ACETYLCHOLINESTERASE AND NEUROPATHY TARGET ESTERASE INHIBITIONS IN NEUROBLASTOMA-CELLS TO DISTINGUISH ORGANOPHOSPHORUS COMPOUNDS CAUSING ACUTE AND DELAYED NEUROTOXICITY

The differential inhibition of the target esterases acetylcholinestera se (AChE) and neuropathy target esterase (NTE, neurotoxic esterase) by organophosphorus compounds (OPs) is followed by distinct neurological consequences in exposed subjects. The present study demonstrates that neuroblastoma cell lines (human SHSY5Y and murine NB41A3) can be used to differentiate between neuropathic OPs (i.e., those inhibiting NTE and causing organophosphorus-induced delayed neuropathy) and acutely n eurotoxic OPs (i.e., those highly capable of inhibiting AChE). In thes e experiments, concentration-response data indicated that the capabili ty to inhibit AChE was over 100x greater than the capability to inhibi t NTE for acutely toxic, nonneuropathic OPs (e.g., paraoxon and malaox on) in both cell lines. Inhibition of AChE was greater than inhibition of NTE, without overlap of the concentration-response curves, for OPs which are more likely to cause acute, rather than delayed, neurotoxic effects in vivo (e.g., chlorpyrifosoxon, dichlorvos, and trichlorfon) . In contrast, concentrations inhibiting AChE and NTE overlapped for n europathy-causing OPs. For example, apparent IC50 values for NTE inhib ition were less than 9.6-fold the apparent IC50 values for AChE inhibi tion when cells were exposed to the neuropathy-inducing OPs diisopropy l phosphorofluoridate, cyclic tolyl saligenin phosphate, phenyl salige nin phosphate, mipafox, dibutyl dichlorovinyl phosphate, and di-octyl- dichlorovinyl phosphate. In all cases, esterase inhibition occurred at lower concentrations than those needed for cytoxicity. These results suggest that either mouse or human neuroblastoma cell lines can be con sidered useful in vitro models to distinguish esterase-inhibiting OP n eurotoxicants. (C) 1997 society of Toxicology.