Differential cytotoxic sensitivity in mouse and human cell lines exposed to organophosphate insecticides.
Neuroblastoma cell lines were used to examine the differential interspecies response (i.e., species selectivity) to organophosphates (OPs). Baseline activities of the major target esterases, i.e., cholinesterase, carboxylesterase, and neurotoxic esterase, were assayed in mouse and several human neural candidate cell lines. These activities were found to be variable within individual cell lines and among the various tested cell lines. Cytotoxicity data using the neutral red fluorometric assay were collected on both human (SH-SY5Y) and mouse (NB41A3) neuroblastoma clones exposed to a variety of OP insecticides. IC50 data indicated that the tested mouse cell line was consistently more sensitive than the human cell line to equimolar doses of various OP compounds (e.g., mipafox, parathion, paraoxon, DFP, leptophos oxon, fenthion, and fenitrothion). This difference in cytotoxic sensitivity was most pronounced in response to compounds requiring metabolic bioactivation (i.e., protoxicants). Cytotoxicity data also demonstrated that the NB41A3 mouse neuroblastoma cell line was more metabolically competent than the SH-SY5Y human cell line in converting the protoxicant parathion to its neurotoxic metabolite, paraoxon. B-lymphoblastoids, genetically engineered with human P450 cDNAs, demonstrated higher cytotoxic sensitivity to parathion than unengineered cells, indicating that cytochrome P450-associated monooxidase activity could also influence cytotoxic sensitivity to parathion in culture. These data suggest that interspecies-selectivity in response to OP-related cytotoxicity is influenced by intercellular differences in metabolism and baseline esterase activities.
U.S. Environmental Protection Agency, Neurotoxicology Division, Research Triangle Park, North Carolina 27711.
B
B
Veronesi
M
M
Ehrich
D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology; D002460:Cell Line / Q000187:drug effects / Q000201:enzymology; D004950:Esterases / Q000378:metabolism*; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D051379:Mice; D009447:Neuroblastoma / Q000201:enzymology; D009943:Organophosphorus Compounds; D013045:Species Specificity; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D007306:Insecticides; D009943:Organophosphorus Compounds; D004950:Esterases