Esterase profiles of organophosphorus compounds in vitro predict their behavior in vivo Galina F. Makhaeva a , Elena V. Rudakova a , Olga G. Serebryakova a , Alexey Yu. Aksinenko a , Sofya V. Lushchekina a, b , Sergey O. Bachurin a , Rudy J. Richardson c, d, * a Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia b Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, 119334, Russia c Toxicology Program, Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, 48109, USA d Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA article info Article history: Received 16 January 2016 Received in revised form 26 April 2016 Accepted 2 May 2016 Available online 3 May 2016 Keywords: Acetylcholinesterase (AChE) Butyrylcholinesterase (BChE) Carboxylesterase (CaE) Esterase profile Neuropathy target esterase (NTE) Organophosphorus compounds (OPCs) 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 stoichio- metric 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 IC 50 and in vivo ED 50 values 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. © 2016 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Certain organophosphorus compounds (OPCs) can inhibit various serine esterases (EOHs) via organophosphorylation of serine residues in their active sites. Varying degrees of adverse or therapeutic effects arise from OPC exposure depending in part on their relative inhibitory selectivities against EOHs of interest e the “esterase profile” of a given OPC [1e4]. We chose to study a panel of 4 EOHs whose inhibition is involved in acute neurotoxicity (acetylcholinesterase, AChE, EC 3.1.1.7) [5], delayed neurotoxicity (neuropathy target esterase, NTE, 3.1.1.5, target of OPC-induced delayed neuropathy, OPIDN) [6,7], and drug metabolism or stoichiometric scavenging of EOH in- hibitors (butyrylcholinesterase, BChE, EC 3.1.1.8; and carbox- ylesterase, CaE, EC 3.1.1.1) [8e10]. Inhibition of AChE and/or BChE can also exert a therapeutic effect of cognition enhancement in Alzheimer’s disease (AD) [11,12]. Analysis of esterase profiles helps to identify the main potential pharmacological effect of the compound and its possible side and toxic effects [2e4,13]. For example, effective inhibitors of AChE and BChE can be used for AD treatment. However, inhibition of CaE by such anticholinesterase compounds leads to adverse drug-drug interactions [14] because CaE is known to hydrolyze numerous drugs or prodrugs containing ester, amide, and carbamate groups such as angiotensin-converting enzyme inhibitors, antiplatelet Abbreviations: AChE, acetylcholinesterase; BChE, butyrylcholinesterase; CaE, carboxylesterase; EOH(s), serine esterase(s); NTE, neuropathy target esterase; OPC(s), organophosphorus compound(s); RIP(s), relative inhibitory potency/po- tencies; OPIDN, organophosphorus compound-induced delayed neurotoxicity; AD, Alzheimer’s disease; diEt-PFP, O,O-diethyl-O-(1-trifluoromethyl-2,2,2- trifluoroethyl) phosphate; diBu-PFP, O,O-dibutyl-O-(1-trifluoromethyl-2,2,2- trifluoroethyl) phosphate; PrDChVP, O,O-di-1-propyl-O-2,2-dichlorvinyl phosphate. * Corresponding author. Computational Toxicology Laboratory, University of Michigan,1415 Washington Heights, Ann Arbor, MI, 48109-2029, USA. E-mail address: rjrich@umich.edu (R.J. Richardson). Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint http://dx.doi.org/10.1016/j.cbi.2016.05.002 0009-2797/© 2016 Elsevier Ireland Ltd. All rights reserved. Chemico-Biological Interactions 259 (2016) 332e342