title: Esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo.
abstract: We studied 4 serine esterases (EOHs) that are associated with the following consequences from their inhibition by organophosphorus compounds (OPCs): acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE; inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the "esterase profile" of an OPC, which we hypothesize can serve as a predictor of its overall physiological effects. To test this hypothesis, we selected 3 OPCs known from previous work on reference enzymes to span a wide range of esterase profiles, neuropathic potential, and acute cholinergic toxicity. For each compound, we determined in vitro IC50and in vivo ED50values for inhibition of AChE, BChE, CaE, and NTE in mouse brain and blood. The results showed good correlations between in vitro and in vivo measures of potency and selectivity except for brain CaE, a tissue-specific isoform of the enzyme that was less sensitive to the test compounds than expected. Thus, this synthesis of new and previously published results indicates that the concept of the esterase profile of OPCs is useful for the prediction of therapeutic and toxic effects in vivo.
authors.affiliation: Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia.
authors.forename: Galina F
authors.initials: GF
authors.lastname: Makhaeva
authors.affiliation: Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Rudakova
authors.affiliation: Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia.
authors.forename: Olga G
authors.initials: OG
authors.lastname: Serebryakova
authors.affiliation: Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia.
authors.forename: Alexey Yu
authors.initials: AY
authors.lastname: Aksinenko
authors.affiliation: Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia; Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia.
authors.forename: Sofya V
authors.initials: SV
authors.lastname: Lushchekina
authors.affiliation: Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia.
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Bachurin
authors.affiliation: Toxicology Program, Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. Electronic address: rjrich@umich.edu.
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Richardson
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004950:Esterases / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism*; D012015:Reference Standards
chemical_list: D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D004950:Esterases
keywords: Acetylcholinesterase (AChE); Butyrylcholinesterase (BChE); Carboxylesterase (CaE); Esterase profile; Neuropathy target esterase (NTE); Organophosphorus compounds (OPCs)