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PubMed1998

Genetically modified ruminal bacteria protect sheep from fluoroacetate poisoning.

Four strains of Butyrivibrio fibrisolvens, transformed with a gene encoding fluoroacetate dehalogenase, maintained a combined population of 10(6) to 10(7) cells ml-1 in the rumens of test sheep. Five inoculated sheep showed markedly reduced toxicological symptoms after fluoroacetate poisoning when behavioral, physiological, and histological effects were compared with those of five uninoculated control sheep.

Animals↗
PubMed2001

Isolation of an aldehyde dehydrogenase involved in the oxidation of fluoroacetaldehyde to fluoroacetate in Streptomyces cattleya.

Streptomyces cattleya is unusual in that it produces fluoroacetate and 4-fluorothreonine as secondary metabolites. We now report the isolation of an NAD(+)-dependent fluoroacetaldehyde dehydrogenase from S. cattleya that mediates the oxidation of fluoroacetaldehyde to fluoroacetate. This is the first enzyme to be identified that is directly involved in fluorometabolite biosynthesis. Production of the enzyme begins in late exponential growth and continues into the stationary phase. Measurement of kinetic parameters shows that the enzyme has a high affinity for fluoroacetaldehyde and glycoaldehyde, but not acetaldehyde.

Acetaldehyde↗
PubMed2006

Calcium gluconate and sodium succinate for therapy of sodium fluoroacetate experimental intoxication in cats: clinical and electrocardiographic evaluation.

Sodium fluoroacetate (SFAC) or Compound 1080 is a potent rodenticide, largely used after 1946 for rodent and home pest control. The toxic effects of SFAC are caused by fluorocitrate action, a toxic metabolite, which has a competitive action with aconitase enzyme, leading to citrate accumulation and resulting in interference in energy production by Krebs cycle blockade. In the present study, domestic cats were intoxicated with oral doses of fluoroacetate (0.45 mg/kg). The intoxicated animals presented emesis, diarrhea with abdominal pain posture and an abdominal palpation, tachypnea, bilateral midriasis, hypothermia, hyperexcitability and convulsions. Blood gas analysis indicated decreased pH and bicarbonate levels. Serum ionized calcium was also decreased. ECG showed non-specific changes in ventricular repolarization and ventricular arrhythmias. The survival rate was 75% in the treated group with calcium gluconate and sodium succinate and 37.5% in the nontreated group.

Animals↗
PubMed1979

Effects of fluoroacetate on the testis of the rat.

Rats recieving 20, 6.6 or 2.2 p.p.m. sodium fluoroacetate in the drinking water were killed daily during the 7 days of treatment and at more widely spaced intervals in the succeeding 21 days. Testicular weight and ATP concentrations decreased in rats receiving 20 or 6 p.p.m. fluoroacetate, while citrate concentrations were elevated and morphological damage was seen in the testes of all the treated rats. Initial cellular changes common to the three treatment groups included altered appearance and decreased numbers of spermatids, and formation of spermatid and spermatocyte giant cells. At the two higher concentrations damage progressed to marked seminiferous tubule atrophy. Regeneration of the seminiferous tubules was complete by 7 days after treatment, in the rats given 2 p.p.m. but regeneration was not complete by Day 21 after treatment in those receiving the higher doses. Spermatogenesis was abnormal in some instances during the regneration period in these groups. The findings are consistent with impaired energy production via blockage of the Krebs cycle, and subsequent impairment of carbohydrate metabolism through the Embden-Meyerhof pathway.

Adenosine Triphosphate↗
PubMed1990

Evaluation of potential antidotes for sodium fluoroacetate in mice.

Pathogenesis in fluoroacetate poisoning is multifactorial. Biochemically it is characterized by lethal synthesis of fluorocitrate, causing hypocalcemia, and energy deficiency through blockade of the TCA cycle. Calcium gluconate (CaG) was chosen to antagonize hypocalcemia, while sodium alpha kelogluterate (NaKG) and sodium succinate (NaSuc) were selected as potential antidotes to revive the TCA cycle. Effectiveness of each of these antidotes individually and in certain combinations was tested in mice exposed to lethal doses (15 mg/kg ip) of sodium fluoroacetate (NaFAC). Antidotal treatments were administered at 15 min, 4 h, 10 h, 24 h, and 36 h after NaFAC. All 3 of the antidotes alone, as well as a combination of CaG with NaKG, were ineffective in reducing mortality in mice after NaFAC. On the other hand, a combination of CaG (130 mg/kg) with NaSuc (240 mg/kg) was effective if the 2 solutions were either injected at separate sites or mixed in the same syringe just prior to injection. Similar solutions, if mixed for 24 h or longer before administrations, were ineffective. Increasing the dose of NaSuc to 360 or 480 mg/kg with CaG (130 mg/kg) was unrewarding. These results indicate that CaG in combination with 240 mg NaSuc/kg offer a promising therapy modality in NaFAC intoxication. Additional studies involving biochemical parameters and other species are needed to confirm the efficacy and mechanism(s) of action of this combination.

Animals↗
PubMedDate not supplied

Capillary gas chromatographic-mass spectrometric determination of fluoroacetate residues in animal tissues.

A method for the quantitative determination of fluoroacetate (FAC) residues in animal tissues is described. The procedure involves tungstic acid extraction, partitioning into ethyl acetate, evaporation of ethyl acetate, derivatization with pentafluorobenzyl bromide (PFB), and analysis of the resulting derivative (PFB-FAC) by capillary gas chromatography-mass spectrometry (CGC-MS) with specific ion monitoring (SIM). The tungstic acid system extracted 96.8 +/- 4.2% of the endogenous 14C-1080 residues in rat tissues. Recovery of FAC during the extraction, purification, and derivatization procedures is established by use of a 14C-FAC spike. 1,2-Dibromobenzene is used as an internal standard for the CGC-MS analysis. PFB-FAC is identified on the basis of comparative retention times and the relative intensities of m/z 257.9 and 181.0. PFB-FAC is quantitated by comparing the response at m/z 257.9 to a PFB-FAC standard curve. Routine sensitivity of the method allows determination of 10 ppb fluoroacetate in tissue.

Animals↗
PubMed1972

Light and electron microscopic studies of the rat kidney after administration of inhibitors of the citric acid cycle in vivo. I. Effects of sodium fluoroacetate on the proximal convoluted tubule.

Light and electron microscopic studies of morphologic changes in the rat proximal convoluted tubule after intraperitoneal injection of sodium fluoroacetate (FAc), 60, 20 and 3.5 mg/kg body weight, have been made. Particular attention was directed toward appreciating different changes in the first (S(1)) and second (S(2)) segments of the proximal tubule. The earliest change was loss of mitochondrial granules and pallor of the mitochondrial matrix, not necessarily associated with matrix swelling. Matrix swelling was greatest at 3 hours after 3.5 mg/kg and was reversible. However, the mitochondria retained their elongate shape and cristae persisted. At 48 hours, some mitochondria appeared normal; in others, abnormal matrix densities of unknown nature were present. Mitochondrial changes were similar in S(1) and S(2) at all times. Enlarged apical vacuoles, most pronounced in S(1), occurred in all rats after 20 mg/kg. The change was uncommon after 3.5 mg/kg. The hypothesis proposed is that vacuoles arise during an FAc-induced hyperglycemic phase, when pinocytotic activity is maintained but the normal pathway of glucose catabolism is inhibited. Moderate dilatation of the rough-surfaced endoplasmic reticulum occurred during the first 2-hour period in S(1) and S(2) tubules after high and low doses, but between 6 and 24 hours, dilatation was extensive in S(1) tubules after 3.5 mg/kg. This change was reversible. Two types of abnormal vacuolar bodies, large and small, have been described, and were unique to S(1) tubules. Acid phosphatase activity was demonstrated in a proportion of the small ones, indiciating that they were a type of lysosome. The larger ones shared features in common with cytosomes of control cells, but acid phosphatase activity was not demonstrated in them and their origins and functions remain obscure. The biochemical lesions induced by fluoroacetate have been discussed and a tentative interpretation of some of the morphologic changes has ben made.

Acid Phosphatase↗
PubMed1997

Use of fluorocitrate and fluoroacetate in the study of brain metabolism.

Fluoroacetate and its toxic metabolite fluorocitrate cause inhibition of aconitase. In brain tissue, both substances are preferentially taken up by glial cells and leads to inhibition of the glial TCA cycle. It is important to realise, however, that the glia-specificity of these compounds depends both on the dosage and on the model used. The glia-inhibitory effect of fluorocitrate as obtained by intracerebral microinjection in vivo is reversible within 24 h. A substantial inhibition of the glial TCA cycle by systemic administration of fluoroacetate requires a lethal dose. Inhibition of the glial aconitase leads to accumulation of citrate and to a reduction in the formation of glutamine. Whereas the former is likely to be responsible for the main toxic effect of these compounds possibly by chelation of free calcium ions, it is the latter that has received most attention in the study of glial-neuronal interactions, since glutamine is an important precursor for transmitter glutamate and GABA.

Animals↗
PubMedDate not supplied

Toxicology of fluoroacetate: a review, with possible directions for therapy research.

Fluoroacetate (FA; CH2FCOOR) is highly toxic towards humans and other mammals through inhibition of the enzyme aconitase in the tricarboxylic acid cycle, caused by 'lethal synthesis' of an isomer of fluorocitrate (FC). FA is found in a range of plant species and their ingestion can cause the death of ruminant animals. Some fluorinated compounds -- used as anticancer agents, narcotic analgesics, pesticides or industrial chemicals -- metabolize to FA as intermediate products. The chemical characteristics of FA and the clinical signs of intoxication warrant the re-evaluation of the toxic danger of FA and renewed efforts in the search for effective therapeutic means. Antidotal therapy for FA intoxication has been aimed at preventing fluorocitrate synthesis and aconitase blockade in mitochondria, and at providing citrate outflow from this organelle. Despite a greatly improved understanding of the biochemical mechanism of FA toxicity, ethanol, if taken immediately after the poisoning, has been the most acceptable antidote for the past six decades. This review deals with the clinical signs and physiological and biochemical mechanisms of FA intoxication to provide an explanation of why, even after decades of investigation, has no effective therapy to FA intoxication been elaborated. An apparent lack of integrated toxicological studies is viewed as a limiter of progress in this regard. Two principal ways of developing effective therapies for FA intoxication are considered. Firstly, competitive inhibition of FA interaction with CoA and of FC interaction with aconitase. Secondly, channeling the alternative metabolic pathways by orienting the fate of citrate via cytosolic aconitase, and by maintaining the flux of reducing equivalents into the TCA cycle via glutamate dehydrogenase.

Aconitate Hydratase↗
PubMed1990

Evaluation of radiolabeled acetate and fluoroacetate as potential tracers of cerebral oxidative metabolism.

We investigated the potential use of radiolabeled acetate (ACE) and fluoroacetate (FACE) as tracers of cerebral oxidative (Krebs cycle) metabolism. The rates of cerebral accumulation of 14C-labeled FACE and ACE were compared with glucose metabolic rates measured simultaneously with 18F-fluorodeoxyglucose (FDG) in awake rats using dual-tracer quantitative digital autoradiography. Both FACE and ACE crossed the blood-brain barrier at approximately the same rate as glucose. Metabolism of FACE by the brain, however, was extremely slow; metabolites were practically undetectable above background precursor levels through 60 min. Metabolic uptake of ACE by the brain was significant by 10 min; its rate of accumulation averaged approximately 70-80% of the glucose rate. While the metabolic images of ACE were similar to those of FDG, variations in the uptake patterns of FDG and ACE occurred in some structures, perhaps related to regional variations in glucose versus oxygen metabolism.

Acetates↗
PubMed1993

Astrocytes and the entry of circulating ammonia into the brain: effect of fluoroacetate.

Chronic hyperammonemia is known to lead to pathological forms of astrocytes. To test the influence of these changes on the neurotoxicity of ammonia, the glial metabolic poison fluoroacetate (FA) was applied locally, through microdialysis to the hippocampal dentate gyrus. The penetration of ammonia into the brain following the i.p. injection of 7.8 mmol/kg NH4 acetate was evaluated by measuring the ammonia and glutamine content of the microdialysate. Field EPSPs (fEPSPs) evoked by perforant path stimulation were recorded 1.5 mm from the microdialysis probe. When 20 mM FA was perfused, NH4 acetate injection increased the ammonia efflux by 300% and decreased fEPSPs by 40%, but glutamine concentration remained low. With no FA in the microdialysate, NH4 acetate treatment increased the efflux of ammonia by only 60%, did not affect fEPSPs but doubled glutamine efflux. Arterial ammonia content, as measured by microdialysis in the common carotid, increased 4-5 fold following i.p. administration of NH4 acetate, while arterial glutamine was not elevated. Systemically administered FA did not affect either of these changes significantly, but slightly reduced arterial pH. These observations indicate that FA applied by microdialysis acted locally on astrocytes and therefore impaired astrocytic function contributes to the development of hepatic encephalopathy by facilitating the entry of ammonia into the brain. Inhibition of excitatory synaptic transmission by elevated brain ammonia may underlay CNS depression in hepatic encephalopathy.

Ammonia↗
PubMed2000

Induction and inhibition of testicular germ cell apoptosis by fluoroacetate in rats.

Fluoroacetate (FA), an inhibitor of aconitase, is known to lower the intracellular level of adenosine triphosphate (ATP), which recently has been suggested to be a possible determinant of the form of cell death, apoptosis or necrosis. To investigate which form of germ cell death occurs in FA-induced testicular toxicity, adult Sprague Dawley rats were given a single oral dose of FA (0.5 or 1.0 mg/kg) and euthanized at 3, 6, 12, 24, 48, and 72 h thereafter. Germ cell degeneration was histologically first found in early round spermatids at stage I and in spermatogonia at stages II-IV of seminiferous tubules 6 and 12 h, respectively, after dosing. Degenerating spermatogonia exhibited characteristic features of apoptosis as demonstrated by both electron microscopy and in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), whereas spermatids did not. At the 24 and 48 h time points, degenerating spermatids were continually present and subsequently formed multinucleated giant cells, while the number of degenerating spermatogonia and TUNEL-labeled spermatogonia was drastically and/or significantly decreased compared to those from the control group, indicating that spontaneous male germ cell apoptosis is inhibited. Coincident with these morphological changes, DNA laddering on gel electrophoresis was apparent only 12 h after dosing. The results demonstrate that FA induces either apoptosis or necrosis of male germ cells in the early stage after dosing and subsequently inhibits spontaneous apoptosis.

Aconitate Hydratase↗
PubMed1983

The enzymatic defluorination of fluoroacetate in mouse liver cytosol: the separation of defluorination activity from several glutathione S-transferases of mouse liver.

The liberation of free fluoride ion from fluoroacetate (FAc) proceeds as an enzyme-catalyzed dehalogenation reaction in the soluble fractions of several organs of the CFW Swiss mouse. Liver contained the highest FAc defluorinating activity. The enzyme activity in other organs decreased in the order kidney greater than lung greater than heart greater than testes. No activity was detected in the brain. Experiments were designed to characterize and identify the enzyme species responsible for FAc metabolism in liver. Enzyme activity was dependent on the concentration of glutathione (GSH) in the assay mixture, with maximal activity occurring above 5 mM. The dehalogenation of FAc had an apparent Km of 7.0 mM when measured in the presence of a saturating concentration of GSH. An increase in the pH of the assay mixture enhanced fluoride release in both phosphate and borate buffer. The defluorination activity was reduced to negligible levels when stored for 24 h at 4 degrees C. The addition of either GSH, dithiothreitol, or 2-mercaptoethanol increased stability, with the latter providing protection for greater than 150 h at a concentration of 15 mM. DEAE anion-exchange chromatography separated the defluorinating activity from 90% of the soluble GSH S-transferase activity measured with 1-chloro-2,4-dinitrobenzene. FAc defluorination activity did not bind to a GSH affinity column which selectively separates it from a group of anionic GSH S-transferases. The GSH-dependent enzyme which dehalogenates FAc has unique properties and can be separated from the liver GSH S-transferases previously described in the literature.

Animals↗
PubMed1986

Acetate and fluoroacetate as possible markers for glial metabolism in vivo.

[3H]Acetate has been shown by light autoradiographic methods to label the neuropil but not the perikarya in brain and retina. [3H]Fluoroacetate behaves similarly. The study provides anatomical data which support the concept of metabolic compartmentation of glutamic acid and associated metabolites previously derived from biochemical studies. It is suggested that these may be markers of non-neuronal metabolism, probably mostly glial, and may be used to develop procedures which will provide complementary data to that obtained with 2-deoxyglucose on regional metabolism in brain.

Acetates↗
PubMed1994

Fluorocitrate and fluoroacetate effects on astrocyte metabolism in vitro.

The Krebs cycle inhibitor fluorocitrate (FC) and its precursor fluoroacetate (FA) are taken up in brain preferentially by glia. These compounds are used experimentally to inhibit glial metabolism in situ. The actions of these agents have been attributed to both the disruption of carbon flux through the Krebs cycle and to impairment of ATP production. We used primary astrocyte cultures to evaluate these two possible modes of action. Astrocyte ATP levels exhibited little or no reduction during incubation with 0.5 mM FC or 25 mM FA. Correspondingly, FC and FA caused less than 30% reductions in glutamate uptake (P > 0.05), an important energy-dependent astrocyte function. Carbon flux through the Krebs cycle was assessed by measuring astrocyte glutamine production in the absence of exogenous glutamate or aspartate. Under these conditions, glutamine production was reduced 65 +/- 5% by 0.5 mM FC and 61 +/- 3% by 25 mM FA (P < 0.01). In contrast, FC and FA had no effect on glutamine production when 50 microM glutamate was provided in the media. These findings suggest that the metabolic effects of FC and FA on astrocytes in vivo result from impairment of carbon flux through the Krebs cycle, and not from impairment of oxidative ATP production.

Animals↗
PubMed1986

Serum citrate as a peripheral indicator of fluoroacetate and fluorocitrate toxicity in rats and dogs.

The utility of serum citrate as a peripheral indicator of toxicity was tested as a possible investigational probe for compounds which inhibit citrate metabolism. Fluoroacetate (FA) and its putative toxic metabolite, fluorocitrate (FC), were given to rats and dogs in a series of studies. In rats, 3 mg/kg FA (po) caused a 46% depletion in heart ATP concentrations and a 15-fold increase in heart citrate concentrations. Both of these changes were significantly correlated with a fivefold elevation in serum citrate. In dogs, citrate accumulation was less pronounced (two-to threefold) in the heart and serum, and heart ATP concentrations were not significantly reduced. However, the time course of serum citrate elevations corresponded with the appearance of serious clinical signs and death. In range-finding studies with rats or dogs, serum citrate elevations were always observed in a dose-related pattern according to the dose of FA or FC administered. In contrast to FA, toxic doses of FC did not reduce heart ATP in either rats or dogs, and heart citrate accumulation was less marked than with FA. Both FA and FC produced significant hyperglycemia (twofold increase) in both rats and dogs and high correlations were established between serum glucose and serum citrate in both species. Serum total calcium was reduced (-18%) in dogs treated with FC (8 mg/kg, iv) and a strong inverse correlation to serum citrate was shown. This correlation is biologically meaningful in light of the known chelating effect of citrate on calcium. Clinical manifestations of tremors, tetany, and convulsions in FC-treated dogs were consistent with known symptoms of hypocalcemia. No decrease in total calcium was observed in rats treated with either FA or FC. Despite certain species differences in response to the two fluoro inhibitors, serum citrate levels were always reflective of nontoxic, toxic, or lethal doses.

Adenosine Triphosphate↗
PubMed1986

Preparation of no carrier added fluorine-18 labeled 16-fluorohexadecanoic and fluoroacetic acids from highly reactive tetraethylammonium [18F]fluoride.

No carrier added tetraethylammonium [18F]fluoride prepared via synthesis and hydrolysis of fluorotrimethylsilane was reacted with methyl 16-iodohexadecanoate in acetonitrile. At 80 degrees C, yields of up to 80% were found with reaction times of 20-30 min. As would be expected for fluoride-for-iodide exchange, reactions were slower than previously-reported cyclic sulfate and triflate displacements. TLC and reverse-phase HPLC indicated that a single pure radioactive product was formed, which was hydrolyzed with alkali to the free acid. NMR spectroscopy of a carrier added preparation was consistent with assignment as 16-fluorohexadecanoic acid and no rearrangement to the 15-fluoro compound. [18F]Fluoroacetic acid was prepared analogously in high yield from ethyl iodoacetate. The results are discussed in terms of guidelines for syntheses of other 18F compounds and of the properties of near anhydrous tetraethylammonium fluoride in acetonitrile.

Coronary Disease↗