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 response of adenylate cyclase to GTP and to dopamine (DA) was investigated in striatal membranes from desipramine (DMI)-treated rats (10 mg/kg, b.i.d., for 5 days). GPT exerted the same biphasic effect on basal and DA-stimulated enzyme activity in membranes from DMI-treated rats as on saline-treated rats. Rats were injected intraventricularly once with islet activating protein (IAP), pertussis toxin, and given extended treatment with DMI in order to study the effects on the inhibitory GTP-binding protein (Gi). Gi loses its function as a signal transducer on being ADP-ribosylated selectively by the IAP. D2 inhibition of adenylate cyclase by DA was attenuated by the IAP treatment in both DMI-and saline-treated rats; peak levels of DA plus GTP stimulation shifted from 1 microM to 100 microM GTP. D1 stimulation of adenylate cyclase by DA was also attenuated by the IAP in the DMI-treated rats. Since long-term treatment with DMI (15 mg/kg, once a day, for 3 weeks) resulted in suppression of D1 stimulation similar to that seen in the present findings, uncoupling between D2 receptors and Gi due to IAP treatment might accelerate DMI-induced adaptive changes of dual control of adenylate cyclase system by DA.
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PMID:Acceleration of desipramine-induced changes on the dopamine receptor-coupled adenylate cyclase system by pertussis toxin. 773 10

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

Morphological changes in mitochondria are observed early in the course of acetaminophen (AA)-induced hepatotoxicity, and mitochondrial dysfunction has been observed both in vivo and in vitro following exposure to AA. This study examined the early effects of AA exposure in vivo on mitochondrial respiration and evaluated the effectiveness of N-acetyl-L-cysteine (NAC) in protecting against respiratory dysfunction. Mitochondria were isolated from the livers of fasted, male CD-1 mice 0, 0.5, 1, 1.5 or 2 h after administration of a hepatotoxic dose of AA (750 mg/kg). Glutamate- and succinate-supported mitochondrial respiration were subsequently assessed by polarographic measurement of state 3 (ADP-stimulated) and state 4 (resting) rates of oxygen consumption and determination of the corresponding respiratory control ratios (RCR: state 3/state 4) and ADP:O ratios. Hepatotoxicity was assessed histologically and by measuring plasma alanine aminotransferase (ALT) activity. The earliest sign of mitochondrial dysfunction observed in this study was a significant decrease in the ADP:O ratio for the oxidation of glutamate 1 h post-dosing. At 1.5 and 2 h post-dosing the RCRs for both glutamate- and succinate-supported respiration were significantly decreased. All of the respiratory parameters measured in this study were significantly decreased, with the exception of succinate-supported state 4 respiration which was significantly increased, 2 h after AA administration. Thus, inhibition of mitochondrial respiration preceded overt hepatic necrosis, indicated by an elevation of ALT activity, which was not observed until 3 and 4 h post-dosing. In addition, mitochondrial respiratory dysfunction correlated with morphological alterations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity. 817 80

Hamster sperm collected from the cauda epididymis were washed and the pellet diluted in a medium containing Triton x 100 (Sigma, Saint Louis, MO, USA) to dissolve the cell membrane and then reactivated with various concentrations of ATP (0-3 mM). Spermatozoal axonemes were initially immotile but the maximal percentage motility was obtained almost immediately following addition of 1 mM ATP. A stepwise increase in the concentration of ATP caused a 5-min delay in development of maximal reactivation and a change in the beating pattern as indicated by a decrease in the percentage of reactivating sperm. Under the same experimental condition GPT, UTP, CTP, and AMP failed to initiate the axonemal motility. In demembranated sperm reactivated by ADP, however, the beat frequency was lower compared with that reactivated by ATP. Pretreatment of the sperm with the mitochondrial phosphorylation blockers oligomycin and 2'4'-DNP (dinitrophenol) failed to inhibit the axonemal movement, although the presence of the dynein ATPase inhibitor, vanadate, was able to inhibit the reactivation. These results suggest that the exogenous ATP, but not the mitochondrial ATP, is responsible for axonemal motility.
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PMID:Specificity of ATP for the initiation of flagellar motility of hamster sperm. 827 42

Quinidine in vitro significantly reduced accumulation of TEA (tetraethyl ammonium) and PAH (p-amino hippurate) and inhibited oxygen consumption in renal cortical slices. Mitochondrial respiratory control index (RCI) and ADP/O ratio were decreased. Intraperitoneal administration of quinidine at 75 mg/kg twice a day for four days inhibited TEA transport in renal cortical slices and decreased oxygen consumption. Mitochondria showed a reduction in ADP/O ratio but no change in RCI. Serum biochemical measurements indicated a significant elevation in serum creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).
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PMID:In vitro and in vivo effects of quinidine on the kidneys in Fischer-344 rats. 830 84

The red blood cell metabolic parameters ATP, ADP, sigma AN, ATP/ADP, ATP/ATP, energy charge, PAD, 2,3-DPH, Pn were studied in 106 patients with generalized meningococcus infection (GMI) and meningitis of other etiology over their natural history. There was a typical adaptative red blood cell response that featured glycolytic stimulation on hypoxia that ran with impaired red blood cell energy metabolism (RBCEM), negative energy balance. It was the most pronounced at the peak of disease. RBCEM changes occurred in the presence of antioxidative disorders of red blood cells as lowered PAD levels. When early complications, such as shock, brain edema, death developed, there was a high incidence of signs of erythrocytic biochemical disadaptation. The RBCEM changes were associated with the magnitude of cytolysis, i.e. serum AST and AST/ALT levels. The significance of the metabolic changes found in the red blood cells in the pathogenesis and clinical picture of GMI and purulent meningitis is discussed in the paper.
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PMID:[Erythrocyte metabolism in meningococcal infection and purulent meningitis]. 899 64

Liver damage as a consequence of rhabdomyolysis (RM) has not been well established on clinical and experimental grounds. Hepatic dysfunction was then investigated in rats 24 h after induction of acute renal failure with glycerol. Forty male Wistar rats (220-270 g) were dehydrated for 24 h and were divided in two group: GI experimental group (n = 14)-50% glycerol was injected (10 ml/Kg, one-half of the dose in each hindlimb muscle) and GII control group (n = 26)-animals received injection of saline solution. Twenty-four hours after the glycerol or saline injection all the animals were killed. Serum urea, creatinine, transaminases (AST, ALT) and CK were measured and significantly high values were obtained in experimental animals. Arterial blood pressure was measured and remained within normal levels in both groups. Hepatocyte mitochondrial respiratory function was estimated polarographically with determination of oxygen consumption without ADP (Basal respiration-State 4) and in the presence of ADP (Activated respiration-State 3). In experimental group (GI) there was significant low values of oxygen consumption in state 3, decrease of respiratory control rate and in ADP/O ratio (p < 0.05). Histological studies of the liver revealed a periportal necrosis and centrilobular degeneration. These studies suggested that hepatic dysfunction is an additional complication of glycerol-induced rhabdomyolysis. The pathogenesis and clinical implications of these abnormalities are discussed.
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PMID:[Hepatic dysfunction in myoglobinuric acute renal failure (rhabdomyolysis)--experimental study in rats]. 923 96

Experiments were performed on eight subjects affected by peripheral arterial occlusive disease (PAOD) of the lower limbs. Each patient was submitted to Ecodoppler, angiography and the "Treadmill test". Two bioptic muscle of these patients. A sample was used for the spectrophotometric and spectrophotofluorimetric determinations of: glycogen, pyruvate, lactate, citrate, alpha-ketoglutarate, malate, aspartate, glutamate, AMP, ADP, ATP and creatine phosphate (CP). The other bioptic sample was used to determine the following enzyme activities: hexokinase, phosphofructokinase, pyruvate kinase, lactate dehydrogenase, citrate synthase, succinate dehydrogenase, malate dehydrogenase, total NADH cytochrome c reductase, cytochrome oxidase, aspartate aminotransferase and alanine aminotransferase. Patients showed an increase in lactate dehydrogenase, total NADH cytochrome c reductase and succinate dehydrogenase activities, a decrease in glycogen, ATP and CP concentrations. Telethermographic data showed patient muscle thermic emission quantitatively different from control group. The telethermographic test can be used as an additional diagnostic tool to determine and monitor the efficiency of a muscle undergoing metabolic failure.
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PMID:Instrumental and metabolic evaluation of patients affected by peripheral arterial occlusive disease (PAOD) following surgical revascularization surgery. 928 78

We studied the alterations in the metabolism of liver mitochondria in rats with acute pancreatitis. Male Wistar rats were allocated to a control group (group I) and to five other groups corresponding to 2, 4, 12, 24 and 48 h after the induction of acute pancreatitis by the injection of 5% sodium taurocholate into the pancreatic duct. Sham-operated animals were submitted to the same surgical steps except for the induction of acute pancreatitis. Mitochondrial oxidation and phosphorylation were measured polarographically by determining oxygen consumption without ADP (basal respiration, state 4) and in the presence of ADP (activated respiration, state 3). Serum amylase, transaminases (ALT and AST) and protein were also determined. Ascitic fluid, contents of amylase, trypsin and total protein were also determined and arterial blood pressure was measured in all groups. In ascitic fluid, trypsin and amylase increased reaching a maximum at 2 and 4 h, respectively. Serum amylase increased at 2 h reaching a maximum at 4 h. Serum transaminase levels increased at 12 and 24 h. After 2 h (and also 4 h) there was an increase in state 4 respiration (45.65 +/- 1.79 vs 28.96 +/- 1.50) and a decrease in respiration control rate (3.53 +/- 0.09 vs 4.45 +/- 0.08) and in the ADP/O ratio (1.77 +/- 0.02 vs 1.91 +/- 0.01) compared to controls (P < 0.05). These results indicate a disruption of mitochondrial function, which recovered after 12 h. In the 48-h groups there was mitochondrial damage similar to that occurring in ischemic lesion. Beat-to-beat analysis (30 min) showed that arterial blood pressure remained normal up to 24 h (111 +/- 3 mmHg) while a significant decrease occurred in the 48-h group (91 +/- 4 mmHg). These data suggest biphasic damage in mitochondrial function in acute pancreatitis: an initial uncoupled phase, possibly secondary to enzyme activity, followed by a temporary recovery and then a late and final dysfunction, associated with arterial hypotension, possibly related to ischemic damage.
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PMID:Hepatic damage during acute pancreatitis in the rat. 936 23

Acetaminophen (AAP), the analgesic hepatotoxicant, is a powerful inducer of oxidative stress, DNA fragmentation, and apoptosis. The anti-apoptotic oncogene bcl-XL, and the pro-apoptotic oncogene p53 are two key regulators of cell cycle progression and/or apoptosis subsequent to DNA damage in vitro and in vivo. This study investigated the effect of AAP on the expression of these oncogenes and whether agents that modulate DNA fragmentation (chlorpromazine, CPZ) and DNA repair through poly(ADP-Ribose) polymerase (PARP) activity (4-AB: 4-aminobenzamide) can protect against AAP-induced hepatotoxicity by inhibiting oxidative stress, DNA fragmentation, and/or by altering the expression of bcl-XL and p53. In addition, the protective effect of supplemental nicotinamide (NICO), known to be depleted in cells with high PARP activity during DNA repair, is similarly evaluated. Male ICR mice (3 months old) were administered vehicle alone; nontoxic doses of 4-AB (400 mg/kg, ip), NICO (250 mg/kg, ip) or CPZ (25 mg/kg, ip), hepatotoxic dose of AAP alone (500 mg/kg, ip), or AAP plus one of the protective agents 1 h later. All animals were sacrificed 24 h following AAP administration. Serum alanine aminotransferase activity (ALT), hepatic histopathology and lipid peroxidation, DNA damage, and expression of bcl-XL and p53 (western blot analysis) were compared in various groups. All of the three agents significantly prevented AAP-induced liver injury, lipid peroxidation, DNA damage, and associated apoptotic and necrotic cell deaths, 4-AB being the most effective and NICO the least. Compared to control, there was a considerable decrease in bcl-XL expression, and an increase in p53 expression in AAP-exposed livers. The effect of AAP on bcl-XL was antagonized and that on p53 was synergized by the PARP-modulator 4-AB as well as NICO, whereas the endonuclease inhibitor CPZ was without effect on either bcl-XL or p53 expression. These results suggest that the hepatotoxic effect of AAP involves multiple mechanisms including oxidative stress, upregulation of endonuclease (or caspase-activated DNAse) and alteration of pro- and anti-apoptotic oncogenes. The observed antagonism of AAP-induced hepatocellular apoptosis and/or necrosis by modulators of multiple processes including DNA repair suggests the likelihood that a more effective therapy against AAP intoxication should involve a combination of antidotes.
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PMID:Ca(2+)-calmodulin antagonist chlorpromazine and poly(ADP-ribose) polymerase modulators 4-aminobenzamide and nicotinamide influence hepatic expression of BCL-XL and P53 and protect against acetaminophen-induced programmed and unprogrammed cell death in mice. 1146 65


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