Comparative effectiveness of organophosphorus protoxicant activating systems in neuroblastoma cells and brain homogenates.
The ability of bromine and rat liver microsomes (RLM) to convert organophosphorus (OP) protoxicants to esterase inhibitors was determined by measuring acetylcholinesterase (AChE) and neuropathy target esterase (NTE) inhibition. Species specific differences in susceptibility to esterase inhibition were determined by comparing the extent of esterase inhibition observed in human neuroblastoma cells and hen, bovine, and rodent brain homogenates. OP protoxicants examined included tri-o-tolyl phosphate (TOTP), O-ethyl O-p-nitrophenyl phenylphosphonothioate (EPN), leptophos, fenitrothion, fenthion, and malathion. Bromine activation resulted in greater AChE inhibition than that produced by RLM activation for equivalent concentrations of fenitrothion, malathion, and EPN. For EPN and leptophos, bromine activation resulted in greater inhibition of NTE than RLM. Only preincubation with RLM activated TOTP; resultant inhibition of AChE was less in hen brain (13 +/- 3%) than in neuroblastoma cells (73 +/- 1%) at 10(-6) M. In contrast, 10(-6) M RLM-activated TOTP produced more inhibition of hen brain NTE (89 +/- 6%) than NTE of human neuroblastoma cells (72 +/- 7%). Human neuroblastoma cells and brain homogenates from hens, the accepted animal model for study of OP-induced neurotoxicity, were relatively similar in sensitivity to esterase inhibition. Homogenates from hens were more sensitive to NTE inhibition induced by phenyl saligenin phosphate (PSP), an active congener of TOTP, than were homogenates from less susceptible species (mouse, rat, bovine). AChE of hen brain homogenates was also more sensitive than homogenates from other species to malaoxon, the active form of malathion.
D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D001966:Bromine / Q000378:metabolism / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors; D002417:Cattle; D002645:Chickens; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D007306:Insecticides / Q000493:pharmacokinetics* / Q000633:toxicity*; D009447:Neuroblastoma / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics* / Q000633:toxicity*; D009946:Organothiophosphorus Compounds; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats