The biochemical toxicology of 1,3-difluoro-2-propanol, the major ingredient of the pesticide gliftor: the potential of 4-methylpyrazole as an antidote.
Administration to rats of 1,3-difluoro-2-propanol (100 mg kg-1 body weight), the major ingredient of the pesticide gliftor, resulted in accumulation of citrate in the kidney after a 3 hour lag phase. 1,3-Difluoro-2-propanol was found to be metabolized to 1,3-difluoroacetone and ultimately to the aconitate hydratase inhibitor (-) erythrofluorocitrate and free fluoride. The conversion of 1,3-difluoro-2-propanol to 1,3-difluoroacetone was found to be catalyzed by an NAD(+)-dependent alcohol dehydrogenase, while the defluorination was attributed to microsomal monooxygenase activity induced by phenobarbitone and inhibited by piperonyl butoxide. 4-Methylpyrazole was found to inhibit both of these processes in vitro and when administered (90 mg kg-1 body weight) to rats, 2 hours prior to 1,3-difluoro-2-propanol, eliminated signs of poisoning, prevented (-) erythrofluorocitrate synthesis, and markedly decreased citrate and fluoride accumulation in vivo. 4-Methylpyrazole also appeared to diminish (-) erythrofluorocitrate synthesis from fluoroacetate in vivo, and this was attributed to its capacity to inhibit malate dehydrogenase activity. The antidotal potential of 4-methylpyrazole and the potential for 1,3-difluoro-2-propanol to replace fluoroacetate (compound 1080) as a vertebrate pesticide is discussed.
Feldwick
M G
MG
School of Biological Sciences and Biotechnology, Murdoch University, Western Australia.
Noakes
P S
PS
Prause
U
U
Mead
R J
RJ
Kostyniak
P J
PJ
D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D002951:Citrates / Q000378:metabolism; D004338:Drug Combinations; D000077604:Fomepizole; D008401:Gas Chromatography-Mass Spectrometry; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D020005:Propanols / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012378:Rodenticides / Q000737:chemistry*
D000931:Antidotes; D002951:Citrates; D004338:Drug Combinations; D020005:Propanols; D011720:Pyrazoles; D012378:Rodenticides; C110243:1,3-difluoro-2-propanol; C048499:gliftor; D000077604:Fomepizole