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)

The changes in the levels of leukotrienes (LTs) and prostaglandins (PGs) in the liver tissue of rats with carbon tetrachloride (CCl4)-induced liver injury were studied. As a result, after the administration of CCl4, the levels of LTs increased at an early stage while the levels of PGs increased at a later stage. This suggests that LTs may have an adverse effect on liver injury induced by CCl4, and that PGs may not have a direct effect on liver injury. In addition, serum GOT and GPT levels improved with the administration of AA-861, a 5-lipoxygenase inhibitor, while these levels did not change with the administration of indomethacin, a cyclooxygenase inhibitor. These results suggest that arachidonic acid metabolites may play an important role in the induction of liver cell injury.
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PMID:Arachidonic acid metabolites in carbon tetrachloride-induced liver injury. 211 99

The role of leukotrienes was investigated in frog virus 3-induced hepatitis in rats. Frog virus 3 elicited an enhanced generation of cysteinyl leukotrienes in vivo as monitored by measurement of N-acetyl-leukotriene E4 as the major endogenous metabolite of cysteinyl leukotrienes secreted into rat bile. N-Acetyl-leukotriene E4 concentrations were elevated for more than 4 hr after frog virus 3 injection. In vitro experiments using cultured rat liver Kupffer cells of high purity indicated that these cells can produce and metabolize leukotrienes and are thus a possible source of leukotrienes elicited in vivo by frog virus 3. The selective 5-lipoxygenase inhibitor AA 861 and the dual inhibitor of arachidonate lipoxygenase and cyclooxygenase, BW 755C, reduced the hepatocellular injury after a high dose of frog virus 3 by about 50 and 80%, respectively, as judged from plasma activities of ALT and sorbitol dehydrogenase at 24 hr after frog virus 3 administration. Our in vivo and in vitro studies argue in favor of an important role of leukotrienes as mediators in frog virus 3 hepatitis in rats.
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PMID:Leukotrienes as mediators in frog virus 3-induced hepatitis in rats. 311 68

The effect of prostacyclin on acetaminophen-induced liver injury has been investigated in the mouse. Two structurally unrelated thromboxane synthetase inhibitors, OKY 1581 and benzyl imidazole, were also examined in order to investigate the role of the prostacyclin-thromboxane balance in the development of hepatic lesions. Whereas prostacyclin or OKY 1581 given shortly after acetaminophen prevented mortality and reduced liver necrosis, as assessed by serum ALT activity and histology, benzyl imidazole was only effective if given prior to acetaminophen. Acetaminophen overdose resulted in an enhanced prostaglandin and thromboxane generation by liver homogenates. While OKY 1581 inhibited thromboxane production by the liver homogenates, prostacyclin synthesis was increased. Pretreatment with the cyclooxygenase inhibitor indomethacin blocked both the increase in prostacyclin generation and the protective effect of OKY 1581. Benzyl imidazole inhibited the synthesis of thromboxane but did not enhance prostacyclin production. In addition, the protective effect of benzyl imidazole was unaltered by indomethacin pretreatment. Furthermore, whereas benzyl imidazole interfered with hepatic drug metabolism, as assessed by prolongation of the pentobarbitone sleeping time, prostacyclin and OKY 1581 were without activity. Prostacyclin treatment can prevent acetaminophen-induced liver necrosis in mice. Enhanced prostacyclin synthesis by the selective thromboxane synthetase inhibitor OKY 1581 also exerts a protective role in this model.
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PMID:Reduction by prostacyclin of acetaminophen-induced liver toxicity in the mouse. 328 85

The changes of the levels of LTC4, PGI2 and TXA2 in the liver tissue in SD rats with GaIN/LPS-induced acute liver injury was studied with radioimmunoassay (RIA). As a result, 12 h after the administration of GaIN/LPS, serum AST (398 +/- 37 u), ALT (565 +/- 43 u) increased (P < 0.001) and the concentration of TXA2 (12,188 +/- 588 pg/g.w.wt) in liver tissue increased significantly (P < 0.001), while the content of LTC4 (9713 +/- 3557 ng/g.w.wt) and PGI2(1748 +/- 560 pg/g.w.wt) in liver tissue were not obviously changed (P > 0.05) and the inflammatory changes of the pathological findings were observed. The improvement of serum ALT (330 +/- 168 u) (P < 0.05) and AST (273 +/- 124 u) (P < 0.05) and histopathological damage was observed after the administration of diethylcarbamazine (DEC), a LTA4 synthesis inhibitor, the liver TXA2 (12,740 +/- 699) concentration significantly increased (P < 0.001), while the levels of LTC4 (8179 +/- 1653) and PGI2 (2320 +/- 630) were not obviously changed. Serum ALT (536 +/- 74 u) and AST (416 +/- 41 u) (P > 0.05) levels and histopathology did not change with administration of indomethacin, a cyclooxygenase inhibitor, but the liver LTC4 (12,166 +/- 1327) contents increased (P < 0.05) and TXA2 (1868 +/- 791) reduced significantly (P < 0.001). The present study suggests that arachidonic acid metabolism in rats with acute liver injury are significantly abnormal. Leukotrienes and thromboxane are important inflammatory mediators in the liver injury.
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PMID:Arachidonic acid metabolism in galactosamine/endotoxin induced acute liver injury in rats. 780 4

Administration of alpha-naphthylisothiocyanate (ANIT) to rats results in periportal cholangiolitic hepatopathy. Inflammation is a hallmark of the liver injury, and expression of toxicity is dependent on blood neutrophils. The role of other cellular mediators of inflammation in ANIT-induced hepatic insult is unknown. We hypothesized that platelets participate in the expression of ANIT hepatotoxicity. To test this, circulating platelets were decreased by administration of anti-rat platelet serum (PAb) prior to treatment of rats with ANIT. The PAb treatment regimen effectively reduced circulating thrombocytes over the course of the experiment. Twenty-four hours after oral ANIT administration, rats were euthanized and liver injury was estimated by increases in serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) activities. Cholestasis was assessed by measurement of serum total bilirubin concentration and bile flow. Reduction in platelet numbers was associated with attenuation of the increases in plasma ALT activity and bilirubin concentration seen after ANIT administration. However, PAb treatment did not attenuate the increase in plasma GGT, a marker of biliary epithelial cell injury. ANIT-induced changes in platelet function were assessed by evaluating platelet aggregation responses in platelet-rich plasma from rats treated with ANIT in vivo. ANIT treatment modestly decreased ex vivo platelet aggregation in response to ADP and collagen stimuli. To address further the role of platelet-derived cyclooxygenase products in ANIT hepatotoxicity, rats were treated with aspirin or ibuprofen. Neither pretreatment ameliorated ANIT-induced hepatic insult. These results suggest that platelets contribute to the expression of ANIT-induced liver injury, but they do not appear to act through the production of cyclooxygenase metabolites.
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PMID:Platelets and alpha-naphthylisothiocyanate-induced liver injury. 799 11

The present study examined the possible involvement of endogenous cyclooxygenase-derived factors in the lethality and hepatic hemorrhagic necrosis induced by phalloidin. Mice were pretreated with indomethacin, aspirin or ibuprofen (all inhibitors of cyclooxygenase) and injected with phalloidin (2 mg/kg). The toxin induced 75% lethality and caused severe hemorrhagic necrosis of the liver associated with increased serum levels of AST and ALT. Indomethacin completely prevented the mortality and hepatic damage elicited by phalloidin as judged by morphologic analysis and serum AST and ALT release. The in vitro addition of indomethacin to suspensions of freshly-isolated hepatocytes decreased plasma membrane bleb formation induced by phalloidin. In contrast to indomethacin, aspirin and ibuprofen did not influence phalloidin toxicity in vivo. These results suggest that inhibition of prostanoids per se may not be the sole mechanism of protection by indomethacin.
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PMID:Protection by indomethacin against the lethality and hepatotoxicity of phalloidin in mice. 816 Feb 14

Tepoxalin [5- (4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole -3-propanamide] is an orally active anti-inflammatory agent, which inhibits both cyclooxygenase and 5-lipoxygenase activities. The oral toxicity of tepoxalin was evaluated in 1- and 6-month rat (up to 50 mg/kg/day) and dog (up to 150 mg/kg bid) studies. In rats, increased liver weight, centrilobular hypertrophy, and hepatic necrosis were observed at dosages >/=20 mg/kg/day. Renal changes indicative of analgesic nephropathy syndrome (i.e., papillary edema or necrosis, cortical tubular dilatation) were seen at >/=15 mg/kg. In rats treated for 1 month, these hepatic and renal effects were largely reversible after a 1-month recovery period. Gastrointestinal erosions and ulcers were seen in female rats given 40 mg/kg/day for 6 months. Changes in clinical pathology parameters included decreases in red blood cell count, hemoglobin, and hematocrit mean values; elevation in platelet counts; and an increase in prothrombin and activated partial thromboplastin times. Mild increases in alanine aminotransferase, aspartate aminotransferase, and cholesterol were also noted in rats. Decreased erythrocyte parameters, increased leukocyte counts, and decreased total protein, albumin, and/or calcium were noted in some dogs in the 300 mg/kg/day group following 6 months of dosing. Small pyloric ulcerations were seen at 100 and 300 mg/kg/day dosages for up to 6 months. In both rats and dogs, no accumulation of tepoxalin or its carboxylic acid metabolite was detected in plasma following multiple dosing over a range of 5 to 50 mg/kg/day for rats and 20 to 300 mg/kg/day for dogs. Plasma concentrations of the carboxylic acid metabolite were severalfold higher than those of the parent compound. The no-effect dosages in rats (5 mg/kg/day) and dogs (20 mg/kg/day) were approximately one and six times the ED50 (3.5 mg/kg), respectively, for inhibition of inflammatory effects in the adjuvant arthritic rat without gastric mucosal damage. In terms of severity, the relative lack of gastrointestinal side effects, within the estimated therapeutic dose range, distinguishes tepoxalin from most marketed anti-inflammatory drugs.
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PMID:Preclinical toxicity evaluation of tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, in Sprague-Dawley rats and beagle dogs. 881 16

In order to study the contribution of eicosanoids to the regulation of the functions of normal and carbon tetrachloride (CCl4)-injured liver cells, primary cultures of hepatocytes (HC) either alone or in coculture with Kupffer cells (KC) were exposed for 4 and 24 h to lipoxygenase inhibitor (nordihydroguaiaretic acid-NDGA) or cyclooxygenase inhibitor (indomethacin-IND) in the presence and in the absence of CCl4. Treatment with CCl4 resulted in increased ALT release and a decreased mitochondrial respiration (MR) in HC and their cocultures with KC. The addition of NDGA decreased ALT levels and increased MR in control and CCL4-injured cells. Urea production (UP) was not significantly affected by NDGA. In contrast, addition of IND) decreased UP by HC (4 h), and did not alter ALT release and MR in control and CCl4-treated cells. These results indicate that arachidonic acid metabolites are involved in the regulation of HC flinctions. There is also evidence that a protective action of lipoxygenase inhibitors on CCl4-injured liver is mediated, at least partly, by their direct effects on HC and KC, in particular by increasing the mitochondrial respiration.
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PMID:Effects of nordihydroguaiaretic acid and indomethacin on the viability and functional activities of normal and carbon tetrachioride-injured rat hepatocytes cultured alone and with Kupffer cells. 1034 18

Celecoxib is a cyclooxygenase- (COX)-1-sparing inhibitor of COX-2 that is indicated for the treatment of osteoarthritis and rheumatoid arthritis. Many agents used for treating these diseases, both symptom-modifying and disease-modifying, are associated with the potential for hepatotoxicity. This article presents an analysis of the hepatic effects of celecoxib in 14 controlled studies of patients with arthritis (2 to 24 weeks' duration), in a long-term, open-label safety study (as long as 2 years), in 11 studies of patients receiving treatment for pain after oral or orthopedic surgery (up to 5 days' duration), and in five pharmacology studies. The overall incidence of hepatic adverse events in arthritis patients receiving celecoxib was similar to that for placebo but significantly lower than in the combined group of patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs). The most commonly reported hepatic adverse events were elevations in liver transaminase levels, most of which occurred in patients receiving diclofenac. Similarly, clinically significant elevations of transaminase levels occurred more frequently with NSAIDs than with celecoxib. A pharmacology study performed in patients with mild or moderate hepatic impairment showed that celecoxib did not produce any clinically relevant changes from baseline in creatinine clearance, alanine aminotransferase, or bilirubin values in these settings. In the four interaction studies performed with drugs metabolized in the liver, none of the adverse events was hepatic in nature, and no clinically relevant liver function test abnormalities occurred. In conclusion, this analysis suggests that celecoxib has a very low potential for hepatic toxicity, even after exposures of as long as 2 years at therapeutic doses.
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PMID:The hepatic safety and tolerability of the novel cyclooxygenase-2 inhibitor celecoxib. 1131 63

The aim of this study was to investigate the role of cyclooxygenase (COX) inhibition in intestinal motility and in the extent of tissue injury of the small intestine and liver with the use of various COX inhibitors. Wistar albino rats were exposed to 90 degrees C water bath for 10s. The intestinal transit index decreased compared to control group and treatment with nimesulide (NIM; 10mg/kg, subcutaneously) or piroxicam (Pir; 5mg/kg, orogastrically) reversed this effect significantly. The intestinal and liver glutathione levels showed a significant decrease in the burn group compared to sham (P<0.001 and P<0.05, respectively). Decrease in intestinal glutathione level was reversed by NIM or Pir treatment (P<0.01 and P<0.01, respectively), whereas all drugs tested were effective in reversing low liver glutathione level. The MPO activity in intestinal segments were significantly high in burned animals compared to sham. All test drugs reversed this effect but ketorolac (Ket; 3mg/kg, orogastrically) was the most effective one. The liver samples characterized by sinusoidal dilatation and pericentral atrophy in burn group were protected by treatment with Ket or Pir (P<0.05). Plasma ALT and AST activities were markedly high in this burn group compared to sham (P<0.0001 and P<0.001, respectively). None of the agents reversed these high enzyme activities. These data suggest that not only COX-2 but also COX-1 inhibition is required for protection against inflammatory changes in liver and small intestine following burn injury.
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PMID:Protective role of cyclooxygenase (COX) inhibitors in burn-induced intestinal and liver damage. 1199 50


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