Fluoroacetate biochemical effects

BIOCHEMICAL EFFECTS LETHAL SYNTHESIS AND INCORPORATION 7.8.1 Fluoroacetate... 

Buffa, P., Guarriero-Bobyleva, V., Pasquali-Ronchetti, J. (1972). Biochemical effects of fluoroacetate poisoning in rat liver. In Carbone-Fluorine Compounds, pp. 303-30. Associated Scientific Compounds, Amsterdam. 

Stewart, G.G., Abbs, E.T., Roberts, D.J. (1970). Biochemical effects of fluoroacetate administration in rat brain, heart and blood. Biochem. Pharmacol. 19 1861-6. 

Biochemical effects lethal synthesis and incorporation 7.8.1 FLUOROACETATE... 

Monofluoroacetic acid (fluoroacetate, figure 7,39) is a compound found naturally in certain South African plants, and which causes severe toxicity in animals eating such plants. The compound has also been used as a rodenticide. The toxicity of fluoroacetate was one of the first to be studied at a basic biochemical level, and Peters coined the term lethal synthesis to describe this biochemical lesion. Fluoroacetate does not cause direct tissue damage and is not intrinsically toxic but requires metabolism to fluoroacetyl CoA (figure 7,39). Other fluorinated compounds which are metabolized to fluoroacetyl CoA therefore produce the same toxic effects. For instance, compounds such as fluoroethanol and fluorofatty acids with even numbers of carbon atoms may undergo /1-oxidation to yield fluoroacetyl CoA. 

Ward, P.F.V. and N.S. Huskisson. 1969. The metabolism of fluoroacetate by plants. Biochem. Jour. 113 9P. Wong, D.H., W.E. Kirkpatrick, D.R. King, and J.E. Kinnear. 1992a. Defluorination of sodium monofluoroacetate (1080) by microorganisms isolated from western Australian soils. Soil Biol. Biochem. 24 833-838. Wong, D.H., W.E. Kirkpatrick, D.R. King, and J.E. Kinnear. 1992b. Environmental factors and microbial inoculum size, and their effect on biodefluorination of sodium monofluoroacetate (1080). Soil Biol. Biochem. 9 838-843. 

Among the most deadly of simple compounds is sodium fluoroacetate. The LD50 (the dose lethal for 50% of animals receiving it) is only 0.2 mg/kg for rats, over tenfold less than that of the nerve poison diisopropylphosphofluoridate (Chapter 12).a b Popular, but controversial, as the rodent poison "1080," fluoroacetate is also found in the leaves of several poisonous plants in Africa, Australia, and South America. Surprisingly, difluoroacetate HCF2-COO is nontoxic and biochemical studies reveal that monofluoroacetate has no toxic effect on cells until it is converted metabolically in a "lethal synthesis" to 2R,3R-2-fluorocitrate, which is a competitive inhibitor of aconitase (aconitate hydratase, Eq. 13-17).b This fact was difficult to understand since citrate formed by the reaction of fluorooxalo-acetate and acetyl-CoA has only weak inhibitory activity toward the same enzyme. Yet, it is the fluorocitrate formed from fluorooxaloacetate that contains a fluorine atom at a site that is attacked by aconitase in the citric acid cycle. 

Effects of Fluoroacetate on Isolated Cells The effects of FA on the physiological and biochemical status of cells and tissues are tightly dependent upon the level of their oxidative metabohsm. Thus, FA does not inhibit phagocytosis because of the low level of TCA cycle... 

Bowman, R.H. (1964). Inhibition of citrate metabolism by sodium fluoroacetate in the perfused rat heart and the effect on phos-phofructokinase activity and glucose utilization. Biochem. J. 93 13-15. 

Taylor, W.M., D Costa, M., Angel, A., Halperin, M.L. (1977). Insulin-like effects of fluoroacetate on lipolysis and lipogenesis in adipose tissue. Can. J. Biochem. 55 982-7. 

The quantitative and qualitative response among different species to fluoro-acetic acid is unique [115]. Lethal doses range from 50 [xg/kg in dogs to 50 mg/kg in some monkeys, while some data indicate that man is intermediate. The mouse responds like the monkey, while the cat and rabbit are nearly as sensitive as the dog. Fluoroacetate is biochemically converted into fluorocitrate, a lethal synthesis, which results in the inhibition of a step in the tricarboxylic acid cycle. Various species may die from central nervous system stimulation, others from cardiac irregularities, and others from a combination of central and cardiac effects. A simple explanation for these variations is not available. 

Andersson, U., Leighton, B., Young, M.E., et al., 1998. Inactivation of aconitase and oxoglutarate dehydrogenase in skeletal muscle in vitro by superoxide anions and/or nitric oxide. Biochem. Biophys. Res. Commun. 249, 512-516. Anikin, I.V., Goncharov, N.V., Tyndyk, M.L., et al., 2013. Effect of sodium fluoroacetate on growth of Ehrlich solid tumor and autochthonous mouse sarcoma. Vopr. Oncol. 59 (6), 777-780. Article in Russian. 

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