Biochemical effects lethal synthesis and incorporation

8 BIOCHEMICAL EFFECTS LETHAL SYNTHESIS AND INCORPORATION 7.8.1 Fluoroacetate 

Monofluoroacetic acid (fluoroacetate) (Fig. 7.61) is a compound found naturally in certain South African plants, 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 (Fig. 7.61). Other fluorinated compounds that are metabolized to fluoroacetyl CoA therefore produce the same toxic effects. For instance, 

Fluorocitrate is therefore a pseudosubstrate. As well as inhibiting cellular respiration, inhibition of the TCA cycle will also reduce the supply of 2-oxoglutarate. This may decrease the removal of ammonia via formation of glutamic acid and glutamine, and this might account for the convulsions seen in some species after exposure to fluoroacetate. The toxicity is manifested as a malfunction of the CNS and heart, giving rise to nausea, apprehension, convulsions, and defects of cardiac rhythm, leading to ventricular fibrillation. Fluoroacetate and fluorocitrate do not appear to inhibit other enzymes involved in intermediary metabolism, and the di- and trifluoroacetic acids are not similarly incorporated and therefore do not produce the same toxic effects. 

A number of biochemical events have been found to occur. RNA and protein synthesis are inhibited, and membrane damage can be observed two hours after dosing. There is also an increase in intracellular calcium, which may be the crucial event that leads to cell death 

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Biochemical effects lethal synthesis and incorporation 7.8.1 FLUOROACETATE... 

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