Action of organophosphates on GABA A receptor and voltage-dependent chloride channels

• Published in: Fundamental and applied toxicology Vol. 9; no. 4; pp. 698 - 704
• Main Authors: Gant, D.B., Eldefrawi, M.E., Eldefrawi, A.T.
• Format: Journal Article
• Language: English
• Published: Elsevier Science (USA) 01.11.1987
• DOI: 10.1016/0272-0590(87)90176-X
• ISSN: 0272-0590

The effects of several organophosphates were studied on the binding of t-[ 35S]butylbicyclophosphorothionate ([ 35S]TBPS) to rat brain GABA A receptor and receptor function as assayed by GABA-induced 36Cl − influx into membrane vesicles and on the binding of [ 35S]TBPS to a voltage-dependent Cl − channel in Torpedo californica electric organ. The organophosphate anticholinesterases diisopropylphosphorofluoridate, soman, sarin, tabun, and VX had little or no effect on GABA-regulated chloride channels. They also had no effect on [ 35S]TBPS binding to the voltage-dependent chloride channel, except for soman which inhibited it with an IC50 of 24 μ m. Triphenyl phosphate was the only one of three organophosphate flame retardants tested that inhibited both GABA-regulated chloride channel and binding of [ 35S]TBPS to the voltagedependent chloride channel with IC50s of 18 and 13 μ m, respectively. The industrial organophosphate tri- o-cresyl phosphate and the anticholinesterase organophosphate insecticides leptophos, leptophos oxon, and O-ethyl O-4-nitrophenyl phenylphosphonothioate inhibited GABA-regulated chloride channels and bound with high affinity to the voltage-dependent chloride channels (IC50 = 0.3 to 8.7 μ m). There was no apparent correlation between the affinities of the GABA A receptor chloride channel or the voltage-dependent chloride channel for the different organophosphates and their potencies in inhibiting acetylcholinesterase or in inducing delayed neurotoxicity. Nevertheless, although the voltage-dependent chloride channel and/or GABA A receptor are not primary targets for organophosphate anticholinesterases and flame retardants, it is suggested that the inhibition of these two proteins by certain organophosphates may contribute to their toxicities.