Organophosphate (OP)
anticholinesterases were found to modulate metabolic activities of human
neuroblastoma cells and hepatocytes, which was detectable by the Cytosensor microphysiometer. The
nerve gas ethyl-S-2-diisopropylaminoethyl methylphosphorothiolate (
VX),
at 10 microM, produced significant reduction in cell metabolism within 2 min, as measured by changes in the acidification rate of the medium. The reduction was dose- and time-dependent and irreversible after 4 h of exposure. Two alkaline degradation products of
VX produced no cytotoxicity. Exposure for 24 h to 3 microM
VX caused 36% and 94% irreversible loss of metabolism in hepatocytes and
neuroblastoma cells, respectively. The
insecticides parathion and
chlorpyrifos stimulated hepatocyte 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, 775, 640, 340, or 672 microM, respectively, whereas 24 h gave an LC50 of 0.7, 3.7, 2.5, 29, and 31 microM, respectively. Preincubation of hepatocytes with
phenobarbital enhanced their response to
parathion and
VX due to metabolic bioactivation.
Atropine partially blocked the effects of
VX and
paraoxon on both cell types, which suggests the involvement of a
muscarinic receptor as the target for cytotoxicity. There was no correlation between OP in vivo neurotoxicity and in vitro cytotoxicity. It is suggested that the former results from their
cholinesterase inhibition, while the latter results from action on different targets and requires much higher concentrations.