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

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.

• Authors: K I Menon, M G Feldwick, P S Noakes, R J Mead
• Journal: Journal of biochemical and molecular toxicology (J Biochem Mol Toxicol) Vol. 15 Issue 1 Pg. 47-54 ( 2001) ISSN: 1095-6670 [Print] United States
• PMID: 11170315 (Publication Type: Journal Article)

Chemical References

• 1,3-difluoroacetone
• Citrates
• Drug Combinations
• Propanols
• Pyrazoles
• Rodenticides
• Acetone
• fluorocitrate
• 1,3-difluoro-2-propanol
• gliftor
• Fomepizole
• Aconitate Hydratase
• Fluorides

Topics

• Acetone (analogs & derivatives, metabolism, toxicity)
• Aconitate Hydratase (metabolism)
• Animals
• Citrates (biosynthesis)
• Drug Combinations
• Drug Interactions
• Fluorides (metabolism)
• Fomepizole
• In Vitro Techniques
• Kidney (drug effects, metabolism)
• Male
• Propanols (metabolism, pharmacology, toxicity)
• Pyrazoles (pharmacology)
• Rats
• Rats, Wistar
• Rodenticides (metabolism, toxicity)
• Toxicity Tests