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

Abstract

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.

Ultrastructural lesions in the myocardium and kidneys of rabbits in experimental acute Amorimia exotropica poisoning

“…It is proposed that an increase in the amount of glycogen in the cell cytoplasm is an indicator of diminished usage and accumulation, rather than a sign of increased metabolic activity (Ghadially 1988). The FA interferes in the Krebs cycle and impairs the production of energy by the hepatocytes (Goncharov et al 2006). This impairment could explain the accumulation of glycogen in the liver cells.…”

“…However, the available information has not established an unequivocal mechanism by which FA acts on mitochondria. Biochemical studies have implicated FA in the production of the specific aconitase inhibitor fluorocitrate, interruption of the citric acid cycle, and the accumulation of citrate in the mitochondria, an excess of which could provide the basis for an explanation of mitochondrial abnormalities (Bovis et al 1966, Goncharov et al 2006. Swelling of the mitochondria with disruption of the cristae, fluid accumulation in the sarcoplasm and disorganization of the sarcomeres were the main ultrastructural changes observed in all poisoned rabbits.…”

“…In electron microscopy of the myocardium in an experimental chronic poisoning by A. exotropica in rabbits, these lesions were not observed . The term fluoroacetate (FA) refers to a large series of chemical compounds of the general formula CH 2 FCOOR, and it was first synthesized in 1896 (Goncharov et al 2006). The sodium salt of FA is known as 'compound 1080' and it is used in some countries for controlling the population of certain vertebrate species: in the USA and UK, rodents are controlled in ships, sewers and warehouses; also, coyotes are controlled by the use of FA-impregnated carcasses or collars on livestock; in Australia and New Zealand rabbits, wallabies, goats, wild pigs, deer and opossums are controlled with the use of baits based on apple, carrot or grain; aerial sowing is used to control large or remote areas (Schultz et al 1982, Twigg & King 1991, Proudfoot et al 2006.…”

Metabolic Regulation of Manganese Superoxide Dismutase Expression via Essential Amino Acid Deprivation

“…Gln enters the tricarboxylic acid cycle through glutamate and ␣-ketoglutarate, so we investigated the contribution of the tricarboxylic acid cycle to the induction of MnSOD by utilizing selective inhibitors to several different key enzymes. We first targeted the inhibition of aconitase with 3-fluoroacetate (44,45), which occurs through the intracellular conversion to the aconitase substrate inhibitor, fluorocitrate. As shown in Fig.…”

2,3,3,3‐Tetrafluoropropene [MAK Value Documentation, 2015]

“…The dog has been shown to be the most sensitive species for this mechanism of action. It is interesting that effects on the heart predominated over central nervous effects in rabbits after the administration of sodium fluoroacetate (Goncharov et al 2006). In rats, heart effects occurred after exposure to 1,3,3,3-tetrafluoropropene and 1,1,1,2,2-pentafluoropropane (Rush et al 2013), while histological heart effects were observed after exposure to 1,3,3,3-tetrafluoropropene and 1,1,1,3,3-pentafluoropropane, but not after 1,1,1,2,2-pentafluoropropane and 2,3,3,3-tetrafluoropropene (Rush et al 2013).…”