Cytotoxicity of organophosphate anticholinesterases

Organophosphate (OP) anticholinesterases were found to modulate metabolic a ctivities of human neuroblastoma cells and hepatocytes, which was detectabl e by the Cytosensor(R) microphysiometer. The nerve gas ethyl-S-2-diisopropy laminoethyl methylphosphorothiolate (VX), at 10 mu M, produced significant reduction in cell metabolism within 2 min, as measured by changes in the ac idification rate of the medium. The reduction was dose- and time-dependent and irreversible after 4 h of exposure. Two alkaline degradation products o f VX produced no cytotoxicity. Exposure for 24 h to 3 mu M VX caused 36% an d 94% irreversible loss of metabolism in hepatocytes and neuroblastoma cell s, respectively. The insecticides parathion and chlorpyrifos stimulated hep atocyte metabolism but inhibited neuroblastoma cells. Their oxons were more active. Exposure of neuroblastoma cells for 4 h to VX, parathion, paraoxon , diisopropylfluorophosphate or chlorpyrifos gave an LC50 of 65, 175, 640, 340, or 672 mu M, respectively, whereas 24 h gave an LC50 of 0.7, 3.7, 2.5, 29, and 31 mu M, respectively. Preincubation of hepatocytes with phenobarb ital enhanced their response to parathion and VX due to metabolic bioactiva tion. Atropine partially blocked the effects of VX and paraoxon on both cel l types, which suggests the involvement of a muscarinic receptor as the tar get for cytotoxicity. There was no correlation between OP in vivo neurotoxi city and in vitro cytotoxicity. It is suggested that the former results fro m their cholinesterase inhibition, while the latter results from action on different targets and requires much higher concentrations.