Some Metabolic Aspects of Fluoroacetate Especially Related to Fluorocitrate

Peters, Rudolph

doi:10.1002/9780470719855.ch4

Cited by 11 publications

(5 citation statements)

References 49 publications

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“…The increase in cellular citrate induces lesions in glucose metabolism through inhibition of the key regulatory enzyme of glycolysis, phosphofructokinase (Bowman, 1964;Peters, 1972). Moreover, succinate dehydrogenase activity is also inhibited (Fanshier et al, 1964), though this requires very high concentrations of FC (Kun, 1969).…”

Section: Clinical Signsmentioning

confidence: 97%

“…To this end, fluoromaleic acid was proposed (Peters, 1972). However, the mechanism of its action was not established, and the positive effect was negligible.…”

Section: Therapy For Fa Intoxicationmentioning

confidence: 99%

“…Subsequently, however, it was reported that insulin administration had no effect on the degree of FA intoxication in general and no symptomatic influence on the 'fluoroacetate diabetes' in particular (Reichelt, 1979). The actual reason for FA-induced hyperglycemia was the blockade of glucose utilization, resulting from phosphofructokinase inhibition (Bowman, 1964;Peters, 1972). Moreover, hyperglycemia initially developed upon FA intoxication can even change into hypoglycemia (Boquist et al, 1988).…”

Section: +mentioning

confidence: 99%

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

2006

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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.

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Section: Clinical Signsmentioning

confidence: 97%

“…To this end, fluoromaleic acid was proposed (Peters, 1972). However, the mechanism of its action was not established, and the positive effect was negligible.…”

Section: Therapy For Fa Intoxicationmentioning

confidence: 99%

Section: +mentioning

confidence: 99%

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

2006

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“…The mechanism of toxic action of FA is widely known as "lethal synthesis" [9], which essentially involves enzymatic conversion of the inherently nontoxic FA into toxic fluorocitrate (FC). The latter has long been believed to inhibit aconitase, thus blocking the TCA cycle [10,11]. It was discovered later that the actual toxicant is 4-hydroxy-trans-aconitate, a fluorine-free fluorocitrate derivative [12], and FC was named a "suicide substrate" [13].…”

Section: Effects Of Fa On the Functional State Of Plateletsmentioning

confidence: 99%

A new method for studying platelets, based upon the low‐angle light scattering technique. 3. Aggregation hypersensitivity of platelets (ADP agonist) and search for corrective agents

Mindukshev

Гончаров

Shabanova

et al. 2006

Journal of Spectroscopy

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A new method for studying platelets based on low-angle light scattering has previously revealed that platelets taken from pregnant women with preeclampsia are hypersensitive to ADP, with aggregation developing at concentrations of 7–15 nmol l−1. The method has been applied to further studies in experimental toxicology and clinical pathology. Toxicological experiments with fluoroacetate (FA), an inhibitor of TCA cycle, showed that the platelet hypersensitivity could also be caused by energy depletion. In modeling experiments, the low-angle light scattering method was applied to assessment of potential corrective agents of the pathological states related to hypersensitivity of platelets. Sodium glutamate (SG) was shown to be a potent antiaggregantin vitro, and subsequentin vivostudies demonstrated that SG can apparently serve as anaplerotic agent and normalize the platelet status of rats intoxicated with FA. Donators of nitric oxide (NO), such as isosorbide-5′-dinitrate, can also normalizein vitrothe hypersensitive status of platelets taken from the patients with preeclampsia.

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“…Referring to the pioneer data available in the literature, there was indeed strong evidence of species-related biodistribution, toxicity, and excretion differences in regard to nonradioactive fluoroacetate. 16 The differences were attributed to the variation in abundance of the enzyme system associated with the relative ease of conversion of fluoroacetate to fluorocitrate. In fact, these data indicated that even different routes of administrating fluoroacetate in the same species could cause a difference in the severity of toxicity, meaning that different organs may have different susceptibility or tolerance.…”

Section: Discussionmentioning

confidence: 99%

[¹⁸F]Fluoroacetate Positron Emission Tomography for Hepatocellular Carcinoma and Metastases: An Alternative Tracer for [¹¹C]Acetate?

Cheung

Chen

et al. 2012

Mol Imaging

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[11C]Acetate (ACT) positron emission tomography/computed tomography (PET/CT) is useful in the detection of hepatocellular carcinoma (HCC). This study aimed to evaluate whether [18F]fluoroacetate (FAC) could be an alternative analogue of [11C]ACT for the diagnosis of HCC. [18F]FAC was synthesized using the precursor t-butyl 2-(methanesulfonyloxy)ethanoate. Five volunteer patients with known HCC were recruited after consent. Whole-body [18F]FAC PET/CT was performed at 20 minutes and 1 hour postinjection and compared to [11C]ACT PET/CT at 20 minutes postinjection to assess biodistribution and tumor uptake characteristics. Qualitative and semiquantitative analyses were performed with statistical correlations on the physiologic organs of accumulation and HCC lesions for both tracers. [18F]FAC was obtained with 99% radiochemical purity, and the reaction yield was 16.0% with 1-hour synthesis time. The biodistribution of [18F]FAC on PET/CT was significantly different from that of [11C]ACT (p < .05) by the lack of preferential uptake in any specific organ, particularly the pancreas, resembling the pattern of blood-pool retention although partly metabolized via the bowel. There was no significant defluorination, and none of the [11C]ACT-avid HCC lesions showed increased [18F]FAC activity. These were different from the results reported on other species. [18F]FAC may not be a potential alternative tracer for [11C]ACT in PET/CT evaluation of HCC in human subjects.

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Some Metabolic Aspects of Fluoroacetate Especially Related to Fluorocitrate

Cited by 11 publications

References 49 publications

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

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

A new method for studying platelets, based upon the low‐angle light scattering technique. 3. Aggregation hypersensitivity of platelets (ADP agonist) and search for corrective agents

[¹⁸F]Fluoroacetate Positron Emission Tomography for Hepatocellular Carcinoma and Metastases: An Alternative Tracer for [¹¹C]Acetate?

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Some Metabolic Aspects of Fluoroacetate Especially Related to Fluorocitrate

Cited by 11 publications

References 49 publications

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

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

A new method for studying platelets, based upon the low‐angle light scattering technique. 3. Aggregation hypersensitivity of platelets (ADP agonist) and search for corrective agents

[18F]Fluoroacetate Positron Emission Tomography for Hepatocellular Carcinoma and Metastases: An Alternative Tracer for [11C]Acetate?

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[¹⁸F]Fluoroacetate Positron Emission Tomography for Hepatocellular Carcinoma and Metastases: An Alternative Tracer for [¹¹C]Acetate?