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PubMedDate not supplied

The recovery and identification of fluoroacetamide and fluoroacetic acid from tissues.

A rapid method is described for the extraction and identification of fluoroacetamide and fluoroacetic acid from tissues, by gas chromatography, using a mass spectrometer in the multiple ion monitoring mode as the detector. Recoveries from animal and human tissue macerates, after the addition of each compound, were approximately 30--35% for fluoroacetamide and 50--55% for fluoroacetic acid. Minimum detectable levels in tissues were found to be circa 0.7 mug/g for the amide and 0.1 mug/g for the acid. Visceral tissue levels were found to be approximately 3 mug/g for fluoroacetamide, and 2.5--10 mug/g fluoroacetic acid in guinea pigs and rabbits which had been fatally poisoned with these compounds.

Acetamides↗

PubMed2004

Reactivity of asparagine residue at the active site of the D105N mutant of fluoroacetate dehalogenase from Moraxella sp. B.

Fluoroacetate dehalogenase from Moraxella sp. B (FAc-DEX) catalyzes cleavage of the carbon-fluorine bond of fluoroacetate, whose dissociation energy is among the highest found in natural products. Asp105 functions as the catalytic nucleophile that attacks the alpha-carbon atom of the substrate to displace the fluorine atom. In spite of the essential role of Asp105, we found that site-directed mutagenesis to replace Asp105 by Asn does not result in total inactivation of the enzyme. The activity of the mutant enzyme increased in a time- and temperature-dependent manner. We analyzed the enzyme by ion-spray mass spectrometry and found that the reactivation was caused by the hydrolytic deamidation of Asn105 to generate the wild-type enzyme. Unlike Asn10 of the l-2-haloacid dehalogenase (L-DEX YL) D10N mutant, Asn105 of the fluoroacetate dehalogenase D105N mutant did not function as a nucleophile to catalyze the dehalogenation.

Amino Acid Substitution↗

PubMed2004

The traditional categories of fluoroacetate poisoning signs and symptoms belie substantial underlying similarities.

Sodium monofluoroacetate (Compound 1080) has been widely used around the world as a vertebrate pest control agent. Following ingestion of 1080 there is a latent period, during which the compound is metabolised into a toxic form, before the onset of symptoms. The timing of this period varies significantly between species as does the median lethal dose. Traditionally different species have also been classified into groups depending on the primary organ system involved in 1080 toxicosis (cardiac, nervous, or mixed signs/symptoms). However, general acceptance of this method of classification has obscured the fact that several signs of fluoroacetate poisoning are common to most vertebrate species. This paper reviews five decades of literature on the signs/symptoms of fluoroacetate poisoning in vertebrates and concludes that there is little justification for the division of animals poisoned by fluoroacetate into symptomatic groups.

Animals↗

PubMed1970

Tricarboxylic acid-cycle metabolism in brain. Effect of fluoroacetate and fluorocitrate on the labelling of glutamate, aspartate, glutamine and gamma-aminobutyrate.

1. The effect of fluoroacetate and fluorocitrate on the compartmentation of the glutamate-glutamine system was studied in brain slices with l-[U-(14)C]glutamate, l-[U-(14)C]aspartate, [1-(14)C]acetate and gamma-amino[1-(14)C]butyrate as precursors and in homogenates of brain tissue with [1-(14)C]acetate. The effect of fluoroacetate was also studied in vivo in mouse brain with [1-(14)C]acetate as precursor. 2. Fluoroacetate and fluorocitrate inhibit the labelling of glutamine from all precursors but affect the labelling of glutamate to a much lesser extent. This effect is not due to inhibition of glutamine synthetase. It is interpreted as being due to selective inhibition of the metabolism of a small pool of glutamate that preferentially labels glutamine.

Acetates↗

PubMedDate not supplied

Characterization of the fluoroacetate detoxication enzymes of rat liver cytosol.

Two forms of fluoroacetate-specific defluorinase (FSD) were purified from rat hepatic cytosol. The first form, FSD1 (molecular weight 38 kDa), contained 81% of the total cytosolic fluoroacetate defluorination activity and did not bind to the glutathione-affinity, orange A or mono P columns used in the purification procedures. The second form, FSD2 (molecular weight 27 kDa), contained only 13% of the fluoroacetate defluorination activity, had a pI = 7.8, and exhibited a high glutathione S-transferase (GST)-like activity towards dichloroacetic acid. The FSD1 proteins were identified from peptide mass data and best matched with rat sorbitol dehydrogenase (SDH) (short form), although pure sheep liver SDH enzyme did not possess defluorination activity when subsequently investigated. The FSD2 protein was identified from peptide mass data and best matched with the amino acid sequence of mouse and human Zeta 1 of glutathione S-transferase (GSTZ1) and showed a high GSTZ1 specific activity. This study suggests that the major FSD component (FSD1) represents a new and unique dehalogenating or dehydrogenating enzyme present in rat liver cytosol. The minor FSD component (FSD2) is due to the GSTZ1 present in rat liver cytosol. However, it is not yet clear that FSD1 is indeed SDH and FSD2 is indeed GSTZ1, due to sequence homology being less than 60 and 45%, respectively.

Amino Acid Sequence↗

PubMed2002

Catalysis-linked inactivation of fluoroacetate dehalogenase by ammonia: a novel approach to probe the active-site environment.

Fluoroacetate dehalogenase from Moraxella sp. B (FAc-DEX) catalyzes the hydrolytic dehalogenation of fluoroacetate and other haloacetates. Asp(105) of the enzyme acts as a nucleophile to attack the alpha-carbon of haloacetate to form an ester intermediate, which is subsequently hydrolyzed by a water molecule activated by His(272) [Liu, J.Q., Kurihara, T., Ichiyama, S., Miyagi, M., Tsunasawa, S., Kawasaki, H., Soda, K., and Esaki, N. (1998) J. Biol. Chem. 273, 30897-30902]. In this study, we found that FAc-DEX is inactivated concomitantly with defluorination of fluoroacetate by incubation with ammonia. Mass spectrometric analyses revealed that the inactivation of FAc-DEX is caused by nucleophilic attack of ammonia on the ester intermediate to convert the catalytic residue, Asp(105), into an asparagine residue. The results indicate that ammonia reaches the active site of FAc-DEX without losing its nucleophilicity. Analysis of the three-dimensional structure of the enzyme by homology modeling showed that the active site of the enzyme is mainly composed of hydrophobic and basic residues, which are considered to be essential for an ammonia molecule to retain its nucleophilicity. In a normal enzyme reaction, the hydrophobic environment is supposed to prevent hydration of the highly electronegative fluorine atom of the substrate and contribute to fluorine recognition by the enzyme. Basic residues probably play a role in counterbalancing the electronegativity of the substrate. These results demonstrate that catalysis-linked inactivation is useful for characterizing the active-site environment as well as for identifying the catalytic residue.

Amino Acid Sequence↗

PubMedDate not supplied

Tissue fluoroacetate residues in prairie dogs dosed with low-level sodium monofluoroacetate.

A total of 83 black-tailed prairie dogs (Cynomys ludovicianus) from South Dakota were subjected to low-level treatment with sodium monofluoroacetate (Compound 1080) in the laboratory (0.01-0.30 mg 1080/kg). The acute oral median lethal dose (LD50) of 1080 administered by oral gavage was established at 0.173 mg/kg. To assay fluoroacetate residues, 8 kinds of tissue from each of 10 prairie dogs dead of low-level 1080 poisoning were analyzed by capillary gas chromatography-mass spectrometry. Of the total of 79 tissues analyzed, 73 contained less than 100 ppb fluoroacetate, and 67 contained less than 50 ppb fluoroacetate. To test the effect of secondary poisoning on non-target species, 8 European ferrets (Mustela furo) were fed ground whole carcasses of prairie dogs dead of low-level 1080 poisoning, with no observable ill effects on the ferrets.

Animals↗

PubMed1975

Sodium fluoroacetate poisoning.

We observed a case of poisoning with sodium fluoroacetate, and extremely lethal rodenticide that has had relatively strict controls placed on its use. The case was unusual in the very long time the rodenticide had been present in the home, the mild nature of the poisoning, and the remarkably delayed onset of serious central nervous system symptoms. It demonstrates the need for even stronger controls on the use of sodium fluoroacetate.

Accidents, Home↗

PubMed1997

Expression cassettes for formaldehyde and fluoroacetate resistance, two dominant markers in Saccharomyces cerevisiae.

We employed two genes in constructing yeast expression cassettes for dominant, selectable markers. The Saccharomyces cerevisiae gene SFA1, encoding formaldehyde dehydrogenase, was placed under the control of the GPD1 promoter and CYC1 terminator. The Moraxella sp. strain B gene dehH1, encoding fluoroacetate dehalogenase, was placed under the control of both the GPD1 and CYC1 promoters. With these constructs it was possible to select directly for yeast strains resistant to either formaldehyde or fluoroacetate. Both selective agents are completely metabolized and inexpensive, making them very useful in the pursuit of yeast gene functions and for industrial applications. An additional advantage of the formaldehyde dehydrogenase marker is that it is an S. cerevisiae gene, thus allowing 'all yeast' constructs.

Aldehyde Oxidoreductases↗

PubMed1983

The effect of monoacetin and calcium chloride on acid-base balance and survival in experimental sodium fluoroacetate poisoning.

Sodium fluoroacetate (compound "1080") was injected intravenously, 3 mmol/kg, to artificially-ventilated anesthetized cats. Blood pressure, ECG, acid-base parameters and serum ionized calcium were monitored in four groups of cats. Group A served as control. Group B cats were treated with calcium chloride to restore normal values of serum ionized calcium. Group C was given monoacetin (glyceryl monoacetate), 0.5 ml/kg every 30 min. Both monoacetin and calcium chloride were given to cats in group D. Fluoroacetate poisoning caused significant decrease in ionized calcium and severe metabolic acidosis with increased levels of lactate and pyruvate. The lactate to pyruvate ratio remained normal as long as there was no significant drop in blood pressure. Correction of blood ionized calcium prolonged survival from 94 to 166 min (group B). Monoacetin prolonged average survival time to 166 min. Metabolic acidosis was aggravated in monoacetin-treated animals (group C). Combined treatment with monoacetin and calcium chloride did not prolong mean survival time above 166 min.

Acid-Base Imbalance↗

PubMed1994

Qualitative and quantitative determination of fluoroacetic acid in Arrabidea bilabiata and Palicourea marcgravii by 19F-NMR spectroscopy.

Qualitative and quantitative examination of Arrabidea bilabiata and Palicourea marcgravii by 19F-NMR spectroscopy has shown the presence of fluoroacetic acid. By acid-base enrichment it is possible to detect amounts of fluoroacetic acid which otherwise are below detection rate. The detection limit (without enrichment) is estimated to be about 4 micrograms/g. Disturbing metal ions of higher oxidation states are also removed by this way. Arrabidea bilabiata contains 64.1 micrograms/g (seeds) and 3.0 micrograms/g (leaves), and Palicourea marcgravii contains 5.4 micrograms/g (leaves).

Fluorine↗

PubMed1984

The role of fluoroacetate-specific dehalogenase and glutathione transferase in the metabolism of fluoroacetamide and 2,4-dinitrofluorobenzene.

2,4-Dinitrofluorobenzene (DNFB) reacts with glutathione to form a stable product similar to that formed with the model glutathione-S-transferase (GST) substrate, 1-chloro-2,4-dinitrobenzene (CDNB). DNFB is approx. 40 times als reactive as CDNB in this chemical reaction. The enzymatic defluorination of DNFB also proceeds at a more rapid rate than that of CDNB in the GST assay. Fluoroacetamide (FAM), like fluoroacetate (FAC), undergoes no discernable chemical defluorination. Its enzymatic defluorination is approx. 10% of that observed for FAC and only 0.2% of the rate for DNFB. An antibody raised to the fluoroacetate specific dehalogenase (FSD) precipitated both FAC and FAM defluorinating activity but had no effect on either CDNB or DNFB activity. The data are consistent with the hypothesis that DNFB is metabolized by the GST while FAM is metabolized by the FSD.

Animals↗

PubMed2006

Ecotoxicological evaluation of sodium fluoroacetate on aquatic organisms and investigation of the effects on two fish cell lines.

Sodium monofluoroacetate (compound 1080) is one of the most potent pesticides. It is also a metabolite of many other fluorinated compounds, including anticancer agents, narcotic analgesics, pesticides or industrial chemicals. Other sources of water contamination are the atmospheric degradation of hydrofluorocarbons and hydrochlorofluorocarbons. However, there is little information available about the adverse effects of sodium fluoroacetate in aquatic organisms. Firstly, the bacterium Vibrio fischeri (decomposer), the alga Chlorella vulgaris (1st producer) and the cladoceran Daphnia magna (1st consumer) were used for the ecotoxicological evaluation of SMFA. The most sensitive models were C. vulgaris and D. magna, with a NOAEL of 0.1 and an EC50 of 0.5 mM at 72 h, respectively. According to the results after the acute exposure and due to its high biodegradation rate and low bioaccumulation potential, sodium fluoroacetate is most unlikely to produce deleterious effects to aquatic organisms. Secondly, two fish cell lines were employed to investigate the effects and mechanisms of toxicity in tissues from 2nd consumers. The hepatoma fish cell line PLHC-1 was more sensitive to SMFA than the fibroblast-like fish cell line RTG-2, being the uptake of neutral red the most sensitive bioindicator. Lysosomal function, succinate dehydrogenase and acetylcholinesterase activities were inhibited, glucose-6-phosphate dehydrogenase activity was particularly stimulated, and metallothionein and ethoxyresorufin-O-deethylase levels were not modified. Intense hydropic degeneration, macrovesicular steatosis and death mainly by necrosis but also by apoptosis were observed. Moreover, sulphydryl groups and oxidative stress could be involved in PLHC-1 cell death induced by SMFA more than changes in calcium homeostasis.

Acetylcholinesterase↗

PubMed2003

Fluorinated natural products: the biosynthesis of fluoroacetate and 4-fluorothreonine in Streptomyces cattleya.

Organofluorine compounds are rare in Nature, with only a handful known to be produced by some species of plant and two microorganisms. Consequently, the mechanism of enzymatic carbon-fluorine bond formation is poorly understood. The bacterium Streptomyces cattleya biosynthesises fluoroacetate and 4-fluorothreonine as secondary metabolites and is a convenient system to study the biosynthesis and enzymology of fluorometabolite production. Using stable-isotope labelled precursors it has been shown that there is a common intermediate in the biosynthesis of the fluorometabolites, which has recently been identified as fluoroacetaldehyde. Studies with cell-free extracts of S. cattleya have identified two enzymes, an aldehyde dehydrogenase and a threonine transaldolase, that are involved in the biotransformation of fluoroacetaldehyde to fluoroacetate and 4-fluorothreonine.

Acetaldehyde↗

PubMed1997

Isolation and quantification of fluoroacetate in rat tissues, following dosing of Z-Phe-Ala-CH2-F, a peptidyl fluoromethyl ketone protease inhibitor.

Peptidyl fluoromethyl ketones (PFMK) are irreversible inhibitors of cathepsin B, a cysteine proteinase thought to be involved in the degradation of cartilage. It has been speculated that PFMK inhibitors may metabolize in rodents to form fluoroacetate (FAC), an extremely toxic poison. A highly selective and sensitive separation and detection scheme was developed to measure trace levels of FAC in rat tissues following PFMK dosing. The procedure consisted of extracting FAC from tissue and spiking the extract with [18O]2-fluoroacetate (18O-FAC) as an internal standard. FAC and 18O-FAC were further isolated from matrix components using ion-exchange, solid-phase extraction. The pentafluorobenzyl esters of FAC and 18O-FAC were formed to facilitate the chromatographic separation. Two-dimensional gas chromatography coupled with selected-ion-monitoring detection provided the final measurement. The assay had a limit of detection of 2 ng FAC per g tissue, and was capable of accurately quantitating as little as 10 ng FAC per g tissue with a S/N ratio of 40:1. Linearity was established over two orders of magnitude, from 2-500 ng ml-1, with 5 microliters injected on-column. The method was used to demonstrate that FAC was formed in rats following dosing with Z-Phe-Ala-CH2-F, a PFMK cathepsin enzyme inhibitor.

Animals↗

PubMed1994

Detoxification of the plant toxin fluoroacetate by a genetically modified rumen bacterium.

We isolated the fluoroacetate dehalogenase gene (H1), from Moraxella species strain B, and placed it under the transcriptional control of a 154 bp fragment of the erm gene promoter. The promoter/gene construct was attached to the Butyrivibrio fibrisolvens shuttle vector pBHerm, and the resulting dehalogenase expression plasmid (pBHf) was transferred to B. fibrisolvens OB156 by electroporation. The erm gene promoter directed expression of dehalogenase activity in both E. coli and B. fibrisolvens OB156. Cell-free lysates of the genetically modified OB156 defluorinated 10.6 nmol fluoroacetate/min/mg protein. Growing cultures of OB156 were able to detoxify fluoroacetate in the culture medium, at the rate of 9.9 nmol/min/mg. Plasmid pBHf was retained by 100% of OB156 cells after 500 generations of non-selective culture. The restriction pattern of pBHf remained unchanged after extensive non-selective growth and host bacteria continued to produce active dehalogenase. The construction of rumen bacteria that are able to detoxify an important natural poison supports the feasibility of using genetically modified rumen bacteria to aid animal production.

Animals↗

PubMed1967

Citrate content of liver and kidney of rat in various metabolic states and in fluoroacetate poisoning.

The citrate content of rat liver changes little when normal rats are starved, when starved rats are re-fed with various diets and when normal animals are made diabetic with alloxan. The citrate content of rat kidney changes little on starvation, but it doubles on induction of diabetes. Fluoroacetate poisoning has relatively little effect on the citrate content of liver under a variety of conditions except that normal female rats show a 2.4-fold increase. Fluoroacetate poisoning leads to increases in the citrate content of kidney under all conditions. The relevance of these observations to the regulation of fatty acid synthesis is discussed. The acetic anhydride-pyridine method and the pentabromoacetone method for the estimation of citrate are compared.

Animals↗

PubMed1981

Subacute fluoroacetate poisoning.

Fluoroacetic acid and some other monofluoro-compounds are among the most poisonous substances known. In man symptoms of poisoning begin after a latent period of one-half to several hours and death follows rapidly. Convulsions and arrhythmia are common terminal signs. No specific changes have been found at postmortem. It is suggested, but unproven, that sudden death of the patient whom this case report concerns was due to subacute fluoroacetate poisoning.

Adult↗