Effects of 4-methylpyrazole on ethanol neurobehavioral toxicity in CD-1 mice.
OBJECTIVE
4-Methylpyrazole (4-MP), an alcohol dehydrogenase (ADH) antagonist, is used for the treatment of ethylene glycol and methanol ingestions. However, ethanol is frequently co-ingested by those who ingest these more toxic alcohols. Several in vitro and in vivo studies have shown a decrease in the elimination rate of ethanol after the administration of 4-MP, but none has evaluated the effects of 4-MP administration on the neurobehavioral toxicity of ethanol. This was a study to determine whether ADH blockade with 4-MP prolongs ethanol neurobehavioral toxicity in a murine model.


METHODS
D-1 mice were pretreated with 4-MP, with observation of its effect on ethanol dose-response curves. 4-MP (25 mg/kg) or an equal volume of saline was administered intraperitoneally. Ten minutes later, incremental ethanol doses of 1-5 g/kg were administered intraperitoneally. Pretreated and control groups were composed of ten mice each for each dose of ethanol tested. Outcomes for assessing ethanol neurobehavioral toxicity were successful performance on the rotarod test and presence of the righting reflex, two established and validated outcome measures for ethanol-induced neurobehavioral toxicity in mice.


RESULTS
The dose of ethanol at which 50% of the animals failed a particular outcome test (toxic dose 50 [TD(50)]) was decreased with 4-MP administration for both the rotarod test and the righting reflex. The TD(50) intergroup differences (control vs. 4-MP) were statistically significant at 60, 120, and 180 minutes (p < 0.05).


CONCLUSIONS
Pretreatment with 4-MP significantly prolonged ethanol neurobehavioral toxicity in CD-1 mice, presumably by inhibiting its metabolism by ADH. Further investigation is warranted to evaluate this interaction.
Division of Emergency Medicine and the Program in Clinical Pharmacology/Toxicology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA. ana.paez@tch.harvard.edu
Ana Maria
AM
Páez
Michael
M
Shannon
Timothy
T
Maher
Lawrence
L
Quang
D020268:Alcohol-Induced Disorders, Nervous System / Q000139:chemically induced / Q000188:drug therapy*; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D000077604:Fomepizole; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010919:Placebos; D004856:Postural Balance / Q000187:drug effects; D011446:Prospective Studies; D011720:Pyrazoles / Q000494:pharmacology*; D012016:Reference Values; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D045442:Rotarod Performance Test
D000931:Antidotes; D010919:Placebos; D011720:Pyrazoles; D000431:Ethanol; D000077604:Fomepizole