The mode of toxic action of the pesticide gliftor: the metabolism of 1,3-difluoroacetone to (-)-erythro-fluorocitrate.
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.
Menon
K I
KI
School of Biological Sciences and Biotechnology, Murdoch University, Western Australia.
Feldwick
M G
MG
Noakes
P S
PS
Mead
R J
RJ
D000096:Acetone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D002951:Citrates / Q000096:biosynthesis*; D004338:Drug Combinations; D004347:Drug Interactions; D005459:Fluorides / Q000378:metabolism; D000077604:Fomepizole; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020005:Propanols / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012378:Rodenticides / Q000378:metabolism / Q000633:toxicity*; D018675:Toxicity Tests
C425643:1,3-difluoroacetone; D002951:Citrates; D004338:Drug Combinations; D020005:Propanols; D011720:Pyrazoles; D012378:Rodenticides; D000096:Acetone; C007744:fluorocitrate; C110243:1,3-difluoro-2-propanol; C048499:gliftor; D000077604:Fomepizole; D000154:Aconitate Hydratase; D005459:Fluorides