Novel Nucleophiles Enhance the Human Serum Paraoxonase 1 (PON1)-mediated Detoxication of Organophosphates

摘要: Paraoxonase 1 (PON1) is a calcium-dependent hydrolase associated with serum high-density lipoprotein particles. PON1 hydrolyzes some organophosphates (OPs), including nerve agents, through nucleophilic attack of hydroxide ion (from water) in the active site. Most OPs are hydrolyzed inefficiently. This project seeks to identify nucleophiles that can enhance PON1-mediated OP degradation. A series novel nucleophiles, substituted phenoxyalkyl pyridinium oximes, has been synthesized which degradation surrogates sarin (nitrophenyl isopropyl methylphosphonate; NIMP) and VX ethyl NEMP). Two types vitro assays have conducted, direct assay using millimolar concentrations substrate spectrophotometric quantitation hydrolysis product (4-nitrophenol) an indirect submicromolar by level inhibition exogenous source acetylcholinesterase from non-hydrolyzed substrate. Neither NIMP nor NEMP effectively if one these oximes absent. However, presence eight both occurs. Computational modeling created model embedded phospholipid indicated general agreement binding enthalpies relative efficacy as enhancers. enhancement could be unique unprecedented mechanism antidotal action.