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PubMed1977

Methoxytyrosine formation as an indicator of catechol-O-methyltransferase activity in rat liver in vivo.

The O-methyl derivative methoxytyrosine accumulated rapidly in rat liver after an intraperitoneal injection of L-dopa (50 mg/kg) in combination with 3-hydroxybenzylhydrazine, an inhibitor of the aromatic amino acid decarboxylase. Methoxytyrosine levels reached a plateau 40--60 min after i.p. injection of L-dopa, of which the tissue concentration declined monoexponentially. Injection of various doses of L-dopa revealed that methoxytyrosine formation was saturable and followed enzyme kinetics in rat liver. The catechol-O-methyltransferase inhibitors pyrogallol, tropolone and alpha-propyldopacetamide as well as the inhibitor of the aromatic amino acid decarboxylase benserazide inhibited the formation of methoxytyrosine dose-dependently and concomitantly increased the tissue concentration of dopa. The accumulation of methoxytyrosine from exogeneously applied L-dopa appears to be a reliable indicator of the in vivo activity of catechol-O-methyltransferase.

Amino Acids↗
PubMed1990

Investigation by scintigraphic methods of neutrophil kinetics under normal and septic shock conditions in the experimental baboon model.

The purpose of this study was the correlation of neutrophil kinetics with the pathogenic course of septic shock in the baboon model. Radioactively labelled neutrophils were traced in vivo in normal baboons (n = 6) and in Escherichia coli-infected baboons, which were reinjected with labelled autologous neutrophils either 2 h after the onset of the E. coli infusion (procedure A) (n = 3) or simultaneously with the infusion (procedure B) (n = 3). Cell isolation was done according to a method developed in this laboratory. The cells were labelled with tropolonate In 111, resuspended in 1-2 ml plasma and reinjected. One-minute images were taken every 5th min and then hourly for 4 h with a gamma camera and analysed with a data processor. Time-activity curves were obtained for neutrophil washout from the lungs and neutrophil accumulation in the liver and spleen. These curves were compared for normal baboons and for those treated according to procedures A and B. A significant retention of neutrophils in the lungs of baboons with E. coli-induced septic shock was noted as well as an abnormally slow rate of accumulation in the liver and spleen. It also seems that any lung injury which could be attributed to changes in neutrophil behaviour should be traced back to events during the early exposure of neutrophils to bacterial infection.

Animals↗
PubMed1979

Monoamine oxidase and catechol-O-methyltransferase activity in hamster and rat insulinomas.

Hamster and rat insulinomas were assayed for norepinephrine, dopamine and serotonin concentration and for monoamine oxidase and catechol-o-ethyltransferase (COMT) activity. The concentration of norepinephrine (mean 0.55 mumol/kg, range less than 0.20 to 2.64 mumol/kg) and serotonin (mean 5.22 mucol/kg, rang less than 0.6 to 26.5 mumol/kg) in hamster insulinomas were comparable to previously reported concentrations. Dopamine conentration (mean 0.34 mumol/kg, range less than 0.20 to 0.95 mumol/kg) was only 2 to 2.5% of that reported previously. Monoamine oxidase activity of the hamster and rat insulinomas were comparable to those of normal hamster islets. In contrast, the COMT activity of both insulinomas was much greater than the COMT activity of normal pancreatic islets of both species and was greater than in several other tissues and tumours. The tumour COMT, which was predominantly in the cytosol, was Mg2+ dependent and had a comparable sensitivity to inhibition by tropolone as purified beef-liver COMT. Hamster insulinoma monoamine oxidase was more sensitive than rat insulinoma monoamine oxidase to inhibition by tranylcypromine and deprenyl, while rat insulinoma monoamine oxidase was more sensitive to inhibition by clorgyline and was more heat labile.

Adenoma, Islet Cell↗
PubMed1990

In vivo imaging of rat lymphocytes with an indium 111-labelled anti-T cell monoclonal antibody: a comparison with indium 111-labelled lymphocytes.

An indium 111-labelled mouse anti-rat T cell monoclonal antibody, MRC OX-19, was injected intravenously into rats to establish the usefulness of radiolabelled anti-lymphocyte antibodies in imaging lymphoid tissues. Antibody binding in vivo, measured by immunofluorescence analysis of cell suspensions made from lymphoid tissues, was detectable on lymphocytes in blood, spleen and lymph nodes. The extent of binding was time and antibody-dose dependent. Doses of antibody above 80 micrograms/kg body weight resulted in modulation, i.e. loss of CD 5 (T1) molecules from the cell surface, although the cells remained in the circulation. Modulation was demonstrable within 2 h and for at least 24 h after a single injection of antibody. Intravenous injection of 111In-MRC OX-19 resulted in levels of in vivo binding comparable with those seen with unlabelled antibody. Scintillation imaging showed early splenic localisation persisting over 48 h, a more gradual localisation in the lymph nodes seen clearly at 24 h and a steady background. Comparison of the in vivo distribution of labelled antibody and 111In-tropolone-labelled lymphocytes showed that both could be used for external imaging of lymphocytes by scintillation camera.

Animals↗
PubMed1982

Effect of colchicine derivatives on the antibody response induced in vitro.

Effect of 44 colchicine derivatives on the induction of antibody response in tissue cultures was tested. Lymphatic cells from the spleen of BALB/c mice were cultivated with antigen (sheep red blood cells) and the number of antibody forming cells was determined by the plaque technique. Most compounds with the immunoinhibitory effect are derived from the colchicine formula (I). The effect was increased by introducing ethyl, formyl or methylenedioxide groups. Colchinols exerted very good immunoinhibitory effect resulting by contraction of tropolone ring C into the aromatic one. A complete loss of the effectivity was detected in the case of glucoside of colchicine, colchiceine, isocolchicine, oxycolchicine, allocolchicine and in lumiderivatives of colchicine. No correlations between the immunoinhibitory effect, toxicity and stathmokinetic effect were detected: decrease of cell viability and arrest of mitoses were not observed in cultured lymphocytes within the range of the immunoinhibitory effect. The effect of colchicine derivatives was manifested as the inhibition of lymphocyte blastogenesis, which is probably the result of membrane transport blockade.

Animals↗
PubMedDate not supplied

The in vitro and in vivo biotransformation of N-deacetyl-N-formylcolchicine.

The major pathway of metabolic transformation of N-deacetyl-N-formylcolchicine is the oxidative cytochrome P450 dependent O-demethylation of substituents in the aromatic ring A and tropolone ring C. It was found that O-demethylation (both, in vitro and in vivo) takes place predominantly in the aromatic ring, especially at position 2.

Animals↗
PubMed2002

Selective preconcentration and determination of tributyltin in fresh water by electrothermal atomic absorption spectrometry.

A rapid and simple method for separation and determination of tributyltin (TBT) in mineral and tap water is described. The procedure is based on the selective retention of TBT by a chelating resin, Amberlite XAD-2 impregnated with tropolone. The addition of 0.8% sulfuric acid to the water sample leads to the retention of TBT by the resin while monobutyltin (MBT), dibutyltin (DBT) and inorganic tin remain in solution. TBT is eluted with methyl isobutyl ketone (MIBK) obtaining a preconcentration factor of 80. Tin concentration is determined by ETAAS using zirconium coated tubes. Multi-injection and hot injection techniques are used in order to enhance the sensitivity of the method. A detection limit of 14.4 ng L(-1) is achieved with recoveries near to 100%. The procedure has been successfully applied to TBT determination in various fresh water samples.

Acids↗
PubMed2004

Determination of organotin compounds in biological samples using accelerated solvent extraction, sodium tetraethylborate ethylation, and multicapillary gas chromatography-flame photometric detection.

A method has been developed for species-selective analysis of organotin compounds in solid, biological samples. The procedure is based on accelerated solvent extraction (ASE) of analytes and includes extraction of the tin species with a methanol-water (90% methanol) solution of acetic acid/sodium acetate containing tropolone (0.03% w/ v), their ethylation with NaBEt(4), and separation and detection by GC-FPD. The analytical procedure was optimized with an unspiked sample of harbor porpoise ( Phocoena phocoena) liver. Effects of ASE operational variables (extraction temperature and pressure, solvent composition, number of static extraction steps) are discussed. Method detection limits (MDL) were in the range 6-10 ng(Sn) g(-1) dry weight and 7-17 ng(Sn) g(-1) dry weight for butyl- and phenyltin compounds, respectively. Recoveries were comparable with or better than those obtained by use of other procedures reported in the literature. The analytical procedure was validated by analysis of NIES No. 11 (fish tissue) certified reference material.

Alkylation↗
PubMed2006

Certification of butyltins and phenyltins in marine sediment certified reference material by species-specific isotope-dilution mass spectrometric analysis using synthesized 118Sn-enriched organotin compounds.

A new marine sediment certified reference material, NMIJ CRM 7306-a, for butyltin and phenyltin analysis has been prepared and certified by the National Metrological Institute of Japan at the National Institute of Advanced Industrial Science and Technology (NMIJ/AIST). Candidate sediment material was collected at a bay near industrial activity in Japan. After air-drying, sieving, and mixing the material was sterilized with gamma-ray irradiation. The material was re-mixed and packaged into 250 glass bottles (15 g each) and these were stored in a freezer at -30 degrees C. Certification was performed by use of three different types of species-specific isotope-dilution mass spectrometry (SSID-MS)-SSID-GC-ICP-MS, SSID-GC-MS, and SSID-LC-ICP-MS, with 118Sn-enriched organotin compounds synthesized from 118Sn-enriched metal used as a spike. The 118Sn-enriched mono-butyltin (MBT), dibutyltin (DBT), and tributyltin (TBT) were synthesized as a mixture whereas the 118Sn-enriched di-phenyltin (DPhT) and triphenyltin (TPhT) were synthesized individually. Four different extraction methods, mechanical shaking, ultrasonic, microwave-assisted, and pressurized liquid extraction, were adopted to avoid possible analytical bias caused by non-quantitative extraction and degradation or inter-conversion of analytes in sample preparations. Tropolone was used as chelating agent in all the extraction methods. Certified values are given for TBT 44+/-3 microg kg(-1) as Sn, DBT 51 +/- 2 microg kg(-1) as Sn, MBT 67 +/- 3 microg kg(-1) as Sn, TPhT 6.9 +/- 1.2 microg kg(-1) as Sn, and DPhT 3.4 +/- 1.2 microg kg(-1) as Sn. These levels are lower than in other sediment CRMs currently available for analysis of organotin compounds.

Chemistry Techniques, Analytical↗
PubMed2001

Effects of prednisone and splenectomy in patients with idiopathic thrombocytopenic purpura: only splenectomy induces a complete remission.

Idiopathic thrombocytopenic purpura (ITP) is a heterogeneous disease, whereby it is unclear if and in which way prednisone and splenectomy affect the platelet kinetics leading to a complete remission. To determine the effects of prednisone and splenectomy on the mean platelet life (MPL) and platelet production, platelet kinetic studies with Indium-111 tropolonate-labeled autologous platelets were performed in patients with ITP ( n=41). In 17 patients platelet kinetic studies were performed before and during prednisone treatment, and in 24 patients before and after splenectomy. MPL increased after prednisone therapy only in patients ( n=13) with a full recovery (FR, platelets >150 x 10(9)/l) and partial recovery (PR, 50 x 10(9)/l <platelets <150 x 10(9)/l) from 2.1+/-1.5 days to 4.9+/-1.3 days in FR patients (p=0.03) and from 1.1+/-0.8 days to 2.4+/-1.1 days in PR patients, which is significantly shorter than in normal controls (9.2+/-1.2, p<0.0001). The platelet production demonstrated an impressive increase (threefold) during prednisone treatment in all responding and nonresponding patients. These results suggest that the clinical response to prednisone is more related to the effect on MPL than on platelet production. In contrast, the group of splenectomized patients showed that a full recovery of platelet count was associated with near normalization of the MPL (2.4+/-1.6 days vs 8+/-1.4 days) and platelet production (119+/-60 vs 162+/-35 x 10(9)/day). These results demonstrate that prednisone as well as splenectomy increase MPL and production in patients with ITP. However, only after splenectomy is a complete remission obtained, defined as a normal platelet count, mean platelet life, and platelet production.

Adult↗
PubMed1985

Prevention of platelet deposition by ibuprofen and calcium dobesilate in expanded polytetrafluoroethylene vascular grafts.

This study was designed to evaluate the platelet-inhibiting effect of a new drug, calcium dobesilate, and to compare its efficacy to the known antiplatelet agent, ibuprofen. Five centimeter long expanded polytetrafluoroethylene grafts (internal diameter 4 mm) were used to replace 48 carotid arteries in 24 dogs. Autologous platelets were labeled with indium-111-labeled tropolone and reinjected into each animal 24 hours before operation. Six animals received an intravenous placebo, six received 12.5 mg/kg of intravenous ibuprofen, six received 100 mg/kg of intravenous calcium dobesilate, and six received 200 mg/kg of intravenous calcium dobesilate before cross-clamping. The grafts were removed after 3 hours, and radioactivity was measured and platelet deposition calculated. The results have indicated that preoperative administration of ibuprofen and calcium dobesilate in this animal model significantly diminishes early platelet deposition. Calcium dobesilate appears to be a dose-dependent, highly effective antiplatelet agent.

Animals↗
PubMed1989

Investigation on glyoxalase I inhibitors.

Several classes of compounds - flavones, coumarins, S- and N-substituted glutathione analogs, transition state analogs, porphyrins, nucleotides and nucleosides - have been reported to inhibit the enzyme gloxalase I. In the current study, examination of some of the aforementioned compounds has revealed that squaric acid does not function as an inhibitor of glyoxalase I and several other compounds are much less effective in this regard than previously reported. Several new potent inhibitors of yeast glyoxalase I have been identified. Compounds containing the tropolone structure were especially inhibitory. Glutathione adducts of benzoquinone and naphthoquinone were also inhibitory and may be of particular interest with regard to the toxicology of normal aromatic metabolites in vivo.

Enzyme Inhibitors↗
PubMed1983

Human kidney thiopurine methyltransferase. Purification and biochemical properties.

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines and thiopyrimidines. Human kidney TPMT was purified over 300-fold and its biochemical properties were determined. TPMT was "soluble" and had a molecular weight of approximately 36,000 daltons as estimated by gel filtration chromatography. The pH optimum of the purified TPMT was 6.7. "True" Km values for 6-mercaptopurine (6-MP) and S-adenosyl-L-methionine (SAM), the two cosubstrates for the reaction, were 0.30 mM and 2.7 microM respectively. "Apparent" Km values for 6-thioguanine and 2-thiouracil, two other methyl acceptor substrates, were 0.55 and 2.0 mM respectively. Aliphatic thiol compounds were either poor substrates for TPMT or were not methylated. S-Adenosyl-L-homocysteine was a competitive inhibitor of TPMT when the varied substrate was SAM, and 6-methylmercaptopurine was a noncompetitive inhibitor with respect to 6-MP. Purified TPMT was neither activated nor inhibited by 1 mM Ca2+ or Mg2+, but exposure to reagents such as N-ethylmaleimide and ethacrynic acid that interact with sulfhydryl groups inactivated the enzyme. Tropolone inhibited TPMT with a Ki of approximately 0.85 mM. Finally, human kidney TPMT activity could be distinguished from human kidney thiol methyltransferase (EC 2.1.1.9) activity on the basis of subcellular distribution, substrate specificity, kinetic characteristics and differential sensitivity to inhibitors.

Cations, Divalent↗
PubMed1990

Binding of colchiceine to tubulin. Mechanisms of ligand association with tubulin.

Colchiceine, a closely related structural analog of colchicine possessing a C-ring tropolone, has been shown to be a potent inhibitor of microtubule assembly in vitro (I50 = 20 microM). The mechanism of inhibition is mediated through binding to tubulin (KA = 1.2 +/- 0.7 x 10(4) M-1), although potentially not through the colchicine receptor site. Supporting the hypothesis of an alternate receptor are the observation of colchiceine binding to the isolated colchicine-tubulin complex (KA = 2.2 +/- 1.0 x 10(4) M-1), the poor correlation between the competitive inhibition of colchicine binding (KI = 125 microM) and the inhibition of microtubule assembly, and different structure-activity relationships for colchiceine analogs as compared to the colchicine series.

Binding, Competitive↗
PubMed1979

Human erythrocyte thiol methyltransferase: radiochemical microassay and biochemical properties.

A radiochemical microassay for the measurement of thiol methyltransferase (TMT) activity in human red blood cell (RBC) membranes has been developed. Both 2-mercaptoethanol and dithiothreitol were used as substrates for the enzyme. The pH optimum of the reaction was approximately 9.0 when glycine NaOH was used as a buffer. The apparent Michaelis-Menten (KM) value for the methyl donor for the reaction, S-adenosyl-L-methionine, was 43 mumol/l. Human RBC TMT activity was neither activated nor inhibited by Ca2+, Mg2+, or tropolone, but the enzyme was inhibited by SKF 525A and by reagents that react with sulfhydryl groups. The mean TMT activity in blood from 289 randomly selected adult white subjects was 10.93 +/- 3.22 units per mg protein (mean +/- S.D.). The activity was the same in samples from men and women. The results of experiments in which TMT activity was measured in mextures of RBC membranes with relatively "low" and relatively "high" activities provided no evidence that individual variations in the enzyme activity were due to variations in endogenous TMT activators or inhibitors.

Chromatography, High Pressure Liquid↗
PubMed1975

Differential blockade of guinea-pig atrial rate and force responses to (--)-noradrenaline by practolol - an uptake phenomenon.

The relative blockade of rate and force responses of guinea-pig isolated atria to catecholamines by practolol was compared. pA2 determinations revealed that with (--)-noradrenaline as the agonist, practolol was more effective in antagonizing rate (pA2, 6.99) than force (pA2, 6.44). This difference was absent in either atria from reserpinized animals incubated with phenoxybenzamine and tropolone or atria incubated with cocaine. Similarly, when (--)-isoprenaline was the agonist, force and rate pA2 values were identical, suggesting that rate and force beta1-adrenoceptors do not differ. The preferential blockade of (--)-noradrenaline-induced rate responses in untreated atria was attributed to the operation of a saturable neuronal uptake mechanism which differs between left and right atria. To avoid high (--)-noradrenaline concentrations encountered during pA2 determinations, the % reduction of responses to single doses of (--)-noradrenaline by practolol were measured in untreated atria. Far from confirming the lack of receptor differentiation indicated by the pA2 determinations, this study revealed force to be more practolol sensitive. The relative merits of the two methods are discussed in an attempt to resolve the question whether rate and force beta1-adrenoceptors differ.

Animals↗
PubMed1977

On the reduced retention of extravesicular noradrenaline in rabbit atria produced by potassium.

The effects of KC1 on the retention of extravesicular (--)-[3H]noradrenaline were investigated. Atria, from reserpine-pretreated rabbits, were exposed to tropolone and pargyline before incubation with (--)-[3H]noradrenaline. After efflux for 50-60 min, exposure of tissues to media containing 65 mM KC1 resulted in increased efflux of (--)-[3H]noradrenaline. This effect was not Ca2+-dependent and was not altered by oxymetazoline, phentolamine, indomethacin or methacholine. The KC1-induced reduction in retention of (-)-[3H]noradrenaline was, however inhibited by cocaine and desipramine, but not by lidocaine. Efflux was not increased by RbCl and CsCl. It is suggested that KCl may have accelerated the efflux of extravesicular (--)-[3H]noradrenaline by increasing a cocaine- and desipramine-sensitive carrier-mediated efflux process.

Animals↗
PubMed1978

Neuronal norepinephrine as mediator for ouabain-induced smooth muscle contraction.

With some latency, ouabain (10(-6)--10(-5) M) induced a long-lasting contractile response of the isolated vas deferens of the guinea-pig. The ouabain-induced contraction was potentiated by pretreatment with tropolone, whereas it was prevented by pretreatment with cocaine, bretylium, reserpine or phentolamine. The response was unaffected byatropine, methysergide and tetrodotoxin. Ouabain, perfused into the isolated tissue, enhanced dose-dependently the release of norepinephrine into the medium. However, this enhancement of norepinephrine release was prevented by reserpine or by removal of Ca from the medium. These findings support the hypothesis that the ouabain-induced contraction of vas deferens might be due to norepinephrine released from the adrenergic nerve ending granules through a Ca2+-dependent process.

Animals↗