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.
Goncharov
Nikolay V
NV
Research Institute of Hygiene, Occupational Pathology and Human Ecology, Saint-Petersburg, Russia.
Jenkins
Richard O
RO
Radilov
Andrey S
AS
D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D005463:Fluoroacetates / Q000506:poisoning / Q000633:toxicity*; D006801:Humans; D009422:Nervous System Diseases / Q000139:chemically induced / Q000473:pathology; D011041:Poisoning / Q000628:therapy*
D000931:Antidotes; D005463:Fluoroacetates; D000154:Aconitate Hydratase