Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pharmacokinetics and hepatotoxicity of diclofenac was studied in a recirculating model of isolated perfused rat liver. Ten male Sprague-Dawley rat (weighing 230-330 g) livers were perfused for 2 h with 250 mL Krebs-Henseleit bicarbonate buffer that contained 10.75 mg (group A, n = 5) and 1.075 mg (group B, n = 5) of diclofenac (approximately 100 and 10 times the therapeutic dose in man, respectively). Samples were collected from the efflux at regular time intervals for the determination of diclofenac concentrations by a high performance liquid chromatography (HPLC) method. Pharmacokinetic analyses were carried out using a computer program. To establish viability of the liver and toxicity of the drug, enzyme activity measurements of lactate dehydrogenase (LDH), aspartate aminotransferase (SGOT) and piruvate aminotransferase (SGPT) were performed by a spectrophotometric method. Oxygen consumption was also recorded during the entire perfusion period. Both groups presented bicompartmental kinetics. Concentration profiles showed that group B had a better metabolizing capacity, reflected in a 85.54 +/- 37.05 min half-life, a 0.52 +/- 0.19 mL min-1 g-1 liver clearance and a 0.517 +/- 0.188 extraction ratio, compared to group A, which presented a 123.95 +/- 88.13 min half-life, a 0.1164 +/- 0.067 mL min-1 g-1 liver clearance (P < 0.002) and a 0.116 +/- 0.680 extraction ratio (P < 0.002). LDH activity showed a significant increase in group A at 90 min in comparison with the control group, while in group B this increase was significantly higher at 10 min (P < 0.004). The aminotransferase levels did not show a significant increase. According to these results, diclofenac would not have a direct hepatotoxic effect, even at doses 100 times higher than therapeutic ones.
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PMID:Pharmacokinetics and hepatotoxicity of diclofenac using an isolated perfused rat liver. 920 85

To evaluate the role of nitric oxide (NO) in hepatic microcirculation and liver injury during endotoxemia, we studied O2 transport in the hepatic microcirculation of endotoxin-infused rats. Rats were continuously infused with Escherichia coli lipopolysaccharide (LPS) (0.8 mg/kg/h) for 7 hours. LPS increased the plasma levels of NO2- + NO3- and aspartate transaminase (AST), and decreased the bile flow rate and hepatic adenosine triphosphate (ATP) level. Hepatic microcirculation was evaluated by two methods: reflectance spectrophotometry showed a decrease in the oxygenation of hemoglobin (Hb) in the liver, and dual-spot microspectroscopy indicated that LPS administration decreased blood velocity, the oxygenation of Hb, and O2 release from sinusoids to hepatocytes. The observed decreases in the O2 transport parameters were prominent in pericentral sinusoids. All of these phenomena were further aggravated by the administration of N(w)-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg/h) plus LPS, and by aminoguanidine (AMG) (5 mg/kg/h) plus LPS, and these could be reversed by the concomitant administration of L-arginine (L-Arg) (100 mg/kg/h). These results suggest that deterioration of hepatic oxygen transport and liver function induced by endotoxin can be ameliorated by NO.
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PMID:Role of nitric oxide in oxygen transport in rat liver sinusoids during endotoxemia. 925 43

1. Living-related liver transplantation has some advantages in the evaluation of novel clinical protocols, since many complicated factors affecting initial graft function are almost uniform in grafts obtained from healthy donors. 2. To compare histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solution in terms of tissue oxygenation in living-related liver transplantation, oxygen saturation of haemoglobin (SO2) in hepatic tissue and its heterogeneity (CV, coefficient of variation) were measured by near-infrared spectroscopy. The HTK and UW groups consisted of 15 and 49 successful transplants respectively, in which no statistical differences in background were observed. 3. In the HTK group, hepatic SO2 after portal vein reflow was higher (P < 0.01) than that in the UW group, as was that after hepatic artery reflow (P < 0.05). In the UW group, hepatic SO2 remained at the lower level at the end of the operation. 4. Furthermore, the increase in CV after portal vein reflow was normalized after hepatic artery reflow in the HTK group. However, the CV remained at a high level at the end of the operation in the UW group. 5. Postoperative peak aspartate aminotransferase level in the HTK group was lower than that in the UW group (P < 0.05). 6. In cadaveric liver transplantation, higher hepatic SO2 and lower CV of hepatic SO2 in the early phase after reperfusion compared with the UW group (n = 18) were also observed in the HTK group (n = 30) (P < 0.05). 7. In conclusion, recovery of tissue oxygenation and its heterogeneity after reperfusion in HTK-preserved livers were more rapid and homogeneous than in UW-preserved livers in living-related liver transplantation. Accordingly, HTK solution may be a potential alternative to UW solution.
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PMID:Hepatic preservation with histidine-tryptophan-ketoglutarate solution in living-related and cadaveric liver transplantation. 927 7

Tacrine is an acetylcholinesterase inhibitor approved for the treatment of Alzheimer's disease. Unfortunately, reversible hepatotoxicity in about 30% of patients at therapeutic doses limits clinical use. The purpose of this study was to develop and characterize a model of tacrine hepatotoxicity to begin to understand the mechanisms of injury. Rats were given tacrine (10-50 mg/kg, intragatrically) and killed 24 hr later. An increase in serum aspartate aminotransferase was observed up to 35 mg/kg and histology revealed pericentral necrosis and fatty changes. Aspartate aminotransferase was increased from 12 to 24 hr and returned to control values by 32 hr. Livers were perfused in a nonrecirculating system to measure oxygen uptake and trypan blue was infused at the end of each experiment to evaluate tissue perfusion. Time for trypan blue to distribute evenly throughout the liver 3 hr after tacrine treatment was significantly increased (6.9 +/- 1.3 min) compared to controls (1.0 +/- 0.3 min) reflecting decreased tissue perfusion. Tacrine also significantly increased the binding of a hypoxia marker, pimonidazole, in pericentral regions almost 3-fold, and increased portal pressure in vivo significantly. It is hypothesized that tacrine, by inhibiting acetylcholine breakdown in the celiac ganglion, increases sympathetic activity in the liver leading to vascular constriction, hypoxia and liver injury. To test this hypothesis, the hepatic nerve was severed and animals were allowed to recover before tacrine treatment. This procedure significantly reduced serum aspartate aminotransferase, time of dye distribution, pimonidazole binding and portal pressure. Furthermore, a free radical adduct was detected with spin trapping and electron spin resonance spectroscopy 8 hr after tacrine treatment, providing evidence for reoxygenation. When catechin (100 mg/kg, i.p.), a free radical scavenger, was given before tacrine, injury was decreased by about 45%. Furthermore, feeding 5% arginine in the diet significantly reduced portal pressure and time of dye distribution. These data are consistent with the hypothesis that tacrine hepatotoxicity is a hypoxia-reoxygenation injury mediated through the sympathetic nervous system.
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PMID:Development and characterization of a new model of tacrine-induced hepatotoxicity: role of the sympathetic nervous system and hypoxia-reoxygenation. 931 76

A 79-year-old female was admitted to our hospital because of a malignant pleural effusion following mastectomy 4 years ago. In the patient's history arterial hypertension and previous inferior myocardial infarction have been known. Two doses of 20 mg mitoxantrone were installed intrapleurally at an interval of 4 weeks. Six hours after the second mitoxantrone application and the patient had increasing dyspnea with consecutive left heart failure, pulmonary congestion, and a drop of blood pressure. The white-cell count was 14800/mm3. The levels of creatinine phosphokinase (CPK), lactate dehydrogenase (LDH) and serum aspartate aminotransferase (SGOT) were in the normal range. Transthoracic echocardiography showed concentric left ventricular hypertrophy and a markedly decreased fractional shortening, but no left ventricular dilatation. The electrocardiogram showed newly appeared down-sloping ST-segments and inverted T-waves. Clinical recovery was achieved after 6 days by application of oxygen, dobutamine and furosemide followed by angiotensin converting enzyme inhibition and digitalis. In the echocardiographic control examination 14 days later left ventricular function had normalized. The changes of electrocardiogram normalized 4 weeks later.
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PMID:[Mitoxantrone-induced acute left heart failure after intrapleural administration]. 937 56

Medium osmolarity sensitively regulates Kupffer cell functions like phagocytosis and prostaglandin (PG) and cytokine production. Betaine and taurine, recently identified as osmolytes in liver cells, interfere with these effects. Because Kupffer cell activation is an important pathogenic mechanism in ischemia-reoxygenation injury, the influence of osmolarity and osmolytes was investigated in a rat liver perfusion model of warm ischemia. Livers were perfused with different medium osmolarities for 60 to 90 minutes in the absence of oxygen, followed by another 90 minutes of reoxygenation. Lactate dehydrogenase (LDH) leakage into the effluent perfusate during the hypoxic and the reoxygenation period was eight- to 10-fold higher with a medium osmolarity of 385 mosmol/L than in normo-osmolarity, and further decreased with hypo-osmolar perfusion buffer. Betaine and taurine addition to the perfusate in near physiological concentrations decreased hypoxia-reoxygenation-induced LDH leakage, aspartate transaminase (AST) leakage, and perfusion pressure increase in hyperosmolar and normo-osmolar perfusions. Stimulation of PGD2, PGE2, thromboxane B2 (TXB2), and tumor necrosis factor alpha (TNF-alpha) release, as well as induction of carbon uptake by the liver during reoxygenation, were suppressed by betaine and taurine, pointing to an interference of these osmolytes with Kupffer cell function. In contrast, endothelial cell function as assessed by hyaluronic acid (HA) uptake was not influenced. It is concluded that warm ischemia-reoxygenation injury in rat liver is aggravated by hyperosmolarity and attenuated by hypo-osmolarity. The osmolytes betaine and taurine have a protective effect, presumably by inhibition of Kupffer cell activation.
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PMID:Cytoprotection by the osmolytes betaine and taurine in ischemia-reoxygenation injury in the perfused rat liver. 939 98

To assess the effect of partial portal arterialization on the remaining liver after usually lethal extended hepatectomy, 30 mongrel dogs underwent 84% partial hepatectomy and were divided into three groups as follows: group 1, 84% partial hepatectomy (n = 10); group 2, 84% partial hepatectomy and splenectomy (n = 10); group 3, 84% partial hepatectomy and splenectomy and splenic artery-vein (A-V) shunt (n = 10). Another five dogs were pre-operatively killed normal controls. Portal vein flow (PVF) decreased to about 60% in groups 1 and 2, but PVF in group 3 was maintained at the pre-operative level. Oxygen saturation of portal vein blood increased markedly, to between 83% (group 1) and 88% (group 3). Portal vein pressure (PVP) increased in groups 1 and 2 by 1.6 to 1.7 times the pre-operative value, but no significant difference in PVP, serum aspartate aminotransferase (AST) and arterial ketone body ratio was found between the three groups. Plasma endotoxin levels after 84% partial hepatectomy were significantly lower in group 3 than in groups 1 and 2. Both of hepatocellular and secretory protein synthesis were enhanced in group 3 compared with the other two groups. These results suggest that partial portal arterialization using a splenic A-V shunt might bring about a beneficial effect on remaining liver function after extended hepatectomy.
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PMID:Short-term effect of portal vein arterialization on hepatic protein synthesis and endotoxaemia after extended hepatectomy in dogs. 940 25

Oxygen free radicals have been implicated in exercise-induced cell and tissue injury, indicating an oxidative stress. Fatigue accompanied by a number of physiological and metabolic changes is in indication of overtraining. This study aimed to examine the influence of a continuous 24-h intermittent speed driving (1 h driving/1 h stop), on the response of hormones, antioxidative factors, lipid, and enzyme levels. Seven race car drivers of national level were examined before, during, and immediately after the trial of speed driving on a test designed to check endurance to stress. The parameters measured were: testosterone (Tes), cortisol (Cor), IgM, IgA, cholesterol, HDL, billirubin, ceruloplasmin, urea, uric acid, creatine kinase, and transaminases. Stress hormone Cor declined significantly (p < 0.05), while Tes did not change significantly. Fatigue enzyme, aspartate transaminase (GOT) increased significantly (p < 0.05), while alanine transaminase (GPT) did not change and urea declined. Muscle enzyme, creatine kinase (CK) increased to sixfold (p < 0.01). IgA, IgM and lipids did not change. The primary antioxidant ceruloplasmin increased significantly (p < 0.001), while antioxidants uric acid and glucose remained unchanged. Among the factors measured, ceruloplasmin, cortisol, urea, GOT, and CK seem to give a picture of the organism's alertness and defence capabilities in conditions of stress and fatigue.
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PMID:Stress hormonal factors, fatigue, and antioxidant responses to prolonged speed driving. 967 60

The effects of endothelin 1 (ET-1) on hemodynamics and acute liver damage were studied using perfused livers of rats treated with D-galactosamine. In control liver perfused in situ with constant pressure, infusion of ET-1 into the portal vein at a concentration of 0.1 nmol/L decreased the flow rate without a significant leakage of lactate dehydrogenase (LDH) or aspartate transaminase (AST) into the effluent. In contrast, in similarly perfused liver 24 hours after treatment with D-galactosamine (800 mg/kg intraperitoneally), ET-1 caused rapid and remarkable increases in the leakage of LDH and AST from the liver accompanied by the reduction of perfusion flow to the extent similar to that observed in control livers. In addition, ET-1 decreased oxygen uptake and bile secretion in galactosamine-treated livers. The potentiating effects of ET-1 on enzyme leakage were also observed under constant flow conditions. Moreover, infusion of the thromboxane A2 analogue at a concentration of 10 nmol/L decreased the flow rate markedly, yet the rapid increases in enzyme leakage were not observed. Infusion of ET-3 induced the responses of flow reduction and the potentiation of rapid enzyme leakage similar to those obtained with ET-1. Neither the endothelin A-receptor antagonist BQ485 nor the endothelin B-receptor antagonist BQ788 could inhibit the acute liver damage caused by ET-1; instead they exaggerated its effects. The combination of both antagonists together, however, almost completely suppressed the flow reduction and the potentiation of enzyme leakage caused by ET-1. These results indicate that ET-1 is capable of aggravating acute liver damage not merely through reduction of the flow rate but through direct action on liver cells. They also suggest that both the endothelin A and endothelin B receptors are involved in this action of ET-1.
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PMID:Endothelin 1 aggravates acute liver injury in perfused livers of rats after treatment with D-galactosamine. 969 17

The aim of this study was to evaluate a possible relationship between lipid peroxidation, cytokine production, such as interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-alpha), and transforming growth factor beta (TGF-beta), and hepatotoxicity of rats after nickel chloride (NiCl2) acute poisoning. Administration of NiCl2 significantly elevated the levels of malondialdehyde (MDA), IL-1, TNF-alpha, and TGF-beta in the serum of rats. The dose-effect relationship for the increase of serum MDA, as observed in the present study, corresponds closely to the increase of IL-1, TNF-alpha, and TGF-beta in serum. Treatment with ascorbic acid (Vit C) significantly lowered the levels of lipid peroxidation, cytokine production, and the activities of alanine transaminase and aspartate transaminase in the serum of the rats given NiCl2. The hepatic toxicity was increased in a dose-dependent manner and corresponds to the increase of serum IL-1, TNF-alpha, and TGF-beta. There was an association between lipid peroxidation and the levels of cytokines in serum of rats after NiCl2 administration. Reactive oxygen species may serve as a mediator of lipid peroxidation and production of cytokines in NiCl2 injection.
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PMID:Association between oxidative stress and cytokine production in nickel-treated rats. 970 2


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