Inhibition of calcium-stimulated ATPase in the hen brain P2 synaptosomal fraction by organophosphorus esters: relevance to delayed neuropathy.
Organophosphorus (OP) compounds have been reported to inhibit Ca/Mg-ATPase, but the relevance of this inhibition to organophosphate-induced delayed neuropathy (OPIDN) has not been explored. To determine if inhibition of this enzyme was related to the development of OPIDN, neuropathic and nonneuropathic OP compounds were sted for their ability to inhibit Ca-stimulated ATPase activity in the P2 synaptosomal fraction from hen brain. Following in vitro exposure to 10(-3) to 10(-5) M OP compounds, Ca-stimulated ATPase activity was inhibited by chlorpyrifos, chlorpyrifos-oxon, phenyl saligenin phosphate (PSP), and tri-o-tolyl phosphate (TOTP), but not by parathion, paraoxon, or diisopropyl fluorophosphate (DFP). Further investigation of inhibition induced by chlorpyrifos determined that inhibition was noncompetitive with respect to calcium and ATP. OP compound hydrophobicity was well correlated with in vitro inhibition of Ca-stimulated ATPase, suggesting that OP compounds interact with membrane lipids, and this interaction may contribute to the noncompetitive inhibition of Ca-stimulated ATPase that was observed. Subsequent to in vivo exposure, DFP, but not PSP, produced inhibition of Ca-stimulated ATPase activity in the hen brain P2 synaptosomal fraction. These data indicate that inhibition of Ca-stimulated ATPase activity is not correlated to neuropathic potential and demonstrate that inhibition of Ca/Mg-ATPase is not responsible for OPIDN.
Barber
D
D
Department of Biomedical Science and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg 24061-0442, USA.
Hunt
J
J
Ehrich
M
M
D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D017301:Ca(2+) Mg(2+)-ATPase / Q000037:antagonists & inhibitors*; D002645:Chickens; D004390:Chlorpyrifos / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D005260:Female; D066298:In Vitro Techniques; D016014:Linear Models; D008563:Membrane Lipids / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000201:enzymology*; D009943:Organophosphorus Compounds / Q000633:toxicity*; D011897:Random Allocation; D013574:Synaptosomes / Q000187:drug effects* / Q000201:enzymology
D002800:Cholinesterase Inhibitors; D008563:Membrane Lipids; D009943:Organophosphorus Compounds; D017301:Ca(2+) Mg(2+)-ATPase; D004390:Chlorpyrifos