An alternative in vitro method for detecting neuropathic compounds based on acetylcholinesterase inhibition and on inhibition and aging of neuropathy target esterase (NTE).
Organophosphorus-induced delayed polyneuropathy (OPIDP) is a syndrome induced by certain organophosphorus compounds (OPs) through a mechanism based on the inhibition and further modification (aging) of neuropathy target esterase (NTE). OECD guidelines for testing the capability of OPs to trigger OPIDP include two in vivo tests with hens. Activities of acetylcholinesterase and NTE found in SH-SY5Y human neuroblastoma cells were inhibited by 10 different OPs with kinetics similar to those found with chicken brain enzymes (model system for in vivo and in vitro-ex vivo assays). NTE in SH-SY5Y cells inhibited by these OPs aged and reactivated similarly to that described for hen brain NTE ex vivo. In short, we have developed an alternative methodology for predicting the capability of OPs to induce OPIDP based on the inhibition kinetics of acetylcholinesterase and NTE and on the capability of OPs to age the inhibited NTE from SH-SY5Y cell line. The results obtained always agreed with the previously reported ex vivo results with hen brain. The developed methodology correctly predicted the neuropathic potential of the tested OPs in eight cases. The in vivo-in vitro discrepancies with two of the tested compounds can be explained on the basis of differences between in vivo and in vitro biotransformation.
Sogorb
Miguel A
MA
Unidad de Toxicología y Seguridad Química, Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, 03202 Elche, Spain. msogorb@umh.es
González-González
Iván
I
Pamies
David
D
Vilanova
Eugenio
E
D000110:Acetylcholinesterase / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001921:Brain / Q000473:pathology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002645:Chickens; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D015233:Models, Statistical; D020258:Neurotoxicity Syndromes / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity*; D009943:Organophosphorus Compounds / Q000633:toxicity; D010261:Paraoxon / Q000633:toxicity
D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D009943:Organophosphorus Compounds; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D000110:Acetylcholinesterase; D010261:Paraoxon