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)

Liver transplantation is the only therapeutic option for patients with end-stage liver disease. Nitric oxide, a free radical produced from L-arginine, a potent vasodilator, also inhibits platelet adhesion and aggregation, reduces adhesion of leukocytes to the endothelium and suppresses proliferation of vascular smooth muscle cells. The inducible form of the nitric oxide synthase may generate large quantities of nitric oxide, and may be induced by the action of cytokines and lipopolysaccharides. Nitric oxide can be released from the hepatic vascular endothelium, platelets and Kupffer cells as a response to ischemia-reperfusion injury and circulatory shock. We analyzed the relationships between the levels of nitric oxide, hepatic enzymes and other clinical parameters (glucose, total proteins, total bilirubin, creatinine, albumin) obtained in serum samples before liver transplantation and every 48 h till day 15 in 15 patients aged 40 +/- 13 years. Aspartate aminotransferase and alanine aminotransferase levels changed from high at the beginning, to almost normal at the end of the study, cholinesterase levels remained decreased throughout the study and nitric oxide remained high, never reaching normal values.
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PMID:Nitric oxide in liver transplantation. 1175 5

We recently reported that following a toxic dose of acetaminophen to mice, tyrosine nitration occurs in the protein of cells that become necrotic. Nitration of tyrosine is by peroxynitrite, a species formed from nitric oxide (NO) and superoxide. In this manuscript we studied the effects of the NO synthase inhibitors N-monomethyl-l-arginine (l-NMMA), N-nitro-l-arginine methyl ester (NAME), l-N-(1-iminoethyl)lysine (l-NIL), and aminoguanidine on acetaminophen hepatotoxicity. Acetaminophen (300 mg/kg) increased serum nitrate/nitrite and alanine aminotransferase (ALT) levels, indicating increased NO synthesis and liver necrosis, respectively. None of the NO synthase inhibitors reduced serum ALT levels. In fact, l-NMMA, l-NIL, and aminoguanidine significantly augmented acetaminophen hepatotoxicity at 4 h. A detailed time course indicated that aminoguanidine (15 mg/kg at 0 h and 15 mg/kg at 2 h) significantly increased serum ALT levels over that for acetaminophen alone at 2 and 4 h; however, at 6 and 8 h serum ALT levels in the two groups were identical. At 2 h following acetaminophen plus aminoguanidine NO synthesis was significantly increased; however, at 4, 6, and 8 h NO synthesis was significantly decreased. Aminoguanidine also decreased acetaminophen-induced nitration of tyrosine. Acetaminophen alone did not induce lipid peroxidation, but acetaminophen plus aminoguanidine significantly increased hepatic lipid peroxidation (malondialdehyde levels) at 2, 4, and 6 h. These data are consistent with NO having a critical role in controlling superoxide-mediated lipid peroxidation in acetaminophen hepatotoxicity. Thus, acetaminophen hepatotoxicity may be mediated by either lipid peroxidation or by peroxynitrite.
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PMID:Effect of inhibitors of nitric oxide synthase on acetaminophen-induced hepatotoxicity in mice. 1189 Jul 40

This study aimed to evaluate the effects of the nitric oxide donor molsidomine on the early stages of liver damage and biochemical changes in rats with bile duct ligation (BDL). Forty prepubertal male Sprague-Dawley rats weighing 125-140 g were studied. Group 1 rats (sham-control, n = 10) were not subjected to any surgical manipulation. Group 2 rats (BDL/untreated, n = 10) were subjected to BDL but no drug was administered. Group 3 rats (BDL/L-NAME, n = 10) received a daily dose of N(G)-nitro-L-arginine methyl ester (L-NAME) intraperitoneally for 7 days after BDL. Group 4 rats (BDL/molsidomine, n = 10) received a daily dose of molsidomine by gastric tube for 7 days after BDL. After 1 week, biochemical and histological evaluations were performed and the liver hydroxyproline content was measured. Serum bilirubin and liver enzymes were significantly increased in the BDL/untreated, BDL/L-NAME and BDL/molsidomine groups in comparison with the sham-control group 1 week after BDL. However, the liver enzymes were significantly decreased in the BDL/molsidomine group in comparison with the BDL/untreated and BDL/L-NAME groups. In the BDL/L-NAME group, proliferation of portal and periportal biliary ductules with disorganization of the hepatocyte plates, dilated portal spaces and areas of polymorphonuclear leukocyte infiltration, fibrosis and hepatocyte necrosis were observed. In the BDL/molsidomine group, polymorphonuclear leukocyte infiltration, hepatocyte necrosis and fibrosis were rarely seen. The hydroxyproline content in the liver was increased 1 week after obstruction in the BDL/untreated and BDL/L-NAME groups when compared to BDL/molsidomine group. Collagen type-IV expression was not observed in the BDL/molsidomine group in contrast to the BDL/untreated and BDL/L-NAME groups. In conclusion, during 1 week of treatment, the nitric oxide donor molsidomine improved hepatic fibrosis in the hepatic parenchyma and did not affect serum bilirubin values, but positively affected the serum aspartate aminotransferase and alanine aminotransferase values.
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PMID:Effects of the nitric oxide donor molsidomine on the early stages of liver damage in rats with bile duct ligation: a biochemical and immunohistochemical approach. 1214 54

Ischemic preconditioning (IPC) may increase the hepatic tolerance of ischemic injury during liver surgery and transplantation via nitric oxide (NO) formation. This study investigates the effect of IPC on hepatic tissue oxygenation and the role of NO stimulation and inhibition on the preconditioning effect in the rat liver. Study groups had 1) sham laparotomy; 2) 45-min lobar liver ischemia and 2-h reperfusion (IR); 3) IPC with 5-min ischemia and 10-min reperfusion before IR; 4) L-arginine before IR; and 5) Nw-Nitro-L-arginine methyl ester (L-NAME) + IPC before IR. Hepatic tissue oxygenation was monitored by near-infrared spectroscopy. Plasma alanine aminotransferase and plasma nitrite/nitrate were measured. Following IR there was significant decrease in oxyhemoglobin and cytochrome oxidase and an increase in deoxyhemoglobin (PA redox state, PL-arginine did not attenuate the impairment in hepatic tissue oxygenation after IR (P>0.05 vs IR). In contrast, inhibition of NO synthesis blocked the effect of IPC and further impaired tissue oxygenation (decreased cytochrome oxidase CuA redox state and increased deoxyhemoglobin, both PL-arginine and increased by NO blockade with L-NAME (Plasma ALT, all P< 0.05 vs IR). Hepatic tissue oxygenation correlated significantly with ALT and plasma nitrite/nitrate. Ischemic preconditioning significantly improved hepatic intra cellular oxygenation and reduced hepatocellular injury. NO stimulation reduced hepatocellular injury, whereas inhibition of nitric oxide synthesis blocked the effect of IPC and reduced tissue oxygenation and increased hepatocellular injury.
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PMID:The relationship of hepatic tissue oxygenation with nitric oxide metabolism in ischemic preconditioning of the liver. 1220 3

We have recently reported that female mice are protected to a much greater extent from the injurious effects of reduced-size liver ischemia and reperfusion (RSL+I/R) than are males by an estrogen-dependent mechanism. The objective of this study was to examine the possibility that the protective effect observed in female mice depends on the up-regulation and/or activation of endothelial cell NO synthase (eNOS). Anesthetized female and male wild-type or eNOS-deficient C57BL/6 mice were subjected to 70% liver ischemia for 45 min followed by resection of the remaining 30% nonischemic lobes and reperfusion of ischemic tissue. Survival was monitored daily, whereas liver injury was quantified by using serum alanine aminotransferase determinations and histopathology. Hepatic eNOS mRNA, protein, and enzymatic activity were determined in male and female mice subjected to RSL+I/R. We found that liver injury was reduced and survival increased in female mice compared with males. This protective effect correlated with significant increases in hepatic eNOS message levels and enzyme activity but not protein expression compared with males subjected to the surgery. Furthermore, N(omega)-nitro-L-arginine methyl ester-treated or eNOS-deficient female mice responded to RSL+I/R with dramatic increases in liver injury and 100% mortality within 2 days of surgery. Finally, we found that pravastatin pretreatment significantly attenuated hepatocellular injury and increased survival of male mice, which was associated with enhanced expression of eNOS message. We conclude that the protective effect afforded female mice is due to the activation of hepatic eNOS activity and enhanced NO production.
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PMID:Sexual dimorphism in reduced-size liver ischemia and reperfusion injury in mice: role of endothelial cell nitric oxide synthase. 1252 62

The metabolism of [1-13C]glucose in the vegetative mycelium of the ectomycorrhizal ascomycete Tuber borchii was studied in order to characterize the biochemical pathways for the assimilation of glucose and amino acid biosynthesis. The pathways were characterized using nuclear magnetic resonance spectroscopy in conjunction with [1-13C]glucose labeling. The enzymes of mannitol cycle and ammonium assimilation were also evaluated. The majority of the 13C label was incorporated into mannitol and this polyol was formed via a direct route from absorbed glucose. Amino acid biosynthesis was also an important sink of assimilated carbon and 13C was mainly incorporated into alanine and glutamate. From this intramolecular 13C enrichment, it is concluded that pyruvate, arising from [1-13C]glucose catabolism, was used by alanine aminotransferase, pyruvate dehydrogenase and pyruvate carboxylase before entering the Krebs cycle. The transfer of 13C-labeled mycelium on [12C]glucose showed that mannitol, alanine, and glutamate carbon were used to synthesize glutamine and arginine that likely play a storage role.
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PMID:Carbohydrate and amino acid metabolism in Tuber borchii mycelium during glucose utilization: a (13)C NMR study. 1278 75

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

1. Complement activation is implicated in the pathogenesis of intestinal ischaemia-reperfusion injury (I/R), although the relative importance of individual complement components is unclear. A C3a receptor antagonist N(2)-[(2,2-diphenylethoxy)acetyl]-l-arginine (C3aRA) has been compared with a C5a receptor antagonist (C5aRA), AcF-[OPdChaWR], in a rat model of intestinal I/R. 2. C3aRA (IC(50)=0.15 microm) and C5aRA (IC(50)=0.32 microm) bound selectively to human polymorphonuclear leukocyte (PMN) C3a and C5a receptors, respectively. Effects on circulating neutrophils and blood pressure in the rat were also assessed. 3. Anaesthetised rats, subjected to intestinal ischaemia (30 min) and reperfusion (120 min), were administered intravenously with either (A) the C3aRA (0.1-1.0 mg x kg(-1)); the C5aRA (1.0 mg x kg(-1)); the C3aRA+C5aRA (each 1.0 mg x kg(-1)); or vehicle, 45 min prior, or (B) the C3aRA (1.0 mg x kg(-1)) or vehicle, 120 min prior to reperfusion. 4. The C3aRA and C5aRA, administered 45 min prior to reperfusion, displayed similar efficacies at ameliorating several disease markers (increased oedema, elevated ALT levels and mucosal damage) of rat intestinal I/R. The combination drug treatment did not result in greater injury reduction than either antagonist alone. However, doses of the C3aRA (0.01-10 mg x kg(-1)) caused transient neutropaenia, and the highest dose (10 mg x kg(-1)) also caused a rapid and transient hypertension. 5. The C3aRA (1.0 mg x kg(-1)), delivered 120 min prior to reperfusion to remove the global effect of C3aRA-induced neutrophil sequestration, did not attenuate the markers of intestinal I/R, despite persistent C3aR antagonism at this time. 6. C3aR antagonism does not appear to be responsible for the anti-inflammatory actions of this C3aRA in intestinal I/R in the rat. Instead, C3aRA-mediated global neutrophil tissue sequestration during ischaemia and early reperfusion may account for the protective effects observed.
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PMID:Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury. 1515 77

The present study was designed to examine the effects of the donor of nitric oxide (NO), NaNO(2) and the inhibitor of NO synthase, N(omega)-nitro-L-arginine (L-NNA), on the development of dimethylnitrosamine (DMNA)-induced chronic hepatitis in rats. L-NNA decreased rat survival and enhanced the severity of hepatic encephalopathy in the DMNA-treated animals. The aggravation of the morphological signs of hepatitis, the activation of serum alanine aminotransferase and cytosolic superoxide dismutase activities and the increase in the liver malondialdehyde content were observed in this group. The treatment with NaNO(2) improved liver morphology, decreased serum marker enzyme activities, lowered the activities of alpha-D-mannosidase and N-acetyl-beta-D-glucosaminidase compared to the DMNA-treated group. The results of the morphological and biochemical studies suggest that L-NNA increased DMNA-induced liver damage, whereas NaNO(2) partially prevented the development of chronic hepatitis. It is proposed that the opposite effects of L-NNA and NaNO(2) are partially explained by a modulation of the free radical-dependent processes in the liver.
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PMID:Effect of the nitric oxide donor and the nitric oxide synthase inhibitor on the liver of rats with chronic hepatitis induced by dimethylnitrosamine. 1559 49

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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