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)

1. We have investigated whether (i) endotoxaemia caused by E. coli lipopolysaccharide in the anaesthetized rat causes a multiple organ dysfunction syndrome (MODS; e.g. circulatory failure, renal failure, liver failure), and (ii) an enhanced formation of nitric oxide (NO) due to induction of inducible NO synthase (iNOS) contributes to the MODS. In addition, this study elucidates the beneficial and adverse effects of aminoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of iNOS activity, and NG-methyl-L-arginine (L-NMMA), a non-selective inhibitor of NOS activity on the MODS caused by endotoxaemia. 2. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 117 +/- 3 mmHg (time 0) to 97 +/- 4 mmHg at 2 h (P < 0.05, n = 15) and 84 +/- 4 mmHg at 6 h (P < 0.05, n = 15). The pressor effect of noradrenaline (NA, 1 micrograms kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with AE-ITU (1 mg kg-1, i.v. plus 1 mg kg-1 h-1 starting at 2 h after LPS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS-rats. Infusion of L-NMMA (3 mg kg-1, i.v. plus 3 mg kg-1 h-1) caused a rapid and sustained rise in MAP and attenuated the delayed vascular hyporeactivity to NA. Neither AE-ITU nor L-NMMA had any effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 3. Endotoxaemia for 6 h was associated with a significant rise in the serum levels of aspartate or alanine aminotransferase (i.e. GOT or GPT), gamma-glutamyl-transferase (gamma GT), and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with AE-ITU significantly attenuated this liver dysfunction (rise in GOT, GPT, gamma GT and bilirubin) (P < 0.05, n = 10). In contrast, L-NMMA reduced the increase in the serum levels of gamma GT and bilirubin, but not in GOT and GPT (n = 5). Injection of LPS also caused a time-dependent, but rapid (almost maximal at 2 h), increase in the serum levels of urea and creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by either AE-ITU (n = 10) or L-NMMA (n = 5). In rats infused with saline rather than LPS, neither AE-ITU (n = 4) nor L-NMMA (n = 4) had any significant effect on the serum levels of GOT, GPT, gamma GT, bilirubin, creatinine or urea. 4. Endotoxaemia for 6 h resulted in a 4.5 fold rise in the serum levels of nitrite (9.13 +/- 0.77 microM, P < 0.01, n = 15), which was significantly reduced by treatment with AE-ITU (6.32 +/- 0.48 microM, P < 0.05, n = 10) or L-NMMA (5.10 +/- 0.40 microM, P < 0.05, n = 5). In addition, endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver homogenates, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with either AE-ITU or L-NMMA. 5. Thus, AE-ITU or L-NMMA (i) inhibits iNOS activity in LPS-rats without causing a significant increase in MAP in rats infused with saline and, hence inhibition of endothelial NOS activity, and (ii) attenuates the delayed circulatory failure as well as the liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanced formation of NO may contribute to the development of liver failure in endotoxic shock.
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PMID:The multiple organ dysfunction syndrome caused by endotoxin in the rat: attenuation of liver dysfunction by inhibitors of nitric oxide synthase. 868 Jul 15

Reactive oxygen species such as nitric oxide (NO) and/or superoxide have been proposed as mediators in the pathogenesis of reperfusion injury and acute endotoxemia. The purpose of this study was to examine the role of NO in a model of hepatic ischemia-reperfusion with endotoxemia (I/R + LPS). Rats subjected to 30 min of partial hepatic ischemia followed by reperfusion and LPS (Salmonella enteritidis, 1 mg/kg, i.v.,) administration, exhibited a marked, time-dependent increase in plasma alanine aminotransferase (ALT) levels compared to sham controls. An abrupt increase in liver nitrite/nitrate levels was also observed in I/R + LPS rats in association with the increases in plasma ALT. Although liver NO production in I/R + LPS rats increased with time, exacerbation of liver damage was not evident. Administration of L-NAME decreased NO production in plasma and liver but did not affect the liver damage in rats subjected to I/R + LPS. Superoxide levels in livers from I/R + LPS rats increased by threefold after 90 min reperfusion as compared to sham controls but dropped to control levels after 4 hr. There was a significant increase in neutrophils in liver lobes subjected to ischemia-reperfusion and LPS compared to sham controls and to non-ischemic lobes which received LPS. The number of neutrophils in the liver increased further in rats given L-NAME. These results suggest that the progressive injury seen in livers of I/R + LPS rats was possibly due to NO interaction with superoxide forming another reactive oxygen species such as peroxynitrite. However, inhibition of NO synthesis did not ameliorate liver damage, possibly because of an increase in tissue accumulation of activated polymorphonuclear leukocytes (PMN). Lung NO production increased in I/R + LPS rats after 4 hr reperfusion compared to sham controls. Prior administration of L-NAME did not prevent a significant rise in pulmonary NO generation (P < 0.05 at 90 min and 4 hr, compared to sham controls). This unexpected rise of pulmonary NO in the L-NAME treated group of rats was associated with a tendency for increased PMN accumulation (based on myeloperoxidase data) and superoxide generation. The results suggest that endogenous NO protected against excessive neutrophil infiltration in the lung in this model of hepatic ischemia-reperfusion and endotoxemia, and the use of L-NAME, a nonselective NOS inhibitor, may aggravate lung injury.
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PMID:Role of nitric oxide in hepatic ischemia-reperfusion with endotoxemia. 884 95

Although researchers have noted high level activation of rodent mononuclear phagocytes for nitric oxide (NO) synthase type 2 (S2) expression and NO production with a variety of agents such as interferon (IFN) gamma and endotoxin, it has been difficult to demonstrate activation of human mononuclear phagocytes. The purpose of this study was to determine if IFN-alpha serves as an activator in vitro and in vivo in humans. Treatment of normal monocytes or mononuclear cells in vitro with IFN-alpha caused a dose-dependent increase in monocyte NOS2 activity and NO production, and increased expression of NOS2 protein and mRNA expression. To determine if in vivo administration of IFN-alpha also modulated NOS2, we studied blood cells from patients with hepatitis C before and after IFN-alpha therapy. Untreated patients with chronic hepatitis C virus infection had levels of NOS activity and NOS2 antigen in freshly isolated mononuclear cells similar to those of healthy subjects, and they expressed minimal or no NOS2 mRNA. However, IFN-alpha treatment of patients with hepatitis C infection was associated with a significant elevation in mononuclear cell NOS activity, NOS2 antigen content, and NOS2 mRNA content. IFN-alpha-treated patients had significant decreases in levels of serum alanine aminotransferase and plasma hepatitis C mRNA. The degree of IFN-alpha-enhanced mononuclear cell NOS2 antigen content correlated significantly with the degree of reduction in serum alanine aminotransferase levels. Thus, IFN-alpha treatment of cells in vitro or administration of IFN-alpha to hepatitis C patients in vivo increases expression of mononuclear cell NOS2 mRNA expression, NOS activity, NOS2 antigen expression, and NO production. Since NO has been reported to have antiviral activity for a variety of viruses, we speculate that induced NO production may be related to the antiviral action(s) of IFN-alpha in hepatitis C infection.
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PMID:Interferon (IFN)-alpha activation of human blood mononuclear cells in vitro and in vivo for nitric oxide synthase (NOS) type 2 mRNA and protein expression: possible relationship of induced NOS2 to the anti-hepatitis C effects of IFN-alpha in vivo. 934 7

The vasodilator nitric oxide (NO) is involved in the regulation of systemic blood pressure and local organ blood flow. Inhibitors of the constitutively expressed nitric oxide synthase in endothelial cells (eNOS), e.g., Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME), aggravated liver injury in a variety of models. On the other hand, inhibitors of the inducible NOS (iNOS), e.g., 2-aminoethyl-isothiourea (AET), were found to be beneficial during endotoxemia. The aim of this investigation was to study the effect of AET compared with L-NAME on liver microvascular blood flow and injury in more complex models with multiple insults, i.e., ischemia (20 min)-reperfusion (8 h) in combination with .5 mg/kg endotoxin (IRE). Male Fisher rats were treated with 10 mg/kg AET or L-NAME and subjected to IRE. At 8 h, liver injury (plasma ALT: 1320+/-164 U/L) was significantly increased in AET-treated (5,018+/-1,379 U/L) and L-NAME-treated groups (2,429+/-228 U/L). Each inhibitor attenuated microvascular blood flow (assessed by laser Doppler flowmetry) to a similar degree. In striking contrast, AET completely reversed the endotoxin-induced impairment of the microvascular blood flow and significantly protected against an endotoxin-induced liver injury (plasma ALT: 3,007+/-268 U/L (ET); 460+/-39 U/L (ET+AET)). Infusion of endothelin-1 reduced microvascular blood flow by 50-60% and caused liver injury. Our data demonstrated that an inhibitor of eNOS (L-NAME) has a consistent detrimental effect on liver injury during ischemia-reperfusion and endotoxemia mainly because it can cause additional ischemia by reducing the microvascular blood flow. However, selective inhibitors of iNOS (AET) can impair hepatic blood flow and aggravate the injury or improve blood flow and attenuate organ injury depending on the experimental model. These results suggest that iNOS inhibitors may not be universally beneficial and should be tested in a variety of experimental models of sepsis/endotoxemia before used in clinical settings.
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PMID:Differential effect of 2-aminoethyl-isothiourea, an inhibitor of the inducible nitric oxide synthase, on microvascular blood flow and organ injury in models of hepatic ischemia-reperfusion and endotoxemia. 968 86

The objective of this study was to determine what roles the endothelial cell and inducible isoforms of nitric oxide synthase (eNOS, iNOS) play in ischemia and reperfusion (I/R)-induced liver injury in vivo in mice genetically deficient in each isoform of NOS. We found that 45 min of partial (70%) liver ischemia and 5 h of reperfusion induced substantial liver injury as assessed by the release of large and significant amounts of the liver-specific enzyme alanine aminotransferase (ALT) into the serum of wild-type (wt) mice. The enhanced ALT levels were not due to increased recruitment of potentially damaging PMNs, which could mediate hepatocyte injury, as neither histopathological inspection nor quantitative MPO determinations revealed the presence of PMNs in the liver at this time point. In addition, we observed a significant enhancement in liver injury in eNOS-deficient but not iNOS-deficient mice subjected to liver I/R compared to postischemic wt mice. Taken together, these data suggest that eNOS- but not iNOS-derived NO plays an important role in limiting or downregulating I/R-induced liver injury in vivo following 5 h of reperfusion.
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PMID:Nitric oxide synthase and postischemic liver injury. 1102 58

Cirrhosis predisposes the liver to secondary stresses such as endotoxemia possibly via dysregulation of the hepatic portal circulation secondary to imbalanced upregulation of vascular stress genes. In this study we determined the effect of cirrhosis on hepatic vasoregulatory gene expression in response to endotoxin (LPS, i.p., 1 mg/kg). Cirrhosis was induced by bile duct ligation (BDL) for 21 days in male Sprague-Dawley rats. Plasma and liver samples were taken 6 h following an injection of LPS for alanine aminotransferase (ALT) assays and RT-PCR analysis of mRNA levels for genes of interest: endothelin (ET-1), its receptors ET(A) and ET(B), endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and heme oxygenase-1 (HO-1). ALT release increased by 5.5-fold in the BDL animals and 9.9-fold in BDL + LPS compared to sham. ET-1 mRNA was increased by either LPS or BDL treatment alone and increased significantly more in BDL + LPS compared to sham + LPS. mRNA levels for ET(B) receptors showed no change, whereas ETA transcripts decreased in BDL animals compared to sham, with no significant difference between the saline and LPS treatment groups. The resultant increased ratio of ET(B) over ET(A) in BDL animals was reflected functionally in the portal pressure responses to ET(A) and ET(B) agonists ET-1 and IRL-1620 (a specific ETB receptor agonist). The pressor response to ET-1 was attenuated, while the response to IRL-1620 was similar in BDL and sham. eNOS mRNA levels did not increase in response to either BDL or LPS or a combination of both compared to sham. The increase in iNOS mRNA was attenuated in BDL + LPS compared to sham + LPS. HO-1 expression increased significantly in sham + LPS, but failed to increase in BDL + LPS. Taken collectively, significantly greater induction of the constrictor ET-1 over the dilation forces (i.e., eNOS, iNOS, and HO-1) was observed in BDL + LPS. This suggests a compromised ability of the cirrhotic liver to upregulate sufficient dilatory forces to counterbalance the constrictive effect of ET-1 upon a secondary insult of endotoxemia. These results may partly explain the increased susceptibility of cirrhotic livers to injury as a result of endotoxemia.
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PMID:LPS-induced imbalanced expression of hepatic vascular stress genes in cirrhosis: possible mechanism of increased susceptibility to endotoxemia. 1195 34

A variety of hepatobiliary abnormalities occur in inflammatory bowel diseases (IBDs). The role of tight junction (TJ) in hepatobiliary complications have been well described. The purpose of this study was to investigate the role of inducible nitric oxide (NOS) in alteration of hepatocyte TJ paracellular barrier and in the rapid transcytotic vesicular pathway modification associated with intestinal inflammation. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated iNOS wild-type (WT) mice, DNBS-treated iNOS knock out mice (iNOSKO) mice experienced a significant less rate of the extent and severity of the histological signs of colon injury. Colon levels of the pro-inflammatory cytokines tumour necrosis factor, interleukin-1beta and interleukin-6 were also significantly reduced in iNOS-KO mice in comparison to wild-type mice. Liver histology from iNOSKO and wild-type mice iNOSWT did not show any parenchymal and portal tract inflammation at 4 days after DNBS administration. Serum total bilirubin and alanine aminotransferase, were significantly reduced in DNBS-iNOSKO mice vs DNBS-iNOSKO mice. Therefore, we found an increase of tight junctional permeability to lanthanum nitrate (molecular weight, 433) in the livers from DNBS-treated IL-10WT mice, lanthanum accumulated throughout the junctional area up to the most apical region bordering the lumen. Absence of a functional iNOS gene in iNOSKO mice resulted in a significant reduction of apical diffusion of lanthanum after DNBS-induced colitis. Immunofluorescent labeling of frozen liver sections from DNBS-iNOSWT mice showed a significant alteration of the immunolocalization for claudin-1 and zonula occludens (ZO)-1. In contrast, a significant reduced alteration in the localization of the immunosignals for claudin-1 and ZO-1 was observed in the liver from iNOSKO mice after DNBS administration. In conclusion, we suggest that the iNOS may represent an important pathophysiological mechanism of hepatobiliary injuries and cholestasis observed in patients with IBD.
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PMID:Role of iNOS in hepatocyte tight junction alteration in mouse model of experimental colitis. 1283 36

Nitric oxide (NO) is suggested to play a role in liver injury elicited by acetaminophen (APAP). Hepatic microcirculatory dysfunction also is reported to contribute to the development of the injury. As a result, the role of NO in hepatic microcirculatory alterations in response to APAP was examined in mice by in vivo microscopy. A selective inducible NO synthase (iNOS) inhibitor,l-N6-(1-iminoethyl)-lysine (L-NIL), or a nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), was intraperitoneally administered to animals 10 min before APAP gavage. L-NIL suppressed raised alanine aminotransferase (ALT) values 6 h after APAP, whereas L-NAME increased those 1.7-fold. Increased ALT levels were associated with hepatic expression of iNOS. L-NIL, but not L-NAME, reduced the expression. APAP caused a reduction (20%) in the numbers of perfused sinusoids. L-NIL restored the sinusoidal perfusion, but L-NAME was ineffective. APAP increased the area occupied by infiltrated erythrocytes into the extrasinusoidal space. L-NIL tended to minimize this infiltration, whereas L-NAME further enhanced it. APAP caused an increase (1.5-fold) in Kupffer cell phagocytic activity. This activity in response to APAP was blunted by L-NIL, whereas L-NAME further elevated it. L-NIL suppressed APAP-induced decreases in hepatic glutathione levels. These results suggest that NO derived from iNOS contributes to APAP-induced parenchymal cell injury and hepatic microcirculatory disturbances. L-NIL exerts preventive effects on the liver injury partly by inhibiting APAP bioactivation. In contrast, NO derived from constitutive isoforms of NOS exerts a protective role in liver microcirculation against APAP intoxication and thereby minimizes liver injury.
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PMID:Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice. 1296 30

Effects of endotoxemia-induced NO production on rat liver and hepatocytes in culture were investigated. Rats were treated intraperitoneally with saline, lipopolysaccharide (LPS, 10 mg/kg), L-nitroarginine methyl ester (L-NAME)+LPS, aminoguanidine (AG)+LPS, FK 506+LPS, S-nitroso-N-acetyl penicillamine (SNAP)+L-NAME+LPS and SNAP+FK 506+LPS. Mortality, hepatocyte viability and liver function test were estimated. Liver morphology was observed by light and electron microscopy. Hepatocyte cultures were treated with LPS, cytokine mixture (CM) with or without FK 506, L-NAME or AG. Hepatocyte function and inducible form of NOS (iNOS) expression were evaluated. Twenty-four hours after treatments with saline, LPS, L-NAME+LPS, AG+LPS, FK 506+LPS, SNAP+L-NAME+LPS and SNAP+FK 506+LPS, rat mortalities were 0%, 10%, 48%, 8%, 20%, 38% and 0%, and hepatocyte viabilities were 93+/-3%, 80+/-3%, 52+/-8%, 88+/-1%, 70+/-3%, 80+/-4% and 82+/-3%, respectively. AG+LPS or L-NAME+LPS administration was followed by excessive vacuolization of hepatocytes with lesions in the intermediary lobule zone characterized by features of secondary necrosis as a continuation of apoptotic processes. SNAP+L-NAME+LPS resulted in a well-preserved structure of central vein lobules with sparse signs of apoptosis. Treatment with LPS or CM increased iNOS expression in hepatocyte culture, which was inhibited by L-NAME, FK 506 or AG. AG reduced LPS-induced rise in alanine aminotransferase leakage. LPS-induced NO exerts cytoprotective effects in vivo, while LPS-induced NO in vitro appears to be toxic. Based on the data of this report, one cannot use in vitro results to predict in vivo responses to LPS-induced NO production. The pharmacological modulation of iNOS expression or NO production in vivo or in vitro, therefore, by the development of specific NO donors or inhibitors is promising for improvement of hepatocyte functions under the two experimental conditions, respectively.
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PMID:Nitric oxide synthase inhibitors modulate lipopolysaccharide-induced hepatocyte injury: dissociation between in vivo and in vitro effects. 1455 88

The aim of this study was to investigate the role of nitric oxide (NO) in hepatic ischemia-reperfusion (I/R) injury in rats. Immunohistochemistry was used to examine the protein expression of endothelial and inducible nitric oxide synthases (eNOS, iNOS) and nitrotyrosine after I/R challenges to the liver, and blood levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), hydroxyl radical and NO were measured before ischemia and after reperfusion. Ischemia was induced by occlusion of the common hepatic artery and portal vein for 40 min, followed by reperfusion for 90 min. Reperfusion of the liver induced a significant increase in the blood concentrations of AST, ALT, LDH (n = 8; P < 0.001), hydroxyl radical (n = 8; P < 0.001) and NO (n = 8; P < 0.01). The eNOS, iNOS, nitrotyrosine, SOD1 and SOD2 protein expression was also found to increase significantly after reperfusion (n = 3). Administration of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (n = 8) had a protective effect on the I/R-related injury, but the NO donor L-arginine (L-Arg) (n = 8) potentiated the damage caused by I/R. These results suggest that reperfusion of the liver induces expression of NOS, which is related to the elevation of blood NO. The increase in hydroxyl radical concentration was accompanied by an increase in antioxidant enzyme expression (SOD1 and SOD2), and an increase in nitrotyrosine expression was also observed, reflecting the increased production of NO and oxygen radicals. We concluded from the protective effect of L-NAME and the potentiation by L-Arg that NOS expression and increases in NO and hydroxyl radical production have deleterious effects on the response to I/R in the liver.
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PMID:Ischemia and reperfusion of liver induces eNOS and iNOS expression: effects of a NO donor and NOS inhibitor. 1561 29


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