicotinic acid (p < or = 0.05) and with combination therapy (-49%) than with the other 3 treatments (p < or = 0.05) at all weeks measured. At week 8, high-density lipoprotein cholesterol levels were increased, in relation to placebo, by nicotinic acid treatment (12%; p < or = 0.05), pravastatin therapy (13%; p < or = 0.01) and combination therapy (16%; p < or = 0.01). Adverse events were less frequent in the pravastatin and placebo groups (p < or = 0.05). In comparison with placebo, treatment with nicotinic acid resulted in significant increases in aspartate and alanine aminotransferase. The placebo and pravastatin groups did not differ significantly regarding adverse events or laboratory parameters. Similar results were observed in the long-term phase. Therefore, pravastatin is very effective and well tolerated in the treatment of type IIa or IIb primary hypercholesterolemia, and is superior to nicotinic acid in both efficacy and adverse event profile.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemia. 810 47

Recently, we demonstrated the hepatoprotective effects of nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) on mice suffering from acetaminophen (AAP)-hepatitis, suggesting that the AAP-induced liver injury involves a step which depends on adenoribosylation. The present study investigates the effects of a diet free of precursors of NAD, the substrate on which PARP acts, in female NMRI mice with AAP hepatitis and evaluates the influence of simultaneous ethanol consumption in these animals. Liver injuries were quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). While AAP caused a 117-fold elevation of serum transaminase activities in mice kept on a standard laboratory diet, which was significantly exacerbated by ethanol and inhibited by nicotinic acid amide (NAA), adverse effects were noted in animals fed a diet free of precursors of NAD. In these animals, only minor increases of serum transaminase activities were measured in the presence of AAP, and unlike the exacerbation caused by ethanol in mice on a standard diet, the liver damage was inhibited by 50% by ethanol. A further 64% reduction of hepatitis was observed, when NAA was given to ethanol/AAP-mice. Our results provide evidence that the AAP-induced hepatitis and its exacerbation by ethanol can either be reduced by end-product inhibition of PARP by NAA or by dietary depletion of the enzyme's substrate NAD. We see the main application of NAA as for the combinational use in pharmaceutical preparations of acetaminophen in order to avoid hepatic damage in patients treated with this widely used analgesic.
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PMID:Influence of diet free of NAD-precursors on acetaminophen hepatotoxicity in mice. 874 98

An array of therapeutically used analgetic and antirheumatic drugs causes severe liver damage. The present study investigates the hepatoprotective effects of inhibitors of NAD-dependent adenoribosylation reactions in analgesics-induced hepatic injury. Male NMRI mice were treated perorally with 500 mg/kg of acetaminophen, and the activities of both glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) were determined in serum. In addition, the activity of poly(ADP-ribose)polymerase (PARP) was quantified in liver cell nuclei. While the PARP-activity remained essentially unchanged, the acetaminophen-induced release of both GOT and GPT from injured liver cells could be inhibited by 90-99%, when mice were injected additionally with the selective PARP-inhibitors nicotinic acid amide, benzamide, caffeine, theophyline, and thymidine, respectively. We see the main application of inhibitors of adenoribosylation reactions as for the combinational use in pharmaceutical preparations of analgesics and antirheumatic drugs in order to avoid hepatic damage.
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PMID:The influence of antagonists of poly(ADP-ribose) metabolism on acetaminophen hepatotoxicity. 874 16

1 Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA, which are caused by reactive oxygen species (ROS). Here we investigate the effects of the PARS inhibitors 3-aminobenzamide (3-AB), nicotinamide and 1,5-dihydroxyisoquinoline (ISO) on the circulatory failure and the organ injury/dysfunction caused by haemorrhage and resuscitation in the anaesthetized rat. 2 Haemorrhage (sufficient to lower mean arterial blood pressure to 50 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure to 66+/-4 mmHg (control, n=13). This circulatory failure was not affected by administration (5 min prior to resuscitation) of 3-AB (10 mg kg-1 i.v., n=7), nicotinamide (10 mg kg-1 i.v., n=6) or ISO (3 mg kg-1 i.v., n=6). 3 Haemorrhage and resuscitation also resulted in rises in the serum levels of urea and creatinine. This renal dysfunction was attenuated by 3-AB and nicotinamide, but not by nicotinic acid (n=7), an inactive analogue of nicotinamide. Although ISO (n=6) also attenuated the renal dysfunction caused by haemorrhage and resuscitation, its vehicle (10% DMSO, n=4) had the same effect. 4 Haemorrhagic shock resulted in enhanced serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lipase, indicating the development of hepatocellular and pancreatic injury, respectively. Similarly, haemorrhagic shock also resulted in an increase in the serum levels of creatine kinase (CK) indicating the development of neuromuscular injury. This was attenuated by 3-AB and nicotinamide, but not by nicotinic acid. Although ISO also attenuated the liver, pancreatic and neuromuscular injury caused by haemorrhagic shock, its vehicle had the same effect. 5 Thus, activation of PARS contributes to the organ injury and dysfunction caused by haemorrhage and resuscitation in the rat.
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PMID:Effects of inhibitors of the activity of poly (ADP-ribose) synthetase on the organ injury and dysfunction caused by haemorrhagic shock. 1057 50

In clinical trials, all lipid-lowering agents have been associated with mild, asymptomatic elevations of alanine aminotransferase (ALT) and asparate aminotransferase enzymes. This, along with the fact that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are hepatotoxic in some animals, led the US Food and Drug Administration (FDA) to recommend monitoring of liver enzymes for all lipid-lowering agents, except the bile acid sequestrants. Because the drugs act by different mechanisms, ALT elevations may be a pharmacodynamic effect related to lipid lowering, rather than a direct effect of the drug. Animal studies support this assumption. ALT elevations of 3 times the upper limit of normal occur in <3% of patients in clinical trials of lipid-lowering drugs. The elevations are transient and often dose-related, and they usually revert to normal while continuing therapy and have never been associated with hepatotoxicity. Confounding factors include alcohol, acetaminophen, and pre-existing liver disease, such as chronic hepatitis C and type II diabetes with fatty liver, which are both associated with mild, intermittent elevations of ALT. The more important issue is whether or not lipid-lowering agents are hepatotoxic. There are case reports of hepatotoxicity (cholestasis, jaundice, hepatitis, chronic active hepatitis, fatty liver, cirrhosis and acute liver failure) with all of the drugs, except cholestyramine. To date there are just 5 cases of documented liver failure linked to lovastatin. There is no evidence that monitoring reduces the rate of hepatotoxicity. Mild elevations of ALT that occur with many drugs, including HMG-CoA reductase inhibitors, do not predict hepatotoxicity. Liver enzyme elevations appear to be a class characteristic of lipid-lowering agents. Hepatotoxicity is a rare idiosyncratic reaction, occurring only with sustained released nicotinic acid.
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PMID:Defining patient risks from expanded preventive therapies. 1085 89

From the leaves of Viburnum tinus L. (Adoxaceae) two acylated iridoid glucosides (viburtinoside A and B), a coumarin diglucoside scopoletin 7-O-beta-D-sophoroside and a natural occurred dinicotinic acid ester 2,6-di-C-methyl-nicotinic acid 3,5-diethyl ester were isolated. In addition to these, 10 known compounds were isolated, namely two bidesmosidic saponins, a hexamethoxy-flavone and five flavonol glycosides, as well as suspensolide A and oleanolic acid were isolated for the first time in this genus and species, respectively. The structures were determined mainly by spectroscopic methods (UV, IR, ESI-MS, 1H-, 13C NMR and DEPT). Toxicity of the investigated extract was determined (LD50=500 mg/kg). CCl4-induced hepatotoxicity has been evaluated in terms of the determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lipid peroxide and nitric oxide levels in serum and compared using adult male rats weighing 150-180 g. Their highly elevated levels were significantly reduced by treatment with the investigated aqueous methanol extract in dose-dependent manner.
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PMID:Phytochemical constituents and hepatoprotective activity of Viburnum tinus. 1630 55


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