Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.109 (AST)
 6,066 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rodent liver carcinogen and hepatic peroxisome proliferator methylclofenapate (MCP) has been evaluated for genetic toxicity in a range of in vitro and rodent genotoxicity assays. It gave a negative response in each of the following assays: mutagenicity to S. typhimurium and E. coli (+/- S9 mix, plate and pre-incubation assays), clastogenicity to cultured human lymphocytes and CHO cells (+/- S9 mix), a mouse bone marrow micronucleus assay (24h and 48h sampling), a rat liver assay for UDS in vivo (12h sampling), assays for lac I (Big Blue) and lac Z (Muta Mouse) mutations in the liver of transgenic mice, and an assay of the ability of MCP to modify the mutagenicity to the liver of dimethylnitrosamine in both transgenic mutation assays. The micronucleus and UDS assays were conducted using a single administration of MCP at its maximum tolerated dose, while the transgenic assays were conducted using nine daily administrations of MCP at its cancer bioassay dose level. These nine daily administrations were shown to double the weight of the liver of non-transgenic, Big Blue and Muta Mice, as well as leading to a dramatic proliferation of peroxisomes (electron microscopy) in the livers of each strain. These changed parameters had returned to control levels when the mutation analyses were conducted (10 days after the final dose of MCP). Despite the liver enlargement observed following MCP administration, no evidence of mitotic activity was observed in treated livers, although an increased number of cells were undergoing replicative DNA synthesis during the final 3 days of the 9 days of administration (BUdR assessment of S-phase). Liver biochemistry parameters (ALT, AST, AP, CK, GGT and albumin) were unaffected by the chronic (9 day) administration of MCP indicating an absence of hepatic toxicity. These combined observations favour a non-genotoxic mechanism of action for the hepatic carcinogenicity of MCP. The clastogenicity in vitro of the perixisome proliferator Wyeth 14,643 has been confirmed in CHO cells, but it is noted that this chemical is more soluble than is MCP. In particular, at the highest dose level at which MCP could be tested, Wy 14,643 was also non-clastogenic.
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PMID:Evaluation of the genetic toxicity of the peroxisome proliferator and carcinogen methyl clofenapate, including assays using Muta Mouse and Big Blue transgenic mice. 785 96

The effects of four Diploptera punctata allatostatin peptides on the stomatogastric nervous system of the crab Cancer borealis were studied. All of the peptides had similar actions on the activity of neurons involved in rhythmic movements of the pyloric region of the stomach, decreasing the frequency of the pyloric rhythm in a dose-dependent manner. Diploptera allatostatin 3 (D-AST-3) was slightly more effective than the others. The absolute change in the frequency of the pyloric rhythm depended on the starting frequency, demonstrating that the effect of D-AST-3 depends on the preceding physiological state of the preparation. The largest decreases were observed when the starting frequency was slower than 0.8 Hz. Whole-mount immunocytochemistry with anti-Diploptera allatostatin 1 antibodies demonstrated the presence of allatostatin-like peptides in the paired commissural ganglia, the unpaired oesophageal ganglion and the stomatogastric ganglion, and in their connecting and motor nerves. Dense processes were labeled in the stomatogastric ganglion, 12-19 cell bodies and neuropil staining were found in each commissural ganglion, two cell bodies were stained in the oesophageal ganglion and two pairs of cell bodies, the gastropyloric receptor neurons, were stained in peripheral nerves.
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PMID:Allatostatin peptides in the crab stomatogastric nervous system: inhibition of the pyloric motor pattern and distribution of allatostatin-like immunoreactivity. 796 2

We report the case of an 80-year-old woman with a previous history of HBP, hysterectomy due to cancer of the uterus and cholelithiasis, who was admitted in our hospital because of diffuse abdominal pain, marked jaundice, choluria and acholia during one week, together with anorexia and loss of weight. Blood chemistry results disclosed a total bilirubin of 11 mg/dl, a direct bilirubin of 8 mg/dl, GGTP 826 U/I, alkaline phosphatase 287 U/I, AST 285 U/I, ALT 837 U/I and LDH 242 U/I. The CA 19-9 marker was higher than 500 U/ml. The abdominal ultrasound examination did not show any space-occupying lesions; the extra and intrahepatic bile ducts were very dilated and the gall bladder showed multiple stones within its contents. The endoscopic retrograde cholangiopancreatography (ERCP) showed a homogeneous filiform defect at the middle third of the common bile duct of approximately 1 cm in length and with a marked dilatation of the bile ducts. A percutaneous drainage of the bile tree was performed, but the patient died.
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PMID:[Cancer of the middle third of the choledochus: an infrequent diagnosis]. 821 88

Several biochemical events accompany and mediate the development of chronic liver disease and its evolution into cancer. Low plasma zinc and high copper levels have been observed in various liver diseases, such as liver cirrhosis and viral hepatitis, while increased oestradiol levels have been documented in chronic liver damage and hepatocellular carcinoma. We administered CCL4 intragastrically to 10 female Sprague Dawley rats for 30 weeks. All animals developed cirrhosis and four also developed hepatocellular carcinoma. Plasma levels of zinc, copper and oestradiol were significantly higher in the latter group than in animals with simple cirrhosis. Progesterone, AST and bilirubin showed a trend toward significant differences whereas testosterone and ALP levels were unchanged. These findings add to the evidence that sex hormones and trace elements are involved in the process of the development of chronic liver damage and carcinogenesis.
Eur J Cancer Prev 1993 Jul
PMID:Sex hormones and trace elements in rat CCL4-induced cirrhosis and hepatocellular carcinoma. 835 89

Light-activated merocyanine 540 (pMC540) has been shown in our earlier studies to be effective against certain types of tumor cells and viruses, including human immunodeficiency virus (HIV-1). To test the potential extracorporeal and systemic use of pMC540, its toxicity was investigated in DBA/2 mice, pigs, and dogs. The lethal dose in DBA/2 mice after an i.p. injection was 370 mg/kg, and the 50% lethal dose (LD50) was 320 mg/kg; however, following i.v. administration, the lethal dose and the LD50 dose were 240 and 160 mg/kg, respectively. Tritium-labeled MC540 was used to study the biodistribution of pMC540 in DBA/2 mice. Almost 70% of the injected radioactivity was excreted within 6 h of injection. After 1 week, the pMC540 was almost completely cleared, with only 1.89% of the activity remaining, and had a plasma half-life of 23 h. Pigs injected with an accumulated dose of 10 mg/kg and followed for a period of 30 days did not show adverse signs of toxicity as monitored by SMAC-28 analysis, CBC profile, and blood-coagulation studies. A dog injected with a single dose of 20 mg/kg showed induction of the hepatic enzymes glutamic oxaloacetic transaminase (AST) and glutamic pyruvic transaminase (AST); however, serum levels of gamma-glutamyl transpeptidase (GGT) remained unchanged. The data presented herein may serve to identify certain drug-dose limitations in the systemic use of pMC540.
Cancer Chemother Pharmacol 1993
PMID:Biodistribution and toxicity of photoproducts of merocyanine 540. 845 86

Hyperthermia has been used to treat cancer in the liver. However, significant hepatotoxicity occurs at a therapeutic temperature of 42-43 degrees C. We have proposed that heat toxicity is the result of oxidative stress from superoxide generation with resultant lipid peroxidation. Further, iron release from liver iron stores (ferritin) appears to play a central role in hyperthermic toxicity. In this study, rat livers were perfused in situ at 37 or 42.5 degrees C with and without deferoxamine for 1 h with an asanguinous perfusate. Oxidative stress was assessed by the efflux of glutathione (GSH) into the perfusage. Prior studies by Skibba et al. (1989a, 1991) showed that perfusage equivalents of GSH were primarily present as oxidized glutathione (GSSG). Lipid peroxidation was assessed by the measurement of aldehydes appearing in the perfusate and formation of hydrocarbon gases (ethane and pentane) in the perfusion chamber head space. Liver injury was assessed by the leakage of cytosolic enzymes, AST and LDH, into the perfusate. Livers perfused at 42.5 degrees C showed significant rises (p < 0.05) in AST and LDH after 60 min of perfusion but perfusion at 42.5 degrees C with deferoxamine added, was not significantly different from perfusion at 37 degrees C. Perfusion at 42.5 degrees C caused an increase in GSH into the perfusate at a level significantly (p < 0.05) greater than at 37 degrees C. GSH levels in the liver after 60 min of perfusion decreased from 4.82 +/- 0.76 microM/gm at 37 degrees C to 1.48 +/- 0.54 microM/gm at 42.5 degrees C (p < 0.05) but only fell to 3.42 +/- 1.23 microM/gm at 42.5 degrees C with deferoxamine added. Efflux of iron into the perfusate increase significantly with time and temperature. Low molecular weight chelated iron within the liver after perfusion increased from 5.88 +/- 1.46 nM/gm at 37 degrees C to 25.8 nM/gm at 42.5 degrees C (p < 0.05). Perfusate total aldehyde levels increased from 0.085 +/- 0.056 to 0.32 +/- 0.09 microM/ml after 60 min at 37 degrees C and 0.87 +/- 0.45 to 2.01 +/- 0.90 microM/ml at 42.5 degrees C (n = 8). There was a significant decrease in total aldehyde levels at 42.5 degrees C with the addition of deferoxamine to the perfusate, 0.36 +/- 0.14 to 0.86 +/- 0.27 microM/ml, when compared to 42.5 degrees C levels (p < 0.05). Levels of ethane and pentane in the perfusion chamber head space showed no significant changes with time or temperature of perfusion. The data suggest that lipid peroxidation may play a causal role in hyperthermia induced liver toxicity and that iron plays a major role in this injury. Failure of hydrocarbon analysis to support this conclusion appears related to the use of membrane oxygenators.
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PMID:Liver hyperthermia and oxidative stress: role of iron and aldehyde production. 914 47

To evaluate the safety of temporary hepatic inflow occlusion during major liver resection, we reviewed 71 consecutive noncirrhotic patients who underwent elective liver resection using this technique. There were 27 males and 44 females (mean age, 54.4 years), the majority of whom had hepatic malignancies. There were 31 right hepatectomies, 21 left hepatectomies, and 19 extended right hepatectomies. Ischemic injury of the liver was assessed using changes in postoperative liver function tests and patient outcome was assessed using morbidity and mortality rates. After preliminary ligation of the blood supply to the lobe to be removed, global hepatic ischemia was produced by temporary occlusion of the main portal vein and hepatic artery proper while the liver parenchyma was divided. The average duration of inflow occlusion was 59 minutes (range, 25 to 90 minutes). There was no operative mortality, and no patient developed liver failure. The liver enzymes reached their peak on the first postoperative day (mean aspartate aminotransferase [AST] level, 283 +/- 227 IU/L; mean alanine aminotransferase [ALT] level, 269 +/- 238 IU/L) and they returned to normal by 7 days. The most common postoperative complications were related to the chest, wound, and urinary tract. The mean intraoperative transfusion was 3.4 +/- 2.6 U of packed red blood cells, and 0.94 +/- 2.13 U of fresh frozen plasma. We conclude that continuous hepatic inflow occlusion for periods of 1 hour during major liver resection is safe and well-tolerated when there is no underlying parenchymal liver disease.
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PMID:The safety of continuous hepatic inflow occlusion during major liver resection. 934 33

We describe 5 cases of fulminant hepatitis caused by the HBV infection in patients with haematological diseases, mostly malignancies (ALL, lymphoma, aplastic anemia, AML) following intensive chemotherapy. Infection was confirmed by serological examination (HBsAg positivity) and by electron microscopy (viral particles). After termination of chemotherapy fulminant hepatitis developed with hepatic failure and very high levels of AST and ALT. Autopsy revealed massive necrosis without signs of regeneration. We suggest that immunosuppressive therapy increases the risk of severe infection of hepatocytes with HBV and subsequent withdrawal of chemotherapy causes "immunological rebound" leading to massive necrosis.
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PMID:Fulminant hepatitis caused by a hepatitis B virus infection in the patients with haematologic malignancies. Report of 5 cases. 943 99

We studied variability in doxorubicin pharmacokinetics in 24 patients with abnormal liver biochemistry tests. Blood samples were collected after the first cycle of single-agent doxorubicin given as an i.v. bolus and plasma levels were measured by high-performance liquid chromatography. The relationship between doxorubicin clearance (dose/AUC) and liver biochemistry tests (AST, bilirubin, albumin, alkaline phosphatase and indocyanine green clearance) was investigated. Patients with a raised bilirubin level had reduced doxorubicin clearance, but there was no clear relationship between the extent of this elevation and the reduction in doxorubicin clearance. Doxorubicin clearance was lower in patients with an isolated increase in AST than in those with normal liver biochemistry, but this difference was not statistically significant. Nevertheless, there was a significant correlation between reduced doxorubicin clearance and both raised serum AST levels and low indocyanine green clearance. These pharmacokinetic data suggest that current dose reductions based solely on the extent to which bilirubin is elevated may not be optimal.
Cancer Chemother Pharmacol 1998
PMID:Doxorubicin pharmacokinetics: the effect of abnormal liver biochemistry tests. 968 58

Photodynamic therapy (PDT) is now being used more frequently in carefully selected cases of malignancies. The drugs used for PDT are mostly derivatives of haematoporphyrine (HPD) and its active component photofrine II. Another compound prepared by total synthesis is meso-tetra-(4-sulfonatophenyl)-porphine (TPPS4) but its application in human medicine was rejected because of its neurotoxicity. Our TPPS4 was prepared by the method of Busby et al. in the modification of Jirsa and Kakac (1987). This product is purer and without neurotoxic effects. In this study, we concentrated our attention on the effect of TPPS4 on nephrotoxicity and its accumulation in some organs. As the parameters of toxic kidney damage we used urine levels of N-acetyl-beta-D-glucosaminidase (NAG), serum creatinine levels, glomerular filtration rate (GFR) and proteinuria. TPPS4 was administered i.v. in a dose of 25 mg/kg b.w. The animals were observed for 21 days after drug application. Urine and blood samples were collected over 24-hour periods on days 0, 5 and 21. The serum creatinine level was significantly higher only on day 5 (65.0+/-1.46 micromol/l vs 56.5+/-2.69 micromol/l on day 0, p<0.05). There were no significant changes in GFR, proteinuria or NAG activity in the urine during the experiment. AST serum activity was increased. We determined the concentration of TPPS4 (pmol/mg w.w.) in rat organs on the 21st day after the injection. The concentration of TPPS4 was high in kidneys (30.8+/-5.5), liver (13.5+/-2.0), lungs (11.7+/-4.6) and spleen (9.7+/-1.5), while the concentration in heart and brain was low. We conclude that TPPS4 has the highest concentration in the kidney 21 days after its administration and does not exert any nephrotoxic effects during this period.
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PMID:The localisation of TPPS4 in some organs and its possible nephrotoxicity in rats. 972 80


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