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)

Recent evidence suggests that macrophages and/or other nonparenchymal cells may release important mediators contributing to the hepatic necrosis induced by high doses of acetaminophen (APAP). The nature and causative role of these mediators has remained elusive, however. To investigate the role of the proinflammatory cytokine, tumor necrosis factor (TNF) in the initiation and early propagation of APAP-induced liver injury, we have used mice deficient in both TNF and the closely related lymphotoxin-alpha (LT-alpha). Male TNF/LT-alpha knockout mice and C57BL/6 wild-type mice were treated with a hepatotoxic dose of APAP (400 mg/kg, intraperitoneally), and the development of liver injury was monitored over 8 hours. Both genotypes exhibited similar basal activities of hepatic cytochrome P450 2E1 and 1A2. After APAP administration, both the rate of glutathione consumption and the extent of subsequent selective protein binding did not differ significantly in the knockout and wild-type mice. The TNF/LT-alpha-deficient mice developed severe centrilobular necrosis and exhibited highly increased levels of serum alanine aminotransferase and aspartate aminotransferase, the extent of which was not significantly different from that in wild-type mice. In C57BL/6 mice exposed to APAP, no increases in hepatic transcripts of TNF or LT-alpha were found by reverse transcription-polymerase chain reaction, nor was immunoreactive serum TNF detected by enzyme-linked immunosorbent assay over 8 hours posttreatment. These data indicate that, in the absence of the genes encoding for TNF and LT-alpha, APAP bioactivation was not altered and mice still developed severe hepatic necrosis. Thus, TNF is unlikely to be a key mediator in the early pathogenesis of APAP-induced hepatotoxicity.
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PMID:Acetaminophen hepatotoxicity in tumor necrosis factor/lymphotoxin-alpha gene knockout mice. 953 42

The potential of protopine to inhibit microsomal drug metabolising enzymes (MDM E) and prevent paracetamol- and CCl4-induced hepatotoxicity was studied in rats. Paracetamol at the dose of 640 mg kg-1 produced hepatic damage in rats as manifested by the rise in serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) to 972+/-186 and 624+/-131 IU (mean+/-sem; n=10), respectively, compared to respective control values of 101+/-29 and 64+/-18 IU. Pretreatment of rats with protopine (11 mg kg-1, orally twice daily for 2 days) lowered significantly the respective serum AST and ALT levels (P<0.05) to 289+/-52 and 178+/-43 IU. The hepatotoxic dose of CCl4 (1.5 ml kg-1; orally) raised serum AST and ALT levels to 543+/-89 and 387+/-69 IU (mean+/-sem; n=10), respectively, compared to respective control values of 98+/-28 and 56+/-17 IU. The same dose of protopine (11 mg kg-1) was able to prevent significantly (P<0.05), the CCl4-induced rise in serum enzymes and the estimated values of AST and ALT were 168+/-36 and 93+/-28 IU, respectively. Protopine caused prolongation (P<0.05) in pentobarbital (55 mg kg-1)-induced sleep as well as potentiated strychnine-induced toxicity in rats, suggestive of an inhibitory effect on MDME. These results indicate that protopine exhibits anti-hepatotoxic action which may be mediated through inhibition of MDME.
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PMID:An assessment of the potential of protopine to inhibit microsomal drug metabolising enzymes and prevent chemical-induced hepatotoxicity in rodents. 978 72

The hepatoprotective effect of DA-9601, a quality-controlled extract of Artemisia asiatica, on liver damage induced by acetaminophen (APAP) and carbon tetrachloride (CCl4) was investigated by means of serum-biochemical, hepatic-biochemical, and histopathological examinations. Doses of DA-9601 (10, 30, or 100 mg/kg) were administered intragastrically to each rat on three consecutive days i.e. 48 h, 24 h and 2 h before a single administration of APAP (640 mg/kg, i.p.) or CCl4 (2 ml/kg, p.o.). Four h and 24 h after hepatotoxin treatment, the animals were sacrificed for evaluation of liver damage. Pretreatment of DA-9601 reduced the elevation of serum ALT, AST, LDH and histopathological changes such as centrilobular necrosis, vacuolar degeneration and inflammatory cell infiltration dose-dependently. DA-9601 also prevented APAP- and CCl4-induced hepatic glutathione (GSH) depletion and CCl4-induced increase of hepatic malondialdehyde (MDA), a parameter of lipid peroxidation, in a dose-dependent manner. These findings suggest that pretreatment with DA-9601 may reduce chemically induced liver injury by complex mechanisms which involve prevention of lipid peroxidation and preservation of hepatic GSH.
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PMID:Studies on protective effect of DA-9601, Artemisia asiatica extract, on acetaminophen- and CCl4-induced liver damage in rats. 987 86

The aim of the paper is to present a case of self-poisoning with paracetamol, overdosed just before a delivery. A 21-year-old woman was admitted to Obstetric and Gynecology Ward of local hospital in the second stage of physiological delivery, more than 6 hours after she had ingested 19 g of acetaminophen for self-poisoning. She delivered a normal infant weighing 3520 g who had Apgar scores of 10, and then both infant and mother were sent in an emergency ambulance to the nearest poison centre. Blood samples for toxicological examination were taken on admission to toxicological intensive care unit i.e. 11 hours post maternal ingestion. Acetaminophen levels of both patients were above the acetaminophen overdose nomogram line and the antidote treatment, i.v. N-acetylcysteine was administered according to the protocol: the mother within 11 hours post-ingestion and approximately 4 hours after a delivery; the neonate within 11 hours post maternal ingestion and 4 hours of life. Higher paracetamol concentration in the blood of infant compared to the mother's was noted in the first and then control toxicological examination performed within 35 hours post maternal ingestion. Peak maternal aspartate aminotransferase (AST) activity was 326 U/L within 35 hours and alanine aminotransferase (ALT) activity was 262 U/L within 56 hours post-ingestion. The highest neonatal enzyme activity was noted within 11 hours post maternal ingestion of paracetamol, and the elevation was not high. Except moderate anaemia in the mother, no clinical or biochemical symptoms of renal, cardiovascular or CNS injury were stated in the mother or infant. Normalisation in the maternal enzymes activity was stated within 226 hours, while in the neonatal within 58 hours post maternal ingestion. The woman recovered without sequelae and was discharged from hospital on the 11th day following paracetamol overdosing. No evidence of the liver injury was found in the infant either.
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PMID:Suicidal paracetamol poisoning of a pregnant woman just before a delivery. 1046 99

Paracetamol-induced hepatic necrosis is the most common form of toxic liver injury experienced in clinical practice in the UK and USA. Recently, reports have described prevention of hepatic necrosis, induced by other hepato-toxins, by inhibiting tumour necrosis factor alpha (TNFalpha). The aim of the present study was to determine the role of TNFalpha in paracetamol-induced hepatic necrosis. Six-week-old CBA/J female mice were given 300 mg/kg paracetamol by intraperitoneal (IP) injection after an 8-h fast. Hepatic expression of TNFalpha was measured by enzyme-linked immunoassay (ELISA) and reverse transcriptase-polymerase chain reaction (RT-PCR). Serum TNFalpha was measured by ELISA. One hour prior to paracetamol injection, mice were also given blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, interleukin 10 (IL-10), and dexamethasone. Hepatic injury was measured by serum aspartate aminotransferase and histological assessment on haematoxylin and eosin (H&E)-stained liver sections. There was a significant increase in serum TNFalpha at 6 h (control 0.002+/-0.002 ng/ml, n=7; paracetamol-treated 0.022+/-0.007 ng/ml, n=5, p<0.05), but hepatic TNFalpha expression did not change up to 24 h following paracetamol injection. Histologically severe centrilobular hepatic necrosis was noted at 3 h and progressed for 24 h after paracetamol poisoning. Death rate, serum aspartate aminotransferase, and hepatic histology were not significantly different between the groups treated with blocking anti-TNFalpha antibodies, soluble TNFalpha receptor, IL-10, and dexamethasone, compared with controls. In conclusion, there is no evidence to suggest that modulation of TNFalpha expression affects hepatic injury following experimental paracetamol poisoning; anti-TNFalpha therapies are therefore unlikely to be effective in the corresponding clinical situation.
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PMID:Inhibition of tumour necrosis factor alpha does not prevent experimental paracetamol-induced hepatic necrosis. 1070

The effect of aqueous leaf extract of Azadirachta indica (A. indica) was evaluated in paracetamol induced hepatotoxicity in rats. Liver necrosis was produced by administering single dose of paracetamol (2 g/kg, p.o.). The liver damage was evidenced by elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (gamma-GT) and by histopathological observations of liver sections. Aqueous A. indica leaf extract (500 mg/kg, p.o.) significantly (P < 0.01) reduced these elevated levels of AST, ALT and gamma-GT. Paracetamol induced liver necrosis was also found to be reduced as observed macroscopically and histologically.
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PMID:Effect of Azadirachta indica (Neem) leaf aqueous extract on paracetamol-induced liver damage in rats. 1091 97

Acetaminophen is a widely used nonprescription analgesic and antipyretic agent. It is also a dose-related hepatotoxin that can cause fulminant liver failure when taken in massive overdoses or, much less commonly, at therapeutic doses in susceptible individuals. Persons who regularly consume alcohol or persons who have been fasting may be more susceptible to this hepatotoxicity. This liver injury is due not to the drug itself but to the formation of the toxic metabolite N-acetyl-p-benzoquinine imine generated through the cytochrome P-450 drug-metabolizing system. Normally, hepatic stores of glutathione combine with the toxic metabolite and prevent liver cell injury. When glutathione stores are depleted by overproduction of this metabolite, however, the reactive metabolite binds to liver cell proteins and causes hepatic necrosis. P-450 2E1 is induced by alcohol consumption and possibly starvation, and glutathione depletion can occur due to the inadequate nutrition occurring in chronic alcohol use or in starvation. Recent studies have shown that activated Kupffer cells and their secreted toxic agents such as cytokines may also play a role in this liver injury. This liver injury is characterized by extremely high levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (> 1000), and bad prognostic signs include severe prolongation of the prothrombin time, renal dysfunction, and, most importantly, acidosis. N-acetylcysteine is a highly effective antidote when given early (within 15 hours) of overdose. Some patients may develop such fulminant liver injury that they require transplantation. Unfortunately, many such patients have a course so rapid that a donor liver may not become available in time. Thus, both the medical community and the general public require a heightened understanding of this clinical problem in order to initiate prevention measures and to implement early therapeutic measures if an overdose situation occurs.
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PMID:Acetaminophen hepatotoxicity: An update. 1098 Sep 26

Paracetamol (5 mmol kg(-1), i.p.) caused liver damage in rats as indicated by increased plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and glutamate dehydrogenase (GDH) activities. No change in plasma bilirubin or creatinine was noted. An equimolar dose of nitroparacetamol (a nitric oxide (NO)-releasing derivative of paracetamol) did not alter plasma levels of any of the markers of liver/kidney damage. No difference in plasma or liver paracetamol was apparent in animals injected with paracetamol or nitroparacetamol. These results indicate that NO released from nitroparacetamol exhibits hepatoprotective activity in these animals and suggest that nitroparacetamol may therefore be considered as a safer alternative to paracetamol in the clinic.
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PMID:A comparison of the effect of nitroparacetamol and paracetamol on liver injury. 1115 55

The hepatoprotective activity of the aqueous-methanolic extract of Ambrosia maritima was investigated against acetaminophen (paracetamol, 4-hydroxy acetanilide) induced hepatic damage. Acetaminophen at the dose of 640 mg/kg produced liver damage in rats as manifested by the significant (P < 0.001) rise in serum levels of glutamate oxaloacetate transaminase (AST), glutamate pyruvate transaminase (ALT) and alkaline phosphatase (ALP) to 1178.5 +/-118.05; 607.5 +/- 32.6 and 274.16 +/- 8.89 IU/l (n = 10), respectively, compared with respective control values of 97.83+/-3.23; 46.0 +/- 3.92 and 168.67 +/- 7.86 IU/l. Pretreatment of rats with the plant extract (100 and 200 mg/kg) lowered significantly (P < 0.001) the respective serum AST to 203.3+/-5.74 and 157.1 +/- 8.78 IU/l, ALT to 138.67 +/- 7.7 and 87.5 +/- 3.6 IU/l and ALP levels to 238.0 +/- 5.89 and 206.5 +/- 7.5 IU/l, respectively. Treatment of rats with acetaminophen led to a marked increase in lipid peroxidation as measured by malondialdehyde (MDA) (42%). This was associated with a significant reduction of the hepatic antioxidant system e.g. reduced glutathione (GSH) (65%), glutathione reductase (GSH-R) (35%), total glutathione peroxidase (GSH-Px) (32%) and glutathione-S-transferase (GST) (16%). These biochemical alterations resulting from acetaminophen administration were inhibited by pretreatment with A. maritima L. extract. These data suggest that the plant A. maritima L. may act as a hepatoprotective and antioxidant agent.
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PMID:Evaluation of the protective potential of Ambrosia maritima extract on acetaminophen-induced liver damage. 1129 46

Acetaminophen overdose causes acute liver injury in both humans and animals. This study was designed to investigate the potential role of the conditionally essential amino acid taurine in preventing acetaminophen-induced hepatotoxicity. Male Sprague-Dawley rats were administered acetaminophen (800 mg/kg) intraperitoneally. Taurine (200 mg/kg) was given 12 h before, at the time of, and 1 or 2 h after acetaminophen injection. Acetaminophen treatment increased the plasma levels of aspartate transaminase, alanine aminotransferase, and alkaline phosphatase and caused hepatic DNA fragmentation and hepatocyte necrosis. Taurine administered before, simultaneously with, or 1 h after acetaminophen resulted in significant improvement in hepatic injury as represented by decrease of hepatocellular enzyme release and attenuation of hepatocyte apoptosis and necrosis, and this correlated with taurine-mediated attenuation of hepatic lipid peroxidation. These results indicate that taurine possesses prophylactic and therapeutic effects in acetaminophen-induced hepatic injury.
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PMID:Role of taurine in preventing acetaminophen-induced hepatic injury in the rat. 1135 21


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