gamma-Aminobutyric acid antagonism produced by an organophosphate-containing combustion product.
Results from [35S]t-butylbicyclophosphorothionate (TBPS) binding and gamma-aminobutyric acid (GABA)-dependent 36Cl- uptake indicated that the pyrolysis product of liquid trimethylol propane (TMP) containing organic phosphates interacts with the GABA/benzodiazepine receptor chloride ionophore complex (GBRC) producing a receptor-mediated reduction in 36Cl- flux. The pyrolysate-ligand interaction was competitive and directly proportional to the trimethylol propane phosphate (TMPP) content of the combustion product. TBPS displacement demonstrated that TMPP had less affinity than did TBPS and picrotoxin, but greater affinity than GABA, racemic dimethylbutyl barbituric acid (DMBB), clonazepam, and phenobarbital for their respective recognition sites. Addition of exogenous GABA was a necessary condition for demonstrating clonazepam-induced ligand displacement, thus being indicative of an allosteric interaction. The same rank order held for altering GABA-dependent 36Cl- uptake with the caveat of inhibitors vs enhancers, and noting that pentobarbital was less potent than DMBB. Concentration-dependent ligand displacement by GBRC agonists and antagonists quantitatively correlated with alterations in GABA-dependent 36Cl- uptake. The median convulsant dose (CD50) of pyrolysate TMPP was higher than that of synthetic TMPP. The presence of combustion by-products altering the dispositional kinetics of the former is felt to be the reason for this difference. Under our experimental conditions, phenobarbital was the most effective antidote for pyrolysate (TMPP) toxicity. The inhalant convulsant, flurothyl, was found not to displace [35S]TBPS binding, not to affect GABA-dependent 36Cl- uptake, and not to respond to the anticonvulsants in a manner consistent with a strict GABAA receptor phenomenon.
Higgins
G M
GM
Department of Pharmacology and Toxicology, School of Medicine, Wright State University, Dayton, Ohio 45435.
Gardier
R W
RW
D000818:Animals; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000032:analysis / Q000037:antagonists & inhibitors / Q000633:toxicity*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds / Q000633:toxicity*; D002712:Chlorides / Q000378:metabolism; D003292:Convulsants / Q000037:antagonists & inhibitors; D005481:Flurothyl / Q000633:toxicity; D018756:GABA Antagonists; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D001952:Bridged-Ring Compounds; D002712:Chlorides; D003292:Convulsants; D018756:GABA Antagonists; D011963:Receptors, GABA-A; C065518:4-ethyl-1-phospha-2,6,7 trioxabicyclo(2.2.2)octane-1-oxide; C037476:tert-butylbicyclophosphorothionate; D005481:Flurothyl