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Toxicology of Fluoroacetate: a Review, with Possible Directions for Therapy

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Toxicology of Fluoroacetate: a Review, with Possible Directions for Therapy See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/7515021 Toxicology of fluoroacetate: A review, with possible directions for therapy research Article in Journal of Applied Toxicology · March 2006 DOI: 10.1002/jat.1118 · Source: PubMed CITATIONS READS 88 3,015 3 authors, including: Nikolay V Goncharov 109 PUBLICATIONS 660 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: Analysis of the chemical composition of the products of La-catalyzed mathanolysis of Russian VX View project The Effects of Weakened Geomagnetic Field View project All content following this page was uploaded by Nikolay V Goncharov on 25 January 2018. The user has requested enhancement of the downloaded file. 148JOURNALN. V. GONCHAROVOF APPLIED TOXICOLOGYET AL. J. Appl. Toxicol. 2006; 26: 148–161 Published online 26 October 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jat.1118 Toxicology of fluoroacetate: a review, with possible directions for therapy research Nikolay V. Goncharov,1 Richard O. Jenkins2,* and Andrey S. Radilov1 1 Research Institute of Hygiene, Occupational Pathology and Human Ecology, Saint-Petersburg, Russia 2 School of Allied Health Sciences, De Montfort University, Leicester, UK Received 30 June 2005; Revised 16 August 2005; Accepted 5 September 2005 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 toxi- city, 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. Copyright © 2005 John Wiley & Sons, Ltd. KEY WORDS: fluoroacetate; compound 1080; fluorocitrate; monofluorides; aconitase; TCA; lethal synthesis; therapy; meta- bolic poison Introduction The sodium salt of FA is known as ‘compound 1080’ and it is used in some countries for controlling the popu- The term fluoroacetate (FA) refers to a large series of lation of certain vertebrate species: in the USA and UK chemical compounds of the general formula CH2FCOOR. rodents are controlled in ships, sewers and warehouses; FA and other monofluorides are highly toxic compounds. also, coyotes are controlled by the use of FA-impregnated Their action characteristically involves a latent period, carcasses or collars on livestock; in Australia and New which for humans is from half to several hours even on Zealand rabbits, wallabies, goats, wild pigs, deer and exposure to lethal doses. opossums are controlled with the use of baits based on FA was first synthesized in 1896 and only much apple, carrot or grain; aerial sowing is used to control later found in Dichapetalum, Gastrolobium, Oxylobium, large or remote areas (Norris, 2001). To replace the Acacia and Palicourea plants prevailing in Australia, highly toxic FA, 1,3-difluoro-2-propanol, which is the southern Africa and South America (Oerlichs and major ingredient of the commercial product gliftor, was McEwan, 1961; McEwan, 1964; Vickery et al., 1973; proposed for pesticide applications. It is less toxic than De Oliveira, 1963; Aplin, 1971). The FA contents of FA (about 100 mg kg−1 in rats), but the mechanism of its Australian plants attain 5 g kg−1 dry weight (Hall, 1972), toxic action is similar to that of FA and involves its and their single or repeated ingestion cause the death of initial conversion into 1,3-difluoroacetone with the help ruminant animals, resulting in considerable economic of NAD-dependent alcohol dehydrogenase (Feldwick damage (Annison et al., 1960; McCosker, 1989; Minnaar et al., 1998). Fluoroacetamide (compound 1081) has been et al., 2000). used in Israel for field rodent control (Braverman, 1979). The conversion of fluoroacemide into FA in vivo occurs via hydrolysis by organophosphate-sensitive amidase * Correspondence to: Dr R. O. Jenkins, School of Allied Health Sciences, (Tecle and Casida, 1989). De Montfort University, The Gateway, Leicester LE1 9BH, UK. It was also found that a series of other compounds E-mail: [email protected] Contract/grant sponsor: BioIndustry Initiative Program, the US Department metabolize to FA as intermediate products: these are of State; Contract/grant number: ISTC BII-2629. the anticancer drugs 5-fluorouracil and fluoroethyl Copyright © 2005 John Wiley & Sons, Ltd. J. Appl. Toxicol. 2006; 26: 148–161 TOXICOLOGY OF FLUOROACETATE 149 nitrosourea, N-(2-fluoroethyl) derivatives of the narcotic substrate coordination to a specific iron atom in this analgesics normeperidin and normetazocin, the industrial cluster, Fea (Lauble et al., 1992). All four 2-fluorocitrate chemicals fluoroethanol and 1-(di)halo-2-fluoroethanes isomers were synthesized and purified to show that (Yamashita et al., 2004; Arellano et al., 1998; Yeh (−)-erythro-2-flurocitrate (2R, 3R) is the single inhibitory and Cheng, 1994; Reifenrath et al., 1980; Tisdale and isomer (Carrell et al., 1970). The reversible character of Brennan, 1985; Tecle and Casida, 1989; Keller et al., competitive inhibition of the enzyme was established 1996; Feldwick et al., 1998). Finally, industrial ‘achieve- (Villafranca and Platus, 1973; Brand et al., 1973; Eanes ments’ have led to the appearance of FA in fog and rain and Kun, 1974). Furthermore, it was shown that aconitase (Rompp et al., 2001). removes fluoride ion from (−)-erythro-2-fluorocitrate Formulators and pest control workers are the largest (2R, 3R isomer) with a stoichiometry of 1 F− per enzyme occupational risk group (Norris, 2001). Exposure to a molecule (Kent et al., 1985; Tecle and Casida, 1989), stock solution during formulation and dermal or respira- whereas from (+)-erythro-2-fluorocitrate (2S, 3S) with tory exposure during application of baits, as well as a stoichiometry of about 1 F− per substrate (Lauble accidental or intentional acute intoxications are the main et al., 1996). These findings imply that (−)-erythro-2- human health concerns. The chemical characteristics of fluorocitrate is responsible for aconitase inhibition. Kent FA, such as high solubility in water and lack of specific et al. (1985) suggested that the defluorination generates taste, and the clinical signs of intoxication warrant re- an actual aconitase inhibitor, 4-hydroxy-trans-aconitate evaluation of the toxic danger of FA and renewed efforts (HTA), which was later confirmed by Lauble et al. in the search for effective therapeutic means. This review (1996). (−)-Erythro-2-flurocitrate is a ‘passive’ aconitase deals with the clinical signs and physiological and bio- inhibitor of a sort, whose activity is associated with a chemical mechanisms of FA intoxication to provide certain sequence of conversions induced by aconitase a clearer understanding of why, even after decades of (mechanism-based inhibitor). Initially it converts to investigation, no effective therapy has been elaborated. fluoro-cis-aconitate, the latter then takes up hydroxyl and The review also addresses the question: is there now a loses fluoride to form HTA that binds very tightly, but gleam of hope for developing one? not covalently, to the enzyme. The bond strength can be judged by the slow displacement of HTA from its complex with aconitase by the natural aconitase substrate Aconitase and Molecular Mechanism isocitrate; HTA is detectable only at a 106-fold excess of of the Toxic Action of FA isocitrate (Lauble et al., 1994; Lauble et al., 1996). The HTA-aconitase complex involves four hydrogen bonds no The mechanism of the inhibitory effect of FA on less than 2.7 Å long, which hold together HTA, a water aconitase [citrate (isocitrate) hydro-lyase, EC 4.2.1.3] is molecule bound to the [4Fe-4S] cluster, Asp165 and one of the most interesting and long-standing problems His167. In comparison, isocitrate has only one such bond. in biochemistry. In the organism, FA undergoes a series of metabolic conversions resulting in the synthesis of an extremely toxic compound, fluorocitrate (FC); this Toxicokinetics and Mechanism of FA process was named ‘lethal synthesis’ (Peters, 1952). FC Detoxication is formed by the enzymatic condensation of fluoroacetyl CoA with oxaloacetate, catalysed by citrate (si)-synthase Defluorination is carried out mainly by anionic proteins (EC 4.1.3.7). Initially, FC was considered to be a com- with glutathione transferase activity. In addition, there petitive aconitase inhibitor. However, in the early 1990s are about 10% of proteins in the anionic fraction that do it was speculated that FC acts as a ‘suicide substrate’ in not have the glutathione transferase activity but do carry the sense that it has a high affinity for aconitase at any out defluorination; also, there are cationic enzymes with concentration of the competitive citrate (Clarke, 1991).
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