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)

The nitric oxide (NO) donor, O2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P450 enzymes to release NO within the liver and is effective in protecting against hepatotoxicity of endotoxin and acetaminophen. This study examined the effects of V-PYRRO/NO on cadmium (Cd) hepatotoxicity in mice. Mice were given multiple injections of V-PYRRO/NO (10 mg/kg, s.c. at 2-h intervals) before and after a hepatotoxic dose of Cd (3.7 mg/kg Cd as CdCl2, i.p.). V-PYRRO/NO administration reduced Cd-induced hepatotoxicity as evidenced by reduced serum alanine aminotransferase activity, improved pathology, and reduced hepatic lipid peroxidation. The protection by V-PYRRO/NO was not mediated by altered Cd distribution to the liver or within hepatic subcellular fractions. Similar inductions of metallothionein, a metal-binding protein, were observed in mice receiving Cd alone or Cd plus V-PYRRO/NO. Real-time reverse transcription-polymerase chain reaction analysis revealed that V-PYRRO/NO administration suppressed the expression of inflammation-related genes such as macrophage inflammatory protein-2, CXC chemokine, thrombospondin-1, intracellular adhesion molecular-1, and interleukin-6. V-PYRRO/NO also suppressed the expression of acute phase protein genes and genes related to cell-death pathways, such as c-jun/AP-1, nuclear factor-kappaB, early response growth factor-1, heme oxygenase-1, caspase-3, growth arrest, and DNA-damaging protein-153. In summary, the liver-selective NO donor, V-PYRRO/NO, protects against Cd hepatotoxicity in mice. This protection is not mediated through altered distribution of Cd but may be related to reduced hepatic inflammation, reduced acute phase responses, and the suppression of cell-death-related components.
 ...
PMID:The nitric oxide donor, O2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), protects against cadmium-induced hepatotoxicity in mice. 1501 May 1

1,1-Dichloroethylene (DCE) causes dysfunction of hepatic mitochondria. As mitochondria have been implicated in apoptosis through opening of the permeability transition pore (PTP), we have undertaken studies to test the hypothesis that DCE induces apoptosis, in addition to necrosis, in murine liver. Our primary objective was to identify the biochemical events associated with DCE-induced apoptosis. Female CD-1 mice were treated with a mildly hepatotoxic dose of DCE (125 mg/kg, i.p.). Using the fluorescent dye JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide), decreased hepatic mitochondrial membrane potential was detected at 2 h. Western blotting of liver cytosolic proteins showed greater immunoreactivity for cytochrome c in fractions from mice treated with DCE for 4 h than in controls. Furthermore, caspase-9 activity was significantly increased 6 h after DCE exposure. Immunohistochemical studies with an antibody to activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining were used to detect apoptotic cells. In both experiments, positive reactivities were observed in centrilobular hepatocytes 12 and 24 h after DCE. Additionally, centrilobular hepatocytes showing morphological criteria of apoptosis were observed at 24 h. Apoptosis and all apoptotic events were inhibited by pretreatment for 20 min with cyclosporine A (CyA) (50 mg/kg), a specific inhibitor of the mitochondrial PTP. To determine a major role for mitochondrial permeability transition (MPT) in DCE hepatotoxicity, serum alanine aminotransferase (ALT) activity was evaluated. ALT activity was significantly elevated 2 to 24 h after DCE, and CyA failed to inhibit this activity. These data suggested that DCE produces apoptosis by inducing MPT, causing release of cytochrome c into the cytosol and caspase activation.
 ...
PMID:Evidence that 1,1-dichloroethylene induces apoptotic cell death in murine liver. 1502 83

Liver injury is an important prognostic indicator during acute pancreatitis. The aim of this study was to determine the role of Fas ligand (FasL) in hepatocyte injury. Liver parenchymal enzymes were measured in cocultures of hepatocytes and Kupffer cells treated with elastase. FasL and FasL mRNA were measured in elastase-treated Kupffer cells. Hepatocytes were treated with FasL and their viability was assessed by monotetrazolium (MTT), apoptosis by flow cytometry, as well as caspase-3 and p38-mitogen-activated protein kinase (MAPK) by immunoblotting. Elastase increased aspartate aminotransferase and lactate dehydrogenase in cocultures of hepatocyte and Kupffer cells (P<0.040). Elastase increased FasL production from Kupffer cells (P=0.02) and upregulated FasL mRNA (FasL/beta-2 microglobulin (BMG): 0.23+/-0.03 vs. 0.11+/-0.003; P=0.04). FasL increased alanine aminotransferase and lactate dehydrogenase (P<0.03) and reduced hepatocyte viability by 45% (P=0.01). FasL increased the number of dually labeled cells with AnnexinV/7AAD (P=0.03) while upregulating cleavage of caspase-3 and the phosphorylation of p38-MAPK. FasL antibody attenuated the FasL-related increase in dually labeled cells (P=0.02), the cleavage of caspase-3, and phosphorylation of p38-MAPK. Pancreatic elastase upregulates FasL within Kupffer cells. FasL induces hepatocyte injury and death and upregulates p38-MAPK and caspase-3 within hepatocytes. The ability to manipulate interactions between Kupffer cells and hepatocytes may have important therapeutic implications.
 ...
PMID:Kupffer cell-derived Fas ligand plays a role in liver injury and hepatocyte death. 1503 92

Recently, liver natural killer T (NKT) cells, which are specifically stimulated by alpha-galactosylceramide (alpha-GalCer), were found to play a critical role in intrahepatic immunity to several infections and certain hepatic disorders. However, the role of psychophysical stress on NKT cell-dependent liver injury induced by alpha-GalCer still remains to be elucidated. In this study, we employed inescapable electric foot shock as the mode of psychophysical stress and evaluated its effect on alpha-GalCer-induced hepatitis. Pre-exposure of 12 hours of foot shock stress before alpha-GalCer administration significantly enhanced alpha-GalCer-triggered increase in serum alanine aminotransferase levels, followed by increases in both liver caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive hepatocytes, thus indicating that the liver NKT cell-dependent apoptotic response was exacerbated by stress. Foot shock stress also significantly increased both the number of liver NKT cells and Fas expression levels on hepatocytes. Pretreatment with RU-486, a glucocorticoid (GC) receptor antagonist, completely reversed such stress-induced enhancement of the alpha-GalCer-triggered serum alanine aminotransferase and hepatocyte Fas antigen responses. In contrast, such a reversal effect was not found in the mice pretreated with naloxone, a micro-opioid receptor antagonist, which thus suggests that an elevation of endogenous GCs, but not beta-endorphin, as responsible for such stress-induced aggravation in mouse hepatitis models. In conclusion, foot shock stress-induced elevation of endogenous GCs exacerbates alpha-GalCer-initiated hepatic apoptosis through the expansion of liver NKT cells and the up-regulation of hepatocyte Fas antigen.
 ...
PMID:Electric foot shock stress-induced exacerbation of alpha-galactosylceramide-triggered apoptosis in mouse liver. 1505 17

We studied the effects of cyclosporin A (CsA) administration 1) on the properties of the permeability transition pore (PTP) in mitochondria isolated from the liver and 2) on the susceptibility to hepatotoxicity induced by lipopolysaccharide of Escherichia coli (LPS) plus D-galactosamine (D-GalN) in rats. CsA exerted a marked PTP inhibition ex vivo, with an effect that peaked between 2 and 9 h of drug treatment and decayed with an apparent half-time of about 13 h. Administration of LPS plus D-GalN to naive rats caused the expected increased serum levels of tumor necrosis factor (TNF)-alpha, liver inflammation with BID cleavage, activation of caspase 3, appearance of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive nuclei, and release of alanine aminotransferase and aspartate aminotransferase into the bloodstream. Treatment with CsA before or within 5 h of the administration of LPS plus D-GalN protected rats from hepatotoxicity despite the normal increase of serum TNF-alpha and BID cleavage. These results indicate that CsA prevents the hepatotoxic effects of TNF-alpha by blocking the mitochondrial proapoptotic pathway through inhibition of the PTP and provides a viable strategy for the treatment of liver diseases that depend on increased production and/or liver sensitization to TNF-alpha.
 ...
PMID:Desensitization of the permeability transition pore by cyclosporin a prevents activation of the mitochondrial apoptotic pathway and liver damage by tumor necrosis factor-alpha. 1520 Dec 76

The normalization of plasma alanine aminotransferase (ALT) has been proved to be a strategy for preventing the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infection. Glycyrrhizin, a plant medicine, normalizes plasma ALT and prevents HCC. However, glycyrrhizin is administered intravenously and thereby chemical which is effective on oral administration is required. Coumarin compounds are active components of herbs used for the treatment of various diseases. The ability of coumarin compounds to lower plasma ALT were examined using mice concanavalin A-induced hepatitis and mice anti-Fas antibody-induced hepatitis. Furanocoumarins pd-Ia, pd-II and pd-III lower plasma ALT, but they are large molecules that are hardly absorbed on oral administration. Furocoumarin effectively lowers plasma ALT, but the safety range between the effective and toxic dosages is narrow. In contrast, osthole, a simple coumarin, causes strong reduction of plasma ALT and also inhibits caspase-3 activation. Furthermore, this chemical is quite safe upon large dose administration. In the structure of osthole, the methoxy group at position-7 and the 3-methyl-2-butenyl group at position-8 were elucidated to be essential for the beneficial effect of this chemical. We conclude that osthole will become a leading chemical for synthesizing a compound which prevents HCC on oral administration.
 ...
PMID:Chemical aspects of coumarin compounds for the prevention of hepatocellular carcinomas. 1572 Feb 60

Taurochenodeoxycholic acid (TCDCA), but not glycochenodeoxycholic acid (GCDCA), activates a phosphatidylinositol 3-kinase (PI3-K)-mediated survival pathway in vitro. Here, the effects of PI3-K inhibition on TCDCA- and GCDCA-induced hepatocellular injury, apoptosis, and bile secretion were examined in the intact liver. In isolated perfused rat livers, bile flow was determined gravimetrically. Hepatovenous lactate dehydrogenase and alanine aminotransferase efflux as markers of liver integrity and biliary secretion of 2,4-dinitrophenyl-S-glutathione (DNP-GS) were determined photometrically. Apoptosis was assessed by immunohistochemistry of active caspase-3 and cytokeratin 18 in liver tissue. Phosphorylation of protein kinase B (PKB/Akt) as a readout of PI3-K activity was determined by immunoblot analysis. Bile acid concentrations were determined by gas chromatography. TCDCA (25 muM) induced moderate liver injury by hepatocellular apoptosis and distinctly reduced bile flow and DNP-GS secretion. In contrast, GCDCA (25 muM) induced severe liver injury by extensive hepatocyte apoptosis. TCDCA strongly activated PI3-K, whereas GCDCA did not markedly affect PI3-K activity. Inhibition of PI3-K by 100 nM wortmannin enhanced TCDCA-induced liver injury and apoptosis and tended to aggravate the cholestatic effect of TCDCA. In contrast, wortmannin reduced GCDCA-induced liver injury and apoptosis. Bile acid uptake tended to be reduced by wortmannin. The cholestatic effect of GCDCA was aggravated by wortmannin. Inhibition of PI3-K markedly aggravated TCDCA-induced but not GCDCA-induced liver damage and hepatocyte apoptosis. Thus TCDCA appears to block its inherent toxicity by a PI3-K-dependent survival pathway in the intact liver.
 ...
PMID:Phosphatidylinositol 3-kinase-dependent signaling modulates taurochenodeoxycholic acid-induced liver injury and cholestasis in perfused rat livers. 1574 12

Ischemia-reperfusion injury is responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. Recently, it has been reported that mitochondrial K(ATP) channel openers have an effect on myocardial protection via a pharmacological preconditioning action. However, it remains unclear as to whether K(ATP) channel openers can reduce ischemia-reperfusion injury in the liver. The aim of this study was to determine the effects of the mitochondrial K(ATP) channel opener, nicorandil, on ischemia-reperfusion injury in the rat liver. Male Wistar rats were subjected to 73% ischemia for 45 minutes followed by 120 minutes of reperfusion. Nicorandil (3 mg/kg) was orally administered 60 minutes before hepatic ischemia. Nicorandil significantly decreased plasma levels of alanine aminotransferase and lactate dehydrogenase by about 50% and inhibited the remarkably increased TUNEL-positive hepatocytes after reperfusion. Some mediators associated with apoptosis were analyzed by Western blotting. Cytochrome-c and caspase-3 levels in the cytosol increased after reperfusion; nicorandil inhibited the release of cytochrome-c and activation of caspase-3. The expression of Bax and Bcl-2 was significantly increased after reperfusion, being slightly inhibited by the administration of nicorandil. These results suggest that the protective effects of nicorandil against hepatic ischemia-reperfusion injury correlate with the inhibition of mitochondrial cytochrome-c release and caspase-3 activation. These findings demonstrate that nicorandil may become a therapeutic drug for ischemia reperfusion-related liver injury.
 ...
PMID:Mitochondrial K(ATP) channel opener prevents ischemia-reperfusion injury in rat liver. 1580 66

Fertile chicken eggs were injected with various concentrations of either d-glucose or l-glucose during the first three days of embryonic development. The exogenous glucose concentrations ranged from 0 to 18.58 micromol/kg egg. At 18 days of development (theoretical stage 44), brains, livers, and blood from chorio-allantoic vessels were isolated from living embryos. Exogenous d-glucose and l-glucose caused increased plasma d-glucose levels, increased plasma alanine aminotransferase (ALT) activities, and decreased embryo viability. Embryo viability was monitored by a reduction in the percentage of living embryos at theoretical stage 44, reduced embryo masses, reduced brain masses, and reduced liver masses. When compared to controls, embryonic exposure to either exogenous d-glucose or l-glucose caused increased caspase-3 activities and increased lipid hydroperoxide (LPO) levels in both brain and liver tissues. Because lipid hydroperoxides are lipid peroxidation intermediates that result in the attack of any unsaturated neutral lipid or unsaturated phospholipid, the effect of exogenous glucose on hepatic membrane fatty acid composition was studied. Exogenous glucose (either d-glucose or l-glucose) promoted reduced levels of several unsaturated, long-chain fatty acids and increased levels of saturated, short-chain fatty acids within hepatic membranes. Exogenous-glucose induced decreases in the ratios of unsaturated/saturated fatty acids and long-chain/short-chain fatty acids within hepatic membranes which strongly correlated with glucose-induced increases in plasma ALT activities and moderately correlated to hepatic LPO levels. These observations are consistent with the hypothesis that embryonic hyperglycemia promotes hepatic membrane lipid peroxidation and hepatic cell death.
 ...
PMID:Hyperglycemia-induced changes in hepatic membrane fatty acid composition correlate with increased caspase-3 activities and reduced chick embryo viability. 1590 50

To examine the role of histamine H1 and H2 receptors in the regulation of lipopolysaccharide (LPS)-induced liver injury, a combination of D-galactosamine and LPS (GalN/LPS) was administered to histamine H1 receptor knockout (H1-R KO) and H2 receptor knockout (H2-R KO) mice. The numbers of necrotic and apoptotic hepatocytes in the liver, as well as the levels of serum aspartate transaminase (AST) and alanine transaminase (ALT), were increased significantly by GalN/LPS treatment compared to the appropriate controls. Pretreatment with histamine ameliorated the GalN/LPS-induced necrotic and apoptotic changes in the hepatocytes and inhibited the elevation of serum AST and ALT levels. Histamine attenuated the GalN/LPS-induced increases in the levels of TNF-alpha, but augmented those of IL-10 both in the liver and serum. Histamine inhibited the GalN/LPS-induced caspase-3 activity in the liver. Furthermore, these effects of histamine were completely or partially attenuated in H2-R KO mice, but not in H1-R KO mice. Peritoneal macrophages from H2-R KO mice exhibited blunted changes in the effects of histamine on LPS-induced TNF-alpha and IL-10 production in vitro compared to the wild-type (WT) controls. In summary, the present findings suggest that the histamine H2-R-TNF-alpha and -IL-10 pathways play protective roles in endotoxin-induced hepatic injury.
 ...
PMID:The role of histamine H1 receptor and H2 receptor in LPS-induced liver injury. 1605 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>