Role of fluroacetate in the toxicity of 2-fluroethylnitrosoureas

Tisdale, Michael J.; Brennan, R A

doi:10.1016/0006-2952(85)90353-3

Cited by 7 publications

(2 citation statements)

References 11 publications

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“…It was also found that a series of other compounds metabolize to FA as intermediate products: these are the anticancer drugs 5-fluorouracil and fluoroethyl nitrosourea, N-(2-fluoroethyl) derivatives of the narcotic analgesics normeperidin and normetazocin, the industrial chemicals fluoroethanol and 1-(di)halo-2-fluoroethanes (Yamashita et al, 2004;Arellano et al, 1998;Yeh and Cheng, 1994;Reifenrath et al, 1980;Tisdale and Brennan, 1985;Tecle and Casida, 1989;Keller et al, 1996;Feldwick et al, 1998). Finally, industrial 'achievements' have led to the appearance of FA in fog and rain (Rompp et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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

2006

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“…Fluoroacetate is a highly toxic substance and is used as a vertebrate pest control agent. It is also a metabolite of a number of other compounds, such as fluoroacetamide, which is used to control rodents; the anticancer drugs 5-fluorouracil and fluoroethyl nitrosourea; and the industrial chemical fluoroethanol − . This transformation of other fluorinated compounds to fluoroacetate offers an explanation for the presence of low concentrations of fluoroacetate in fog and rain samples from northeast Bavaria .…”

Section: Introductionmentioning

confidence: 99%

Treatment of Fluoroacetate by a Pseudomonas fluorescens Biofilm Grown in Membrane Aerated Biofilm Reactor

Heffernan

Murphy

Syron

et al. 2009

Environ. Sci. Technol.

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Fluorinated organic compounds have widespread applications, and their accumulation in the environment is a concern. Biofilm reactors are an effective technology for the treatment of contaminated wastewater, yet almost no research has been conducted on the effectiveness of biofilms for the biodegradation of fluorinated aliphatic compounds. In this paper we describe experiments undertaken to investigate the degradation of fluoroacetate using a membrane aerated biofilm reactor (MABR) by Pseudomonas fluorescens DSM8341. The concentration of fluoroacetate in the medium influenced biofilm structure, with less dense biofilm observed at lower fluoroacetate loading rates. As biofilm thickness increased, oxygen utilization decreased, probably as a consequence of increased resistance to oxygen transfer. Furthermore, most of the biofilm was anaerobic, since oxygen penetration depth was less than 1000 µm. Biofilm performance, in terms of fluoroacetate removal efficiency, was improved by decreasing the fluoroacetate loading rate, however increasing the intramembrane oxygen pressure had little effect on biofilm performance. A mathematical model showed that while fluoroacetate does not penetrate the entire biofilm, the defluorination intermediate metabolite glycolate does, and consequently the biofilm was not carbon limited at the biofilm-membrane interface where oxygen concentrations were highest. The model also showed the accumulation of the free fluoride ion within the biofilm. Overflow metabolism of glycolate was identified to be most likely a result of a combination of oxygen limitation and free fluoride ion inhibition. The study demonstrated the potential of MABR for treating wastewater streams contaminated with organofluorine compounds.

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