Organophosphorus neuropathy target esterase inhibitors selectively block outgrowth of neurite-like and cell processes in cultured cells.
This study compares two direct-acting neuropathy target esterase (NTE) inhibitors (mipafox and 2-octyl-4H-1,3,2-benzodioxophosphorin 2-oxide (OBDPO)), a metabolic precursor to an NTE inhibitor (tri-o-cresyl phosphate or TOCP) and a potent acetylcholinesterase inhibitor (chlorpyrifos oxon or CPO) for their effects on outgrowth of neurite-like and cell processes and on viability in differentiated cultured cells (rat adrenal pheochromocytoma (PC-12) and brain glial tumor (C6)). The direct-acting NTE inhibitors block process outgrowth by 50% or more at 50-100 microM for OBDPO and 100-200 microM for mipafox, well below their cytotoxic levels (EC50 values, 445-474 microM for OBDPO and 1021-1613 microM for mipafox). In contrast, the effects on process development for TOCP and CPO parallel their cytotoxicity. These findings suggest that inhibition of neurite-like and cell process outgrowth by OBDPO and mipafox may be associated with NTE inhibition.
Li
W
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Department of Environmental Science, Policy and Management, University of California, Berkeley 94720-3112, USA.
Casida
J E
JE
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D004390:Chlorpyrifos / Q000031:analogs & derivatives / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007531:Isoflurophate / Q000031:analogs & derivatives* / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects* / Q000201:enzymology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D014317:Tritolyl Phosphates / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology
C092561:2-octyl-4H-1,3,2-benzodioxaphosphorin-2-oxide; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D014317:Tritolyl Phosphates; D007531:Isoflurophate; C005238:mipafox; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase; D004390:Chlorpyrifos; C025541:tri-o-cresyl phosphate