Inhibition of carboxylesterases in SH-SY5Y human and NB41A3 mouse neuroblastoma cells by organophosphorus esters.
Carboxylesterases (CbxE) can be inhibited by organophosphorus esters (OPs) without causing clinical evidence of toxicity. CbxE are thought to protect the critical enzyme acetylcholinesterase (AChE) from OP inhibition in animals. CbxE and AChE are both present in neuroblastoma cells, but, even though these cells have potential to be an in vitro model of OP toxicity, the effect of OPs on CbxE and the relationship of CbxE inhibition and AChE inhibition have not yet been examined in these cells. Therefore, this study examined concentration-related OP-induced inhibition of CbxE in human SH-SY5Y and mouse NB41A3 neuroblastoma cells with 11 active esterase inhibitors: paraoxon, malaoxon, chlorpyrifos-oxon, tolyl saligenin phosphate (TSP), phenyl saligenin phosphate (PSP), diisopropyl phosphorofluoridate (DFP), mipafox, dichlorvos, trichlorfon, dibutyryl dichlorovinyl phosphate (DBVP), and dioctyl dichlorovinyl phosphate (DOVP). All could inhibit CbxE, although the enzyme was less likely to be inhibited than AChE following exposure to 9 of the test compounds in the human cell line and to all 11 of the test compounds in the murine cell line. Species differences in concentration-related inhibitions of CbxE were evident. When cells were exposed first to an OP with a low IC50 toward CbxE (PSP), followed by an OP with high affinity for AChE (paraoxon or malaoxon), inhibitions of CbxE and AChE were additive. This indicated that CbxE did not protect AChE from OP-induced inhibition in this cell culture model.
Ehrich
M
M
Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, Virginia 24061-0442, USA.
Correll
L
L
D000110:Acetylcholinesterase / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology*; D002265:Carboxylic Ester Hydrolases / Q000187:drug effects* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004950:Esterases / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured
D009943:Organophosphorus Compounds; D004950:Esterases; D002265:Carboxylic Ester Hydrolases; D000110:Acetylcholinesterase