Influence of oxygenated fuel additives and their metabolites on gamma-aminobutyric acidA (GABAA) receptor function in rat brain synaptoneurosomes.
Experimental and occupational inhalational exposure to oxygenate fuel additives in reformulated gasoline has been reported to induce neurological symptoms (e.g., headache, nausea, dizziness). We reported previously that the ether additives (methyl-t-butyl ether (MTBE), t-amyl-methyl ether (TAME) and ethyl-t-butyl ether (ETBE)) and their metabolites (t-amyl alcohol (TAA), t-butyl alcohol (TBA) and ethanol) alter the binding of [3H]t-butylbicycloorthobenzoate ([3H]TBOB), a ligand for the gamma-aminobutyric acidA (GABAA) receptor in rat brain membrane preparations. To more directly assess the effects of the ethers and their alcohol precursors on GABAA receptor function, the uptake of 36Cl- was measured in synaptoneurosomes, a preparation of closed membrane sacs comprised of pre- and postsynaptic membranes from adult rat cerebral cortex. Each of the compounds caused a concentration-dependent enhancement of muscimol-stimulated uptake of 36CI-, which diminished with further increasing concentrations. The potency of the enhancement by the compounds was in the rank order: MTBE = TAME > TAA = ETBE > TBA > ethanol. The half-maximally effective concentration (EC50) for the facilitation of muscimol-stimulated 36Cl- uptake ranged from 0.06 to 3 mM, and that for the higher-dose inhibitory effect (IC50) ranged from 3 to 50 mM. The facilitatory concentrations of the compounds are in the range of the blood concentrations reported in experimental animals after exposures known to induce CNS effects such as ataxia. The results suggest a potential role of the GABAA receptor in some of the reported neurotoxic effects of gasoline additives.
Martin
Joseph V
JV
Biology Department, Rutgers University, 315 Penn Street, Camden, NJ 08102, USA. jomartin@camden.rutgers.edu
Iyer
Sonal V
SV
McIlroy
Patrick J
PJ
Iba
M Michael
MM
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005019:Ethyl Ethers / Q000378:metabolism / Q000633:toxicity; D005742:Gasoline; D066298:In Vitro Techniques; D008297:Male; D008738:Methyl Ethers / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014106:Tosylarginine Methyl Ester / Q000378:metabolism / Q000633:toxicity
D000393:Air Pollutants; D002712:Chlorides; D005019:Ethyl Ethers; D005742:Gasoline; D008738:Methyl Ethers; D018079:Receptors, GABA; C043243:methyl tert-butyl ether; C098546:ethyl tert-butyl ether; D014106:Tosylarginine Methyl Ester