Rudy J Richardson | University of Michigan (original) (raw)
Papers by Rudy J Richardson
Target Organ Toxicity, 2020
Journal of occupational medicine. : official publication of the Industrial Medical Association, 1983
ABSTRACT S,S,S,-Tributylphosphorotrithioate (DEF) and merphos are commercially used organophospho... more ABSTRACT S,S,S,-Tributylphosphorotrithioate (DEF) and merphos are commercially used organophosphorus defoliants that are of particular interest in occupational medicine because both compounds can produce delayed neurotoxicity in animals. The putative molecular target in neural tissue for the initiation of delayed neuropathy is neurotoxic esterase (NTE). The discovery of this enzyme in peripheral lymphocytes prompted us to determine whether or not measurement of its inhibition might be useful in monitoring workers exposed to organophosphates that can cause delayed neurotoxicity. We measured the occupational exposure to DEF and merphos of seven workers during aerial and ground application of these defoliants in cotton fields by determining environmental air and dermal concentrations of the organophosphates. We also measured the NTE activity in lymphocytes before and several times during the exposure. Peripheral nerve function was measured before and after the exposure (electromyograph and nerve conduction studies) to correlate possible biochemical and physiologic effects. Environmental measurements suggested that the major route of exposure to DEF and merphos for workers involved in the defoliation of cotton fields is through the skin. This exposure did not result in any detectable subclinical effect on the peripheral nervous system. However, it did affect lymphocyte NTE in the exposed workers. Both the intensity and the length of exposure seemed to be important in determining the inhibition of NTE in lymphocytes, which was about 50% of the preexposure values when measured three to four weeks after the beginning of the exposure. Blood acetylcholinestrase and plasma butyrylcholinesterase levels did not change during the study period. This level of NTE inhibition did not have any associated detectable electrophysiologic effects. Measurement of NTE in lymphocytes in workers exposed to organophosphates represents a rational biomonitor for organophosphates capable of producing delayed neuropathy.
Neurotoxicology
A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in met... more A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson's disease (PD). Non-demented men and women 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 144) and controls (n = 464) were frequency-matched for sex, race and age (+/- 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects' case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not assoc...
: This report will be a brief review of the investigations which provide data supportive of the h... more : This report will be a brief review of the investigations which provide data supportive of the hypothesis that a membrane-associated protein is the initial target of neurotoxic organophosphorus compounds (the term neurotoxic OP will be used in this paper to refer to organophosphorus compounds which produce delayed neuropathy). Findings from more recent studies will be used to develop a picture of the molecular state of the protein at the outset of the neurotoxic process.
Biotechnology Letters, 2005
A graphite-paste tyrosinase biosensor was improved by adding 1-methoxyphenazine methosulfate as a... more A graphite-paste tyrosinase biosensor was improved by adding 1-methoxyphenazine methosulfate as a mediator. Mediator modification enhanced sensitivity to phenol 4-fold and long-term stability 3-fold. Phenol could be detected at 25 nM (S/N=2) using an Ag/AgCl reference electrode. The biosensor was used to measure the activity of a toxicologically significant enzyme, neuropathy target esterase (NTE), which yields phenol by hydrolysis of the substrate, phenyl valerate. Using the new biosensor, blood and brain NTE inhibition by organophosphorus (OP) compounds with different neuropathic potencies were well correlated (r=0.990, n=7), supporting the use of blood NTE as a biochemical marker of exposure to neuropathic OP compounds.
Molecules
A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the k... more A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biolo...
Molecules
New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring link... more New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement...
Molecules
New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring link... more New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement...
Pure and Applied Chemistry
A new series of homobivalent Dimebon analogs, bis-γ-carbolines with alkylene, phenylenedialkylene... more A new series of homobivalent Dimebon analogs, bis-γ-carbolines with alkylene, phenylenedialkylene, and triazole-containing spacers, was synthesized. Doubling the γ-carboline pharmacophore increased inhibitory potency against acetylcholinesterase (AChE) compared with Dimebon, while keeping Dimebon’s anti-butyrylcholinesterase activity; therefore, leading to inversion of selectivity. Molecular docking revealed the reasons for the increased anti-AChE activity and ability to block AChE-induced aggregation of β-amyloid for bis-γ-carbolines, which became double-site inhibitors of AChE. Conjugates with ditriazole-containing spacers were the most active antioxidants in both the ABTS-test and prevention of lipid peroxidation in brain homogenates without inhibiting the mitochondrial permeability transition (MPT). Conjugates with alkylene (4a–d), phenylenedialkylene (4e), and monotriazole (8) spacers were less active as antioxidants but prevented induction of the MPT and increased the calcium ...
Toxicological sciences : an official journal of the Society of Toxicology, 2018
Two oxidized metabolites of n-butylparaben (BuP) and iso-butylparaben (IsoBuP) discovered in huma... more Two oxidized metabolites of n-butylparaben (BuP) and iso-butylparaben (IsoBuP) discovered in human urine samples exhibit structural similarity to endogenous estrogens. We hypothesized that these metabolites bind to the human estrogen receptor (ER) and promote estrogen signaling. We tested this using models of ER-mediated cellular proliferation. The estrogenic properties of 3-hydroxy n-butyl 4-hydroxybenzoate (3OH) and 2-hydroxy iso-butyl 4-hydroxybenzoate (2OH) were determined using the ER-positive, estrogen-dependent human breast cancer cell lines MCF-7, and T47D. The 3OH metabolite induced cellular proliferation with EC50 of 8.2 µM in MCF-7 cells. The EC50 for 3OH in T47D cells could not be reached. The 2OH metabolite induced proliferation with EC50 of 2.2 µM and 43.0 µM in MCF-7 and T47D cells, respectively. The EC50 for the parental IsoBuP and BuP was 0.30 and 1.2 µM in MCF-7 cells, respectively. The expression of a pro-proliferative, estrogen-inducible gene (GREB1) was induced ...
Bioorganic & Medicinal Chemistry
We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylc... more We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) using the methods of enzyme kinetics and molecular docking. Antioxidant activity of the compounds was determined using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) radical decolorization assay as their ability to scavenge free radicals. Analysis of the esterase profiles and antiradical activities of the acridine derivatives showed that 9-aryl(heteroaryl)-N-methyl-9,10-dihydroacridines have a high radical-scavenging activity but low potency as AChE and BChE inhibitors, whereas 9-aryl(heteroaryl)-N-methyl-acridinium tetrafluoroborates effectively inhibit cholinesterases but do not exhibit antiradical activity. In contrast, a group of derivatives of 9-heterocyclic amino-N-methyl-9,10-dihydroacridine has been found that combine effective inhibition of AChE and BChE with rather high radical-scavenging activity. The results of molecular docking well explain the observed features in the efficacy, selectivity, and mechanism of cholinesterase inhibition by the acridine derivatives. Thus, in a series of acridine derivatives we have found compounds possessing dual properties of effective and selective cholinesterase inhibition together with free radical scavenging, which makes promising the use of the acridine scaffold to create multifunctional drugs for the therapy of neurodegenerative diseases.
Journal of Applied Toxicology, 2016
The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organo... more The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organophosphorus compound-induced delayed neurotoxicity (OPIDN). Recently, we developed a mouse model for biochemical assessment of the neuropathic potential of OP compounds based on brain neuropathy target esterase (NTE) and acetylcholinesterase (AChE) inhibition. We carried out the present work to further develop the mouse model by testing the hypothesis that whole blood NTE inhibition could be used as a biochemical marker for exposure to neuropathic OP compounds. Because brain NTE and AChE inhibition are biomarkers of OPIDN and acute cholinergic toxicity, respectively, we compared NTE and AChE 20-min IC50 values as well as ED50 values 1 h after single intraperitoneal (i.p.) injections of increasing doses of two neuropathic OP compounds that differed in acute toxicity potency. We found good agreement between the brain and blood for in vitro sensitivity of each enzyme as well for the ratios IC50 (AChE)/IC50 (NTE). Both OP compounds inhibited AChE and NTE in the mouse brain and blood dose-dependently, and brain and blood inhibitions in vivo were well correlated for each enzyme. For both OP compounds, the ratio ED50 (AChE)/ED50 (NTE) in blood corresponded to that in the brain despite the somewhat higher sensitivity of blood enzymes. Thus, our results indicate that mouse blood NTE could serve as a biomarker of exposure to neuropathic OP compounds. Moreover, the data suggest that relative inhibition of blood NTE and AChE provide a way to assess the likelihood that OP compound exposure in a susceptible species would produce cholinergic and/or delayed neuropathic effects. Copyright © 2016 John Wiley & Sons, Ltd.
Target Organ Toxicity, 2020
Journal of occupational medicine. : official publication of the Industrial Medical Association, 1983
ABSTRACT S,S,S,-Tributylphosphorotrithioate (DEF) and merphos are commercially used organophospho... more ABSTRACT S,S,S,-Tributylphosphorotrithioate (DEF) and merphos are commercially used organophosphorus defoliants that are of particular interest in occupational medicine because both compounds can produce delayed neurotoxicity in animals. The putative molecular target in neural tissue for the initiation of delayed neuropathy is neurotoxic esterase (NTE). The discovery of this enzyme in peripheral lymphocytes prompted us to determine whether or not measurement of its inhibition might be useful in monitoring workers exposed to organophosphates that can cause delayed neurotoxicity. We measured the occupational exposure to DEF and merphos of seven workers during aerial and ground application of these defoliants in cotton fields by determining environmental air and dermal concentrations of the organophosphates. We also measured the NTE activity in lymphocytes before and several times during the exposure. Peripheral nerve function was measured before and after the exposure (electromyograph and nerve conduction studies) to correlate possible biochemical and physiologic effects. Environmental measurements suggested that the major route of exposure to DEF and merphos for workers involved in the defoliation of cotton fields is through the skin. This exposure did not result in any detectable subclinical effect on the peripheral nervous system. However, it did affect lymphocyte NTE in the exposed workers. Both the intensity and the length of exposure seemed to be important in determining the inhibition of NTE in lymphocytes, which was about 50% of the preexposure values when measured three to four weeks after the beginning of the exposure. Blood acetylcholinestrase and plasma butyrylcholinesterase levels did not change during the study period. This level of NTE inhibition did not have any associated detectable electrophysiologic effects. Measurement of NTE in lymphocytes in workers exposed to organophosphates represents a rational biomonitor for organophosphates capable of producing delayed neuropathy.
Neurotoxicology
A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in met... more A population-based case-control study was conducted in the Henry Ford Health System (HFHS) in metropolitan Detroit to assess occupational exposures to manganese, copper, lead, iron, mercury and zinc as risk factors for Parkinson's disease (PD). Non-demented men and women 50 years of age who were receiving primary medical care at HFHS were recruited, and concurrently enrolled cases (n = 144) and controls (n = 464) were frequency-matched for sex, race and age (+/- 5 years). A risk factor questionnaire, administered by trained interviewers, inquired about every job held by each subject for 6 months from age 18 onward, including a detailed assessment of actual job tasks, tools and environment. An experienced industrial hygienist, blinded to subjects' case-control status, used these data to rate every job as exposed or not exposed to one or more of the metals of interest. Adjusting for sex, race, age and smoking status, 20 years of occupational exposure to any metal was not assoc...
: This report will be a brief review of the investigations which provide data supportive of the h... more : This report will be a brief review of the investigations which provide data supportive of the hypothesis that a membrane-associated protein is the initial target of neurotoxic organophosphorus compounds (the term neurotoxic OP will be used in this paper to refer to organophosphorus compounds which produce delayed neuropathy). Findings from more recent studies will be used to develop a picture of the molecular state of the protein at the outset of the neurotoxic process.
Biotechnology Letters, 2005
A graphite-paste tyrosinase biosensor was improved by adding 1-methoxyphenazine methosulfate as a... more A graphite-paste tyrosinase biosensor was improved by adding 1-methoxyphenazine methosulfate as a mediator. Mediator modification enhanced sensitivity to phenol 4-fold and long-term stability 3-fold. Phenol could be detected at 25 nM (S/N=2) using an Ag/AgCl reference electrode. The biosensor was used to measure the activity of a toxicologically significant enzyme, neuropathy target esterase (NTE), which yields phenol by hydrolysis of the substrate, phenyl valerate. Using the new biosensor, blood and brain NTE inhibition by organophosphorus (OP) compounds with different neuropathic potencies were well correlated (r=0.990, n=7), supporting the use of blood NTE as a biochemical marker of exposure to neuropathic OP compounds.
Molecules
A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the k... more A new series of conjugates of aminoadamantane and γ-carboline, which are basic scaffolds of the known neuroactive agents, memantine and dimebon (Latrepirdine) was synthesized and characterized. Conjugates act simultaneously on several biological structures and processes involved in the pathogenesis of Alzheimer’s disease and some other neurodegenerative disorders. In particular, these compounds inhibit enzymes of the cholinesterase family, exhibiting higher inhibitory activity against butyrylcholinesterase (BChE), but having almost no effect on the activity of carboxylesterase (anti-target). The compounds serve as NMDA-subtype glutamate receptor ligands, show mitoprotective properties by preventing opening of the mitochondrial permeability transition (MPT) pore, and act as microtubule stabilizers, stimulating the polymerization of tubulin and microtubule-associated proteins. Structure–activity relationships were studied, with particular attention to the effect of the spacer on biolo...
Molecules
New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring link... more New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement...
Molecules
New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring link... more New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement...
Pure and Applied Chemistry
A new series of homobivalent Dimebon analogs, bis-γ-carbolines with alkylene, phenylenedialkylene... more A new series of homobivalent Dimebon analogs, bis-γ-carbolines with alkylene, phenylenedialkylene, and triazole-containing spacers, was synthesized. Doubling the γ-carboline pharmacophore increased inhibitory potency against acetylcholinesterase (AChE) compared with Dimebon, while keeping Dimebon’s anti-butyrylcholinesterase activity; therefore, leading to inversion of selectivity. Molecular docking revealed the reasons for the increased anti-AChE activity and ability to block AChE-induced aggregation of β-amyloid for bis-γ-carbolines, which became double-site inhibitors of AChE. Conjugates with ditriazole-containing spacers were the most active antioxidants in both the ABTS-test and prevention of lipid peroxidation in brain homogenates without inhibiting the mitochondrial permeability transition (MPT). Conjugates with alkylene (4a–d), phenylenedialkylene (4e), and monotriazole (8) spacers were less active as antioxidants but prevented induction of the MPT and increased the calcium ...
Toxicological sciences : an official journal of the Society of Toxicology, 2018
Two oxidized metabolites of n-butylparaben (BuP) and iso-butylparaben (IsoBuP) discovered in huma... more Two oxidized metabolites of n-butylparaben (BuP) and iso-butylparaben (IsoBuP) discovered in human urine samples exhibit structural similarity to endogenous estrogens. We hypothesized that these metabolites bind to the human estrogen receptor (ER) and promote estrogen signaling. We tested this using models of ER-mediated cellular proliferation. The estrogenic properties of 3-hydroxy n-butyl 4-hydroxybenzoate (3OH) and 2-hydroxy iso-butyl 4-hydroxybenzoate (2OH) were determined using the ER-positive, estrogen-dependent human breast cancer cell lines MCF-7, and T47D. The 3OH metabolite induced cellular proliferation with EC50 of 8.2 µM in MCF-7 cells. The EC50 for 3OH in T47D cells could not be reached. The 2OH metabolite induced proliferation with EC50 of 2.2 µM and 43.0 µM in MCF-7 and T47D cells, respectively. The EC50 for the parental IsoBuP and BuP was 0.30 and 1.2 µM in MCF-7 cells, respectively. The expression of a pro-proliferative, estrogen-inducible gene (GREB1) was induced ...
Bioorganic & Medicinal Chemistry
We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylc... more We investigated the inhibitory activity of 4 groups of novel acridine derivatives against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and carboxylesterase (CaE) using the methods of enzyme kinetics and molecular docking. Antioxidant activity of the compounds was determined using the 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) radical decolorization assay as their ability to scavenge free radicals. Analysis of the esterase profiles and antiradical activities of the acridine derivatives showed that 9-aryl(heteroaryl)-N-methyl-9,10-dihydroacridines have a high radical-scavenging activity but low potency as AChE and BChE inhibitors, whereas 9-aryl(heteroaryl)-N-methyl-acridinium tetrafluoroborates effectively inhibit cholinesterases but do not exhibit antiradical activity. In contrast, a group of derivatives of 9-heterocyclic amino-N-methyl-9,10-dihydroacridine has been found that combine effective inhibition of AChE and BChE with rather high radical-scavenging activity. The results of molecular docking well explain the observed features in the efficacy, selectivity, and mechanism of cholinesterase inhibition by the acridine derivatives. Thus, in a series of acridine derivatives we have found compounds possessing dual properties of effective and selective cholinesterase inhibition together with free radical scavenging, which makes promising the use of the acridine scaffold to create multifunctional drugs for the therapy of neurodegenerative diseases.
Journal of Applied Toxicology, 2016
The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organo... more The adult hen is the standard animal model for testing organophosphorus (OP) compounds for organophosphorus compound-induced delayed neurotoxicity (OPIDN). Recently, we developed a mouse model for biochemical assessment of the neuropathic potential of OP compounds based on brain neuropathy target esterase (NTE) and acetylcholinesterase (AChE) inhibition. We carried out the present work to further develop the mouse model by testing the hypothesis that whole blood NTE inhibition could be used as a biochemical marker for exposure to neuropathic OP compounds. Because brain NTE and AChE inhibition are biomarkers of OPIDN and acute cholinergic toxicity, respectively, we compared NTE and AChE 20-min IC50 values as well as ED50 values 1 h after single intraperitoneal (i.p.) injections of increasing doses of two neuropathic OP compounds that differed in acute toxicity potency. We found good agreement between the brain and blood for in vitro sensitivity of each enzyme as well for the ratios IC50 (AChE)/IC50 (NTE). Both OP compounds inhibited AChE and NTE in the mouse brain and blood dose-dependently, and brain and blood inhibitions in vivo were well correlated for each enzyme. For both OP compounds, the ratio ED50 (AChE)/ED50 (NTE) in blood corresponded to that in the brain despite the somewhat higher sensitivity of blood enzymes. Thus, our results indicate that mouse blood NTE could serve as a biomarker of exposure to neuropathic OP compounds. Moreover, the data suggest that relative inhibition of blood NTE and AChE provide a way to assess the likelihood that OP compound exposure in a susceptible species would produce cholinergic and/or delayed neuropathic effects. Copyright © 2016 John Wiley & Sons, Ltd.