The mode of toxic action of the pesticide Gliftor: The metabolism of 1,3-difluoroacetone to (-)-erythro-fluorocitrate

K.I. Menon; M.G. Feldwick; P.S. Noakes; R.J. Mead

doi:10.1002/1099-0461(2001)15:1<47::AID-JBT6>3.0.CO;2-E

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The mode of toxic action of the pesticide Gliftor: The metabolism of 1,3-difluoroacetone to (-)-erythro-fluorocitrate

Journal article

Peer reviewed

The mode of toxic action of the pesticide Gliftor: The metabolism of 1,3-difluoroacetone to (-)-erythro-fluorocitrate

K.I. Menon, M.G. Feldwick, P.S. Noakes and R.J. Mead

Journal of Biochemical and Molecular Toxicology, Vol.15(1), pp.47-54

2001

DOI: https://doi.org/10.1002/1099-0461(2001)15:1<47::AID-JBT6>3.0.CO;2-E

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Abstract

The biochemical toxicology of 1,3-difluoroacetone, a known metabolite of the major ingredient of the pesticide Gliftor (1,3-difluoro-2-propanol), was investigated in vivo and in vitro. Rat kidney homogenates supplemented with coenzyme A, ATP, oxaloacetate, and Mg2+ converted 1,3-difluoroacetone to (-)-erythro-fluorocitrate in vitro. Administration of 1,3-difluoroacetone (100 mg kg-1 body weight) to rats in vivo resulted in (-)-erythro-fluorocitrate synthesis in the kidney, which was preceded by an elevation in fluoride levels and followed by citrate accumulation. Animals dosed with 1,3-difluoroacetone did not display the 2-3 hour lag phase in either (-)-erythro-fluorocitrate synthesis or in citrate and fluoride accumulation characteristic of animals dosed with 1,3-difluoro-2-propanol. We demonstrate that the conversion of 1,3-difluoro-2-propanol to 1,3-difluoroacetone by an NAD+-dependent oxidation is the rate-limiting step in the synthesis of the toxic product, (-)-erythro-fluorocitrate from 1,3-difluoro-2-propanol. Prior administration of 4-methylpyrazole (90 mg kg-1 body weight) was shown to prevent the conversion of 1,3-difluoro-2-propanol (100 mg kg-1 body weight) to (-)-erythro-fluorocitrate in vivo and to eliminate the fluoride and citrate elevations seen in 1,3-difluoro-2-propanol-intoxicated animals. However, administration of 4-methylpyrazole (90 mg kg-1 body weight) to rats 2 hours prior to 1,3-difluoroacetone (100 mg kg-1 body weight) was ineffective in preventing (-)-erythro-fluorocitrate synthesis and did not diminish fluoride or citrate accumulation in vivo. We conclude that the prophylactic and antidotal properties of 4-methylpyrazole seen in animals treated with 1,3-difluoro-2-propanol derive from its capacity to inhibit the NAD+-dependent oxidation responsible for converting 1,3-difluoro-2-propanol to 1,3-difluoroacetone in the committed step of the toxic pathway.

Details

Title: The mode of toxic action of the pesticide Gliftor: The metabolism of 1,3-difluoroacetone to (-)-erythro-fluorocitrate
Authors/Creators: K.I. Menon (Author/Creator) - Murdoch University
M.G. Feldwick (Author/Creator) - Murdoch University
P.S. Noakes (Author/Creator) - Murdoch University
R.J. Mead (Author/Creator) - Murdoch University
Publication Details: Journal of Biochemical and Molecular Toxicology, Vol.15(1), pp.47-54
Publisher: John Wiley and Sons Inc.
Identifiers: 991005540973007891
Copyright: © 2001 John Wiley & Sons, Inc.
Murdoch Affiliation: School of Biological Sciences and Biotechnology
Language: English
Resource Type: Journal article

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Citation topics: 3 Agriculture, Environment & Ecology; 3.35 Zoology & Animal Ecology; 3.35.274 Wildlife Ecology
Web Of Science research areas: Biochemistry & Molecular Biology; Toxicology
ESI research areas: Pharmacology & Toxicology