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

• Published in: Journal of biochemical and molecular toxicology Vol. 15; no. 1; pp. 47 - 54
• Main Authors: Menon, K. I., Feldwick, M. G., Noakes, P. S., Mead, R. J.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 2001
• Subjects: (−)-erythro-Fluorocitrate; 1,3‐Difluoroacetone; 1,3‐Difluoro‐2‐propanol; 1080; 3-Difluoro-2-propanol; 3-Difluoroacetone; 4-Methylpyrazole; Acetone - analogs & derivatives; Acetone - metabolism; Acetone - toxicity; Aconitate Hydratase; Aconitate Hydratase - metabolism; Animals; Citrates - biosynthesis; Drug Combinations; Drug Interactions; Fluorides - metabolism; Fluoroacetate; In Vitro Techniques; Kidney - drug effects; Kidney - metabolism; Male; Propanols - metabolism; Propanols - pharmacology; Propanols - toxicity; Pyrazoles - pharmacology; Rats; Rats, Wistar; Rodenticides - metabolism; Rodenticides - toxicity; Toxicity Tests
• ISSN: 1095-6670; 1099-0461
• DOI: 10.1002/1099-0461(2001)15:1<47::AID-JBT6>3.0.CO;2-E

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. © 2001 John Wiley & Sons, Inc. J Biochem Mol Toxicol 15:47–54, 2001