Action of organophosphates on GABAA receptor and voltage-dependent chloride channels.
The effects of several organophosphates were studied on the binding of t-[35S]butyl-bicyclophosphorothionate ([35S]TBPS) to rat brain GABAA 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 microM. 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 voltage-dependent chloride channel with IC50s of 18 and 13 microM, 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 microM). There was no apparent correlation between the affinities of the GABAA 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 GABAA 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.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004557:Electric Organ / Q000187:drug effects / Q000378:metabolism; D005411:Flame Retardants / Q000633:toxicity; D066298:In Vitro Techniques; D007306:Insecticides / Q000633:toxicity; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D014101:Torpedo / Q000378:metabolism
D002712:Chlorides; D002800:Cholinesterase Inhibitors; D005411:Flame Retardants; D007306:Insecticides; D007473:Ion Channels; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A