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 objective of the present study was to determine the effects of concanavalin A (Con A) administration on the interleukin 1beta converting enzyme (ICE) activity and CPP32-like activity in mouse liver. Treatment with Con A (0.2 mg/mouse, i.v.) caused an elevated plasma alanine aminotransferase (ALT) level at 8 hr after Con A injection. ICE activity was decreased at 8 and 24 hr after Con A treatment. In contrast, CPP32-like activity was increased at 24 hr after Con A injection. Since CPP32-like activity was induced after ALT had increased, the induction of CPP32-like activity may not be involved in Con A-induced hepatitis.
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PMID:Induction of CPP32-like activity and inhibition of interleukin 1beta converting enzyme activity in the liver of a mouse concanavalin A-induced hepatitis model. 971 74

The mechanism of liver cell injury induced by an overdose of the analgesic acetaminophen (AAP) remains controversial. Recently, it was hypothesized that a significant number of hepatocytes die by apoptosis. Since caspases have been implicated as critical signal and effector proteases in apoptosis, we investigated their potential role in the pathophysiology of AAP-induced liver injury. Male C3Heb/FeJ mice were fasted overnight and then treated with 500 mg/kg AAP. Liver injury became apparent at 4 h and was more severe at 6 h (plasma ALT activities: 4110 +/- 320 U/liter; centrilobular necrosis). DNA fragmentation increased parallel to the increase of plasma ALT values. At 6 h there was a 420% increase of DNA fragmentation and a 74-fold increase of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells located predominantly around central veins. However, the activity of the proapoptotic caspase-3 was not increased at any time after AAP. In contrast, injection of the anti-Fas antibody Jo-2 (positive control) caused a 28-fold increase of caspase-3 activity and severe DNA fragmentation before significant ALT release. Treatment with the caspase inhibitor ZVAD-CHF2 had no effect on AAP toxicity but completely prevented Jo-mediated apoptosis. In contrast, Jo-induced caspase activation and apoptosis could be inhibited by AAP treatment in a time- and dose-dependent manner. We conclude that AAP-induced DNA fragmentation does not involve caspases, suggesting a direct activation of endonucleases through elevated Ca2+ levels. In addition, electrophilic metabolites of AAP may inactivate caspases or their activation pathway. This indicates that AAP metabolism has the potential to inhibit signal transduction mechanisms of receptor-mediated apoptosis.
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PMID:Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice. 1022 10

Interferon-gamma (IFN-gamma) transgenic mice strongly express IFN-gamma in the liver and develop chronic hepatitis. Furthermore, hepatocyte apoptosis was shown by the TdT-mediated dUTP-biotin nick endlabeling method. In the present study, interleukin-1beta-converting enzyme (ICE) and CPP32-like protease activities in the liver of IFN-gamma transgenic mice were measured, using the synthetic substrates Ac-YVAD-MCA and Ac-DEVD-MCA. Plasma aspartate aminotransferase and alanine aminotransferase activities as well as CPP32-like activity were significantly elevated, while ICE activity was significantly reduced. The addition of the ICE inhibitor Ac-YVAD-CHO to IFN-gamma transgenic mouse liver cell cytosol had no effect on the CPP32 activity, in contrast to a CPP32 inhibitor. The present results indicate that chronic hepatitis in the IFN-gamma transgenic mouse is associated with a decrease in ICE and induction of CPP32-like activity.
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PMID:Chronic hepatitis in interferon-gamma transgenic mice is associated with elevated CPP32-like activity and interleukin-1beta-converting enzyme activity suppression. 1023 Aug 56

The effect of cyclosporine A (CsA) on anti-Fas antibody-induced hepatitis was studied. The administration of anti-Fas antibody (250 microg/kg) to mice elevated plasma alanine aminotransferase (ALT) activity at 3 hr. This anti-Fas antibody-induced elevation of ALT was inhibited by treatment with CsA (10, 30 and 100 mg/kg) in a dose-dependent manner. Anti-Fas antibody administration elevated CPP32-like protease activity at 3 hr in mouse liver, and this elevation of CPP32-like activity was inhibited by treatment with CsA. The present results show that CsA treatment inhibits the anti-Fas antibody-induced apoptotic process of hepatitis, at least in part, by affecting a reaction upstream of CPP32-like protease activation.
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PMID:The protective effect of cyclosporine A on anti-Fas antibody-induced hepatitis in mice. 1036 89

We investigated whether tumor necrosis factor (TNF) and caspase-3 activity are involved in the induction of hepatocellular apoptosis in D-galactosamine (D-GalN)-induced hepatotoxicity in mice. Acute hepatotoxicity was induced by the intraperitoneal injection of D-GalN into female BALB/c mice. D-GalN (0.75-3.0 g/kg) increased the serum glutamate pyruvate transaminase (s-GPT) activity and the percentage of liver DNA fragmentation, an indicator of hepatotoxicity, after 48 h, in a dose-dependent manner. Furthermore, after D-GalN (3.0 g/kg) administration, increased liver DNA fragmentation was detected biochemically at 24 h, then increased s-GPT activity accompanied by increased liver DNA fragmentation was observed after 48 h. The serum TNF (s-TNF) level and the TNF mRNA expression in the liver after D-GalN (3.0 g/kg, i.p.) administration were examined by an ELISA kit and reverse transcription polymerase chain reaction (RT-PCR), respectively, to investigate the relation between the s-GPT activity and liver DNA fragmentation. The s-TNF level and TNF mRNA expression in the liver after D-GalN (3.0 g/kg) administration were detected earlier than liver DNA fragmentation, then increased with time. However, there was almost no association of caspase-3 activity with the increase in liver DNA fragmentation. Increases in the s-TNF level, TNF mRNA expression and the percentage of DNA fragmentation in the liver and s-GPT activity were inhibited by dexamethasone (Dex; 0.4-2.5 mg/kg, i.p.) in a dose-dependent manner. Based on these findings, it was considered that the intracellular apoptosis signal in D-GalN-induced hepatotoxicity in mice did not depend on caspase-3 activity, and that other signals mediated by TNF may be involved.
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PMID:D-galactosamine-induced mouse hepatic apoptosis: possible involvement with tumor necrosis factor, but not with caspase-3 activity. 1054 70

The effect of pentoxifylline on anti-Fas antibody-induced hepatitis was studied. The administration of anti-Fas antibodies (250 microg/kg, i.v.) to mice elevated plasma alanine aminotransferase (ALT) activity at 3 h. This anti-Fas antibody-induced elevation of ALT was inhibited by treatment with pentoxifylline at the doses of 10 and 100 mg/kg (i.p.). Anti-Fas antibody administration also elevated the CPP32-like protease activity in the liver at 3 h. Although pentoxifylline at 100 mg/kg, i.p., inhibited the anti-Fas antibody-induced elevation of plasma ALT, this treatment did not significantly inhibit the anti-Fas antibody-induced elevation of CPP32-like activity. The present results clearly showed that treatment with pentoxifylline inhibited anti-Fas antibody-induced hepatitis, at least in part, by affecting a reaction downstream of CPP32-like protease activation.
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PMID:Pentoxifylline inhibits anti-Fas antibody-induced hepatitis by affecting downstream of CPP32-like activity in mice. 1056 69

Aminoguanidine is an inhibitor of inducible nitric oxide synthase (iNOS) and is of potential clinical usefulness. Treatment of mice with anti-Fas antibodies (150 microg/kg, i.v.) induced elevation of plasma alanine aminotransferase activity at 4 h and this elevation was inhibited by pretreatment of mice with aminoguanidine (3, 10 and 30 mg/kg, i.p.). The anti-Fas antibody-induced elevation of caspase-3 activity was inhibited by aminoguanidine (30 mg/kg, i.p.), but the addition of aminoguanidine to the cytosol up to 10(-4) M did not inhibit the caspase-3 activity in vitro. Thus, aminoguanidine prevents anti-Fas antibody-induced hepatitis by affecting the apoptotic pathway upstream of caspase-3 activation.
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PMID:Inhibition of anti-Fas antibody-induced hepatitis by aminoguanidine in mice. 1097 30

Lymphocytes can kill target cells including hepatocytes during various inflammatory diseases by Fas receptor-mediated apoptosis. Caspase-8 is activated at the receptor level, thereby initiating the processing of downstream effector caspases. The aim of this study was to investigate the time course of caspase-8 activation and to evaluate the efficacy of the caspase-8 inhibitor IETD-CHO in a model of Fas-induced apoptosis in vivo. C3Heb/FeJ mice were treated with the anti-Fas antibody Jo-2 (0.6 mg/kg). Western blot analysis demonstrated increased cytochrome c in the cytosol (20 min), which was followed by the progressive activation of caspase-3, -9 (40-120 min), and caspase-8 (120 min). At 90 and 120 min, extensive hemorrhage was observed, indicating damage to sinusoidal lining cells. In addition, high plasma ALT levels (997 +/- 316 U/L) and histological evaluation indicated severe parenchymal cell injury. Parenchymal and nonparenchymal cells showed a similar increase in caspase-3 activity and DNA fragmentation. Treatment with IETD-CHO (10 mg/kg) attenuated the increase in caspase-3 activity and DNA fragmentation by 80-90% and completely prevented hemorrhage and parenchymal cell damage. IETD-CHO also prevented the early release of mitochondrial cytochrome c and the processing of caspase-3, -8, and -9. Thus, our data support the hypothesis that Fas-mediated apoptosis is dependent on caspase-8 activation in hepatocytes and nonparenchymal cells. However, the bulk of procaspase-8 is processed late, suggesting that only a small amount of procaspase-8 may actually be activated at the Fas receptor. This initial signal may be amplified by further activation of caspase-8 by effector caspases, i.e., after mitochondrial activation. Caspase-8 is a promising therapeutic target for inhibition of Fas-mediated apoptosis.
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PMID:Protection against Fas receptor-mediated apoptosis in hepatocytes and nonparenchymal cells by a caspase-8 inhibitor in vivo: evidence for a postmitochondrial processing of caspase-8. 1105 47

Excessive apoptotic cell death is implicated in a growing number of acute and chronic disease states. Caspases are critical for the intracellular signaling pathway leading to apoptosis. The aim of this investigation was to evaluate the efficacy and the mechanism of action of the novel caspase inhibitor CV1013 in a well-characterized model of TNF-induced apoptosis. Administration of 700 mg/kg galactosamine/100 microg/kg endotoxin (Gal/ET) induced hepatocellular apoptosis in C3Heb/FeJ mice as indicated by increased caspase-3 activity (706% above controls) and enhanced DNA fragmentation (3400% above controls) at 6 h. In addition, apoptosis was aggravated by the neutrophil-induced injury at 7 h (ALT activities: 4220 +/- 960 U/L and 48 +/- 4% necrosis). All animals died 8-12 h after Gal/ET treatment from shock and liver failure. A dose of 10 or 1 mg/kg of CV1013 administered three times (3, 4.5, and 5.5 h after Gal/ET) effectively prevented caspase-3 activation and parenchymal cell apoptosis at 6 h as well as the subsequent neutrophil-induced aggravation of the injury at 7 h after Gal/ET treatment. Animals treated with 10 mg/kg CV1013 survived for 24 h without liver injury. CV1013 reduced the processing of caspase-3 and caspase-8. This suggests that CV1013 may have inhibited the small amount of active caspase-8 generated at the receptor level. Because of the multiple amplification loops used to activate the entire caspase cascade, blocking the initial intracellular signal by CV1013 was highly effective in preventing apoptotic cell death. CV1013 has therapeutic potential for disease states with excessive apoptosis.
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PMID:Protection against TNF-induced liver parenchymal cell apoptosis during endotoxemia by a novel caspase inhibitor in mice. 1107 99

Hepatocyte growth factor (HGF) has a potent antiapoptotic effect on hepatocytes in D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-treated rats. Here, we report that adenovirus mediated HGF gene transfer into liver prevents liver failure and reduces mortality of rats treated with d-GalN/LPS. Fisher 344 rats, which were given intraperitoneal injections of pAxCAHGF 48 h before, were treated with D-GalN/LPS. Serum ALT in the HGF group at 6 and 12 h after D-GalN/LPS was decreased to 1/6 and 1/12 of the control group (P < 0.01, each). Concomitant reduction of apoptotic cells were also observed. The Kaplan-Meier analysis showed that a survival rate in the HGF group was improved, compared to that in the control group (P < 0.05). Caspase-3 activity in the HGF group decreased, compared to that in the control group, especially at 12 h (P < 0.05), although it maintained a high level in the control group. Expression of Bcl-xL and cyclooxygenase-2 (Cox-2) was induced in liver by HGF gene transfer. These data suggest that HGF exerts an antiapoptotic effect through dual induction of Bcl-xL and Cox-2, which suppresses caspase-3 activity.
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PMID:Adenovirus-mediated hepatocyte growth factor gene transfer prevents lethal liver failure in rats. 1109 40


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