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PubMed1980

Gas-liquid chromatographic determination of sodium fluoroacetate (Compound 1080).

An analytical method is described for the determination of Compound 1080 (sodium fluoroacetate) residues in 1--10 g tissue. Sample extracts of tissues are cleaned up with silica gel, and Compound 1080 (as fluoroacetic acid) is separated by a micro-distillation procedure. The fluoroacetic acid in the distillate is derivatized with pentafluorobenzyl bromide to form pentafluorobenzyl fluoroacetate which is measured by electron capture gas-liquid chromatography. Recoveries of sodium fluoroacetate from fortified tissue samples averaged about 25%. Despite the limited recoveries, results were quite reproducible, and levels as low at 2 ppm were determined in fortified 1 g samples, and 0.2 ppm in 10 g samples. The method is relatively simple and has been used routinely in our laboratory for the analysis of various types of samples such as grain, and tissues from birds, rodents, and larger animals.

Animals↗
PubMed1996

Fluoroacetate-mediated toxicity of fluorinated ethanes.

A series of 1-(di)halo-2-fluoroethanes reported in the literature to be nontoxic or of low toxicity were found to be highly toxic by the inhalation route. Experiments were performed that showed the compounds, 1,2-difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane to be highly toxic to rats upon inhalation for 4 hr. All four compounds had 4-hr approximate lethal concentrations of < or = 100 ppm in rats. In contrast, 1,1-difluoroethane (commonly referred to as HFC-152a) has very low acute toxicity with a 4-hr LC50 of > 400,000 ppm in rats. Rats exposed to the selected toxic fluoroethanes showed clinical signs of fluoroacetate toxicity (lethargy, hunched posture, convulsions). 1,2-Difluoroethane, 1-chloro-2-fluoroethane, 1-chloro-1,2-difluoroethane, and 1-bromo-2-fluoroethane were shown to increase concentrations of citrate in serum and heart tissue, a hallmark of fluoroacetate intoxication. 19F NMR analysis confirmed that fluoroacetate was present in the urine of rats exposed to each toxic compound. Fluorocitrate, a condensation product of fluoroacetate and oxaloacetate, was identified in the kidney of rats exposed to 1,2-difluoroethane. There was a concentration-related elevation of serum and heart citrate in rats exposed to 0-1000 ppm 1,2-fluoroethane. Serum citrate was increased up to 5-fold and heart citrate was increased up to 11-fold over control citrate levels. Metabolism of 1,2-difluoroethane by cytochrome P450 (most likely CYP2E1) is suspected because pretreatment of rats or mice with SKF-525F, disulfiram, or dimethyl sulfoxide prevented or delayed the toxicity observed in rats not pretreated. Experimental evidence indicates that the metabolism of the toxic fluoroethanes is initiated at the carbon-hydrogen bond, with metabolism to fluoroacetate via an aldehyde or an acyl fluoride. The results of these studies show that 1-(di)halo-2-fluoroethanes are highly toxic to rats and should be considered a hazard to humans unless demonstrated otherwise.

Animals↗
PubMed1951

The relation of the Krebs cycle to viral synthesis. II. The effect of sodium fluoroacetate on the propagation of influenza virus in mice.

A further study has been made of the relationship of reactions of the Krebs cycle to the propagation of influenza virus. By the administration of sublethal doses of sodium fluoroacetate which were found to increase the concentration of citrate in the mouse lung, it was possible to demonstrate a blocking of the citric acid cycle in that organ. Further, the intraperitoneal administration of these concentrations of fluoroacetate was found to inhibit markedly the propagation of influenza, Type A, virus in the lungs of mice. The inhibition was observed when the fluoroacetate was administered 15 minutes, 6 hours, or 12 hours after the mice were inoculated with virus. This effect was also demonstrable when the concentration of the viral inoculum was varied over a range of virus titers from 10(3.5) to 10(6.5). Sodium fluoroacetate was found to have no effect in vitro on the infectivity or hemagglutinating property of the virus. The significance of these findings with regard to chemotherapy and to the mechanism of viral synthesis is described.

Animals↗
PubMed1990

Seizures induced by fluoroacetic acid and fluorocitric acid may involve chelation of divalent cations in the spinal cord.

Fluoroacetic and fluorocitric acid toxicity is often characterized by seizures, however the mechanism of this activity is unknown. Intrathecal (i.t.) injection of fluorocitrate in mice resulted in seizures after an average latency of 15 s, while intracerebroventricular (i.c.v.) injection produced seizures after 36.5 min, and required higher doses to achieve this effect. This indicates the probable site of fluoroacetate and fluorocitrate neurotoxicity is the spinal cord. To mimic citrate accumulation, characteristic of fluoroacetate and fluorocitrate poisoning, citric acid was injected i.t. and also found to produce seizures. The structurally unrelated compounds EDTA, EGTA, glutamic acid and lactic acid also produced seizures identical to fluorocitrate. The ability of these compounds to chelate Ca2+ correlates well with their ability to cause seizures when administered i.t. and coadministration of calcium greatly attenuated the neurotoxicity of these compounds as well as fluoroacetate and fluorocitrate. In contrast, Ca2+ was unable to inhibit seizures elicited by strychnine, suggesting calcium's ability to inhibit chelators of divalent cations is not due to a general anticonvulsant effect. These results suggest that changes in Ca2+ concentration in the spinal cord may be responsible for some forms of seizure activity.

Animals↗
PubMed2004

Homology modeling and S(N)2 displacement reaction of fluoroacetate dehalogenase from Burkholderia sp. FA1.

Fluoroacetate dehalogenase (EC 3.8.1.3) catalyzes the dehalogenation of fluoroacetate and other haloacetates. In order to investigate the relation between the structure and the function, and understand the reaction mechanism of the enzyme, a 3D model of fluoroacetate dehalogenase FAc-DEX FA1 was built by homology-based modeling. The 3D model was optimized by unconstrained molecular dynamics simulation. Furthermore, the optimized 3D model was assessed by comparison of specific properties with two known protein structures. From the final 3D model, we find that the main residues involved in the active site in FAc-DEX FA1 were Phe34, Trp148, Tyr147, Tyr212, Asp104, and His271; especially Asp104 was the key nucleophilic residue in substrate binding. A reaction model including Asp104 and the substrate fluoroacetate was then constructed and used to characterize explicit enzymatic reactions. In order to further illustrate catalytic properties, the equilibrium geometries, energies, and frequencies of stationary points (reactants, products, and transition states) of the reaction model were calculated at the B3LYP/6-31G level of theory in both gas phase and solution. The results showed that the reaction in gas was dynamically more favorable than in solution.

Amino Acid Sequence↗
PubMed2006

New approach to fully automated synthesis of sodium [18F]fluoroacetate -- a simple and fast method using a commercial synthesizer.

A simple, rapid and fully automated preparation of sodium [(18)F]fluoroacetate has been developed by taking advantage of the similarities between the reaction pathways of [(18)F]fluoroacetate and [(18)F]-2-fluoro-deoxyglucose (FDG). The automated synthesis of sodium [(18)F]fluoroacetate was achieved with a commercial [(18)F]FDG synthesizer, the TRACERlab MX(FDG). The method produced the desired compound in a short synthesis time (32 min) and with a high and reproducible radiochemical yield (50.2 +/- 4.8%, decay corrected). The radiochemical purity of sodium [(18)F]fluoroacetate was greater than 99%.

Equipment Design↗
PubMed2003

Assay for the enantiomeric analysis of [2H1]-fluoroacetic acid: insight into the stereochemical course of fluorination during fluorometabolite biosynthesis in streptomyces cattleya.

A sensitive method for the configurational analysis of (R)- and (S)-[2H1]-fluoroacetate has been developed using 2H[1H]-NMR in a chiral liquid crystalline solvent. This has enabled biosynthetic experiments to be conducted which reveal stereochemical details on biological fluorination occurring during the biosynthesis of fluoroacetate and 4-fluorothreonine in the bacterium Streptomyces cattleya. In particular, feeding experiments to S. cattleya with isotopically labeled (1R, 2R)- and (1S, 2R)-[1-2H1]-glycerol 3d and 3e and [2,3-2H(4)]-succinate 4a gave rise to samples of enantiomerically enriched [2-2H1]-fluoroacetates 1a. The predominant enantiomer resulting from each experiment suggests that the stereochemical course of biological fluorination takes place with an overall retention of configuration between a glycolytic intermediate and fluoroacetate 1. Consequently, this outcome suggests that the stereochemical course of the recently identified fluorinase enzyme which mediates a reaction between fluoride ion and S-adenosyl-l-methionine (SAM), occurs with an inversion of configuration.

Deuterium↗
PubMed1997

Trafficking of amino acids between neurons and glia in vivo. Effects of inhibition of glial metabolism by fluoroacetate.

Glial-neuronal interchange of amino acids was studied by 13C nuclear magnetic resonance spectroscopy of brain extracts from fluoroacetate-treated mice that received [1,2-(13)C]acetate and [1-(13)C]glucose simultaneously. [13C]Acetate was found to be a specific marker for glial metabolism even with the large doses necessary for nuclear magnetic resonance spectroscopy. Fluoroacetate, 100 mg/kg, blocked the glial, but not the neuronal tricarboxylic acid cycles as seen from the 13C labeling of glutamine, glutamate, and gamma-aminobutyric acid. Glutamine, but not citrate, was the only glial metabolite that could account for the transfer of 13C from glia to neurons. Massive glial uptake of transmitter glutamate was indicated by the labeling of glutamine from [1-(13)C]glucose in fluoroacetate-treated mice. The C-3/C-4 enrichment ratio, which indicates the degree of cycling of label, was higher in glutamine than in glutamate in the presence of fluoroacetate, suggesting that transmitter glutamate (which was converted to glutamine after release) is associated with a tricarboxylic acid cycle that turns more rapidly than the overall cerebral tricarboxylic acid cycle.

Acetates↗
PubMed1990

Fluoroacetate-metabolizing pseudomonad isolated from Dichapetalum cymosum.

A pseudomonad was isolated from the fluoroacetate-producing plant Dichapetalum cymosum (Hook) Engl. and identified as Pseudomonas cepacia. We established that this isolate was capable of growing in fluoroacetate-enriched solutions without any reduction in growth rate. Our isolate of P. cepacia was capable of defluorinating 2.69 mg of fluoroacetate per 10(9) cells per h. Fluoroacetate was degraded to CO2 at a rate of 23.53 ng/10(9) cells per h.

Citric Acid Cycle↗
PubMed1977

Metabolic control of circulation. Effects of iodoacetate and fluoroacetate.

The circulatory effects of selective metabolic inhibition of glycolysis and of the tricarboxylic acid cycle by iodoacetate and fluoroacetate were studied in intact chloralose-anesthetized dogs. Pulmonary arterial blood pressure and vascular resistance increased after administration of both inhibitors, but neither systemic hemodynamics nor myocardial contractility changed significantly. Coronary blood flow did not change after iodoacetate administration but increased four- to five-fold after fluoroacetate. Administration of normal saline had no effect on any of the parameters. The changes in pulmonary arterial blood pressure and coronary blood flow after fluoroacetate were not mediated via the autonomic nerves or adrenergic neurohumors because they still occurred after autonomic nervous system inhibition. Neither myocardial oxygen consumption nor left ventricular work changed. A selective increase in myocardial blood flow also occurred in conscious dogs after fluoroacetate administration; hepatic artery flow was reduced, but other organ flows did not change significantly. These results indicate that pulmonary pressor and coronary dilator effects may be produced in intact dogs by selective metabolic blockade, in the absence of reduced oxygen supply or impairment in the electron transport system. These results also suggest that the increases in pulmonary arterial blood pressure, coronary blood flow, and cardiac output that occur during hypoxia probably are related to separate metabolic events in the tissue.

Animals↗
PubMed1997

[Determination of fluoroacetatamide and fluoroacetic acid by capillary gas chromatography].

A rapid qualitative and quantitative analysis of fluoroacetatamide and fluoroacetic acid in rodenticides by capillary gaschromatography was described in this paper. Isoamyl alcohol was used as the internal standard. The determination curves of fluoroacetatamide and fluoroacetic acid in rodenticides were linear in the ranges of 0.0625-4 mg/ml and 0.625-20 mg/ml. The detection limits of fluoroacetatamide and fluoroacetic acid were 31.25 micrograms/ml (32.5 ng) and 625 micrograms/ml (625 ng), 87.5% and 30% of rodenticides sold in Taiyuan ground market from May, 1995 to May, 1996 contain fluoroacetatamide and fluoroacetic acid.

Chromatography, Gas↗
PubMedDate not supplied

[Accidental fatal poisoning with ethyl fluoroacetate].

Fluoroacetic salts belong to the most toxic chemicals. They are used for various purposes, and form stable compounds in some plants. A case of poisoning with ethyl fluoroacetate is presented in detail. Diagnostic problems and therapy which failed due to the late diagnosis and dramatic progress in the symptoms of poisoning are also discussed. Fluoroacetic ion alone is non-toxic but in vivo forms fluorotricarboxylic acid, which blocks cellular metabolism at the citrate stage. Symptoms occur with a delay but lethal synthesis of fluorotricarboxylic acid leads to the irreversible cellular dysfunction, especially in CNS and circulatory system. Poisoning may be treated with monoacetin and acetamide. An emphasis is on health hazards resulting from the exposure to fluoroacetate and necessity to observe strictly safety regulations.

Accidents↗
PubMedDate not supplied

Determination of fluoroacetate in biological matrixes as the dodecyl ester.

A new method for the quantitative determination of fluoroacetate in biological samples was applied to a number of avian samples. Fluoroacetate is isolated as its potassium salt by ion-exchange chromatography and directly converted to its dodecyl ester, using a novel derivatization procedure. The ester is quantified by capillary gas chromatography with a flame ionization detector for the range 1.0-10.0 micrograms/g and by selected ion monitoring GC/mass spectrometry for the range 0.01-1.00 microgram/g. Recoveries from 1 g chicken muscle were about 80%. The method was applied to the determination of fluoroacetate in the crop, stomach, liver, heart, intestine, and breast muscle of 5 Zebra finches (Peophila guttata) that had been fed millet containing 9 micrograms/g of sodium fluoroacetate. Despite a wide variation in dose, the levels in organs and tissues were approximately 1 microgram/g except for heart tissue which was about 2 micrograms/g. The presence of interfering peaks at low levels necessitated the use of selected ion monitoring GC/MS when sample weights were less than 1 g or when levels were less than 1 microgram/g. Samples can be analyzed within hours of receipt; therefore, the method is suitable for routine use in a diagnostic laboratory.

Animals↗
PubMed1979

Metabolism and defluorination of fluoroacetate in the brush-tailed possum (Trichosurus vulpecula).

The brush-tailed possum (T. vulpecula) from Western Australia was found to be nearly 150 times more resistant to fluoroacetate intoxication in vivo than the same species from South Australia. Acetone powder preparations from the liver of animals from both populations showed similar abilities to convert fluoroacetate into fluorocitrate. Aconitate hydratase activity in liver preparations from both Western Australian and South Australian animals was similarly and competitively inhibited by fluorocitrate. Both animals were capable of defluorinating fluoroacetate at similar rates by a glutathione-dependent enzymic mechanism resulting in the formation of free fluoride ion and S-carboxymethylcysteine. Glutathione was also capable of partial protection against the toxic effects of fluoroacetate in vitro by a further unelucidated mechanism.

Aconitate Hydratase↗
PubMed1984

Purification of a fluoroacetate-specific defluorinase from mouse liver cytosol.

Fluoraocetate-specific defluorinase, an enzyme which catalyzes the release of fluoride ion from the rodenticide fluoroacetate, has been purified 347-fold from mouse liver cytosol and shown to be distinct from multiple cationic and anionic glutathione S-transferase isozymes. Fluoroacetate-specific defluorinase was obtained at a final specific activity of 659 nmol of F-/min/mg of protein and was prepared in an overall yield of 12%. The isoelectric point of this hepatic enzyme was acidic, at pH 6.4, as determined by column chromatofocusing. The molecular weight of the active species was estimated at 41,000, and sodium dodecyl sulfate-polyacrylamide gels of the purified defluorinase demonstrated a predominant subunit, Mr = 27,000. Chromatofocusing completely partitioned the fluoroacetate-specific defluorinase from two separate peaks of murine anionic glutathione S-transferase activity. Rabbit antibodies prepared against the purified hepatic defluorinase quantitatively precipitated native defluorinase from mouse and rat liver, but were unable to immunoprecipitate cationic or anionic glutathione S-transferase enzymes from the same preparation. The evidence presented suggests that fluoroacetate-specific defluorinase and glutathione S-transferase activities are catalyzed by separate proteins present in the cytosol of mouse liver.

Animals↗
PubMed2006

Determination of fluoroacetic acid in water and biological samples by GC-FID and GC-MS in combination with solid-phase microextraction.

A novel procedure has been developed for determination of fluoroacetic acid (FAA) in water and biological samples. It involves ethylation of FAA with ethanol in the presence of sulfuric acid, solid-phase microextraction of the ethyl fluoroacetate formed, and subsequent analysis by GC-FID or by GC-MS in selected-ion-monitoring mode. The detection limits for FAA in water, blood plasma, and organ homogenates are 0.001 microg mL(-1), 0.01 microg mL(-1), and 0.01 microg g(-1), respectively. The determination error at concentrations close to the detection limit was less than 50%. For analysis of biological samples, the approach has the advantages of overcoming the matrix effect and protecting the GC and GC-MS systems from contamination. Application of the approach to determination of FAA in blood plasma and organ tissues of animals poisoned with sodium fluoroacetate reveals substantial differences between the dynamics of FAA accumulation and clearance in rabbits and rats.

Animals↗
PubMed1984

Inhibition of mixed-function oxidation in perfused rat liver by fluoroacetate treatment.

The effect of fluoroacetate, an inhibitor of the citric acid cycle, on the mixed-function oxidation of p-nitroanisole in isolated perfused livers from fed rats was studied. The citric acid cycle was inhibited by injection of 5 mg/kg sodium fluoroacetate into rats 3 hr prior to liver perfusion experiments. Inhibition of the citric acid cycle was marked by accumulation of citrate (5-fold) and decreases in rates of glycolysis and glycogenolysis by 50-90%. Fluoroacetate treatment inhibited mixed function oxidation in the perfused liver by about 50% without affecting p-nitroanisole O-demethylation by isolated microsomes. Fluorocitrate, at concentrations up to 50 microM, did not inhibit microsomal p-nitroanisole O-demethylation in vitro. These data support the hypothesis that mixed-function oxidation in intact hepatocytes is dependent upon reducing equivalents generated via the citric acid cycle.

Animals↗
PubMed1990

Glucose-supported oxidative metabolism and evoked potentials are sensitive to fluoroacetate, an inhibitor of glial tricarboxylic acid cycle in the olfactory cortex slice.

Optical absorbance change was measured by reflectance spectrophotometry in the olfactory cortex slice prepared from the rat brain. Optical absorbance of the piriform area of the slice was increased by perifusion with an anoxic (N2-gassed) solution. Components of the absorbance spectrum recorded from the slice in anoxia corresponded to that of cytochromes (cyt) aa3 and c + c1, but did not to that of cyt c. Reduction of cytochromes in anoxia coincided with decrease in the amplitude of the presynaptic potential and a slower negative wave (N-wave). The reduced state of cytochromes switched to an oxidized state when a well-oxygenated solution was reintroduced. An almost complete recovery of redox state coincided with full recovery of the evoked potential. A metabolic inhibitor, 2-deoxy-D-glucose (2DG) (10 mM) or iodoacetic acid (IAA) (3 mM) caused little or slight oxidation of cytochromes, but significantly decreased the amplitude of evoked potentials. Marked oxidation of cytochromes was observed only by perifusion with a solution containing 2 DG (10 mM) and IAA (3 mM). The rate of oxygen uptake was significantly lowered by these metabolic inhibitors. When the slice was perifused with a solution containing fluoroacetate (1 or 10 mM), a selective inhibitor of glial metabolism, cytochromes shifted to oxidized levels. The amplitude of evoked potentials tended to decline by a low dose (1 mM), and significantly decreased by a high dose (10 mM) of fluoroacetate. Oxygen consumption of the slice was dose-relatedly lowered by fluoroacetate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗