A retrospective cumulative risk assessment of dietary exposure to pesticide residues was conducted for chronic inhibition of acetylcholinesterase. The pesticides considered in this assessment were identified and characterised in a previous scientific report on the establishment of cumulative assessment groups of pesticides for their effects on the nervous system. The exposure assessments used monitoring data collected by Member States under their official pesticide monitoring programmes in 2016, 2017 and 2018, and individual food consumption data from 10 populations of consumers from different countries and from different age groups. Exposure estimates were obtained by means of a two-dimensional probabilistic model, which was implemented in SAS ((a)) software. The characterisation of cumulative risk was supported by an uncertainty analysis based on expert knowledge elicitation. For each of the 10 populations, it is concluded with varying degrees of certainty that cumulative exposure to pesticides contributing to the chronic inhibition of acetylcholinesterase does not exceed the threshold for regulatory consideration established by risk managers.

Title:

Estevez J, Rodrigues de Souza F, Romo M, Mangas I, Franca TCC, Vilanova E

Ref:

PubMed

ESTHER: Estevez_2019_Arch.Toxicol_93_1281
PubMedSearch: Estevez 2019 Arch.Toxicol 93 1281
PubMedID: 30877329

Abstract

Phenyl valerate (PV) is a substrate for measuring the PVase activity of neuropathy target esterase (NTE), a key molecular event of organophosphorus-induced delayed neuropathy. A protein with PVase activity in chicken (model for delayed neurotoxicity) was identified as butyrylcholinesterase (BChE). Purified human butyrylcholinesterase (hBChE) showed PVase activity with a similar sensitivity to inhibitors as its cholinesterase (ChE) activity. Further kinetic and theoretical molecular simulation studies were performed. The kinetics did not fit classic competition models among substrates. Partially mixed inhibition was the best-fitting model to acetylthiocholine (AtCh) interacting with PVase activity. ChE activity showed substrate activation, and non-competitive inhibition was the best-fitting model to PV interacting with the non-activated enzyme and partial non-competitive inhibition was the best fitted model for PV interacting with the activated enzyme by excess of AtCh. The kinetic results suggest that other sites could be involved in those activities. From the theoretical docking analysis, we deduced other more favorable sites for binding PV related with Asn289 residue, situated far from the catalytic site ("PV-site"). Both substrates acethylcholine (ACh) and PV presented similar docking values in both the PV-site and catalytic site pockets, which explained some of the observed substrate interactions. Molecular dynamic simulations based on the theoretical structure of crystallized hBChE were performed. Molecular modeling studies suggested that PV has a higher potential for non-competitive inhibition, being also able to inhibit the hydrolysis of ACh through interactions with the PV-site. Further theoretical studies also suggested that PV could yet be able to promote competitive inhibition. We concluded that the kinetic and theoretical studies did not fit the simple classic competition among substrates, but were compatible with the interaction with two different binding sites.

Title:

Estevez J, Benabent M, Selva V, Mangas I, Sogorb MA, Del Rio E, Vilanova E

Ref:

410

PubMed

ESTHER: Estevez_2018_Toxicology_410_73
PubMedSearch: Estevez 2018 Toxicology 410 73
PubMedID: 30176330

Abstract

Some effects of organophosphorus compounds (OPs) esters cannot be explained by action on currently recognized targets acetylcholinesterase or neuropathy target esterase (NTE). In previous studies, in membrane chicken brain fractions, four components (EPalpha, EPbeta, EPgamma and EPdelta) of phenyl valerate esterase activity (PVase) had been kinetically discriminated combining data of several inhibitors (paraoxon, mipafox, PMSF). EPgamma is belonging to NTE. The relationship of PVase components and acetylcholine-hydrolyzing activity (cholinesterase activity) is studied herein. Only EPalpha PVase activity showed inhibition in the presence of acetylthiocholine, similarly to a non-competitive model. EPalpha is highly sensitive to mipafox and paraoxon, but is resistant to PMSF, and is spontaneously reactivated when inhibited with paraoxon. In this papers we shows that cholinesterase activities showed inhibition kinetic by PV, which does not fit with a competitive inhibition model when tested for the same experimental conditions used to discriminate the PVase components. Four enzymatic components (CP1, CP2, CP3 and CP4) were discriminated in cholinesterase activity in the membrane fraction according to their sensitivity to irreversible inhibitors mipafox, paraoxon, PMSF and iso-OMPA. Components CP1 and CP2 could be related to EPalpha as they showed interactions between substrates and similar inhibitory kinetic properties to the tested inhibitors.

Title:

Mangas I, Estevez J, Vilanova E, Franca TCC

Ref:

376

PubMed

ESTHER: Mangas_2017_Toxicology_376_30
PubMedSearch: Mangas 2017 Toxicology 376 30
PubMedID: 27311923

Abstract

Organophosphorus compounds (OPs) are a large and diverse class of chemicals mainly used as pesticides and chemical weapons. People may be exposed to OPs in several occasions, which can produce several distinct neurotoxic effects depending on the dose, frequency of exposure, type of OP, and the host factors that influence susceptibility and sensitivity. These neurotoxic effects are mainly due to the interaction with enzyme targets involved in toxicological or detoxication pathways. In this work, the toxicological relevance of known OPs targets is reviewed. The main enzyme targets of OPs have been identified among the serine hydrolase protein family, some of them decades ago (e.g. AChE, BuChE, NTE and carboxylesterases), others more recently (e.g. lysophospholipase, arylformidase and KIA1363) and others which are not molecularly identified yet (e.g. phenylvalerate esterases). Members of this family are characterized by displaying serine hydrolase activity, containing a conserved serine hydrolase motif and having an alpha-beta hydrolase fold. Improvement in Xray-crystallography and in silico methods have generated new data of the interactions between OPs and esterases and have established new methods to study new inhibitors and reactivators of cholinesterases. Mass spectrometry for AChE, BChE and APH have characterized the active site serine adducts with OPs being useful to detect biomarkers of OPs exposure and inhibitory and postinhibitory reactions of esterases and OPs. The purpose of this review is focus specifically on the interaction of OP with esterases, mainly with type B-esterases, which are able to hydrolyze carboxylesters but inhibited by OPs by covalent phosphorylation on the serine or tyrosine residue in the active sites. Other related esterases in some cases with no-irreversible effect are also discussed. The understanding of the multiple molecular interactions is the basis we are proposing for a multi-target approach for understanding the organophosphorus toxicity.

Title:

Mangas I, Radic Z, Taylor P, Ghassemian M, Candela H, Vilanova E, Estevez J

Ref:

PubMed

ESTHER: Mangas_2017_Arch.Toxicol_91_909
PubMedSearch: Mangas 2017 Arch.Toxicol 91 909
PubMedID: 26838044

Abstract

Multiple epidemiological and experimental studies have demonstrated that exposure to organophosphorus compounds (OPs) is associated with a variety of neurological disorders. Some of these exposure symptoms cannot be precisely correlated with known molecular targets and mechanisms of toxicity. Most of the known molecular targets of OPs fall in the protein family of serine esterases. We have shown that three esterase components in the soluble fraction of chicken brain (an animal model frequently used in OP neurotoxicity assays) can be kinetically distinguished using paraoxon, mipafox and phenylmethyl sulfonyl fluoride as inhibitors, and phenyl valerate as a substrate; we termed them Ealpha, Ebeta and Egamma. The Ealpha-component, which is highly sensitive to paraoxon and mipafox and resistant to PMSF, has shown sensitivity to the substrate acetylthiocholine, and to ethopropazine and iso-OMPA (specific inhibitors of butyrylcholinesterase; BChE) but not to BW 284C51 (a specific inhibitor of acetylcholinesterase; AChE). In this work, we employed a large-scale proteomic analysis B with a LC/MS/MS TripleTOF system; 259 proteins were identified in a chromatographic fractionated sample enriched in Ealpha activity of the chicken brain soluble fraction. Bioinformatics analysis revealed that BChE is the only candidate protein identified to be responsible for almost all the Ealpha activity. This study demonstrates the potential information to be gained from combining kinetic dissection with large-scale proteomics and bioinformatics analyses for identification of proteins that are targets of OP toxicity and may be involved in detoxification of phosphoryl and carbonyl esters.

Title:

Mangas I, Vilanova E, Estevez J

Ref:

PubMed

ESTHER: Mangas_2017_Arch.Toxicol_91_3295
PubMedSearch: Mangas 2017 Arch.Toxicol 91 3295
PubMedID: 28299395

Abstract

Phenyl valerate is used for detecting and measuring neuropathy target esterase (NTE) and has been used for discriminating esterases as potential target in hen model of organophosphorus delayed neuropathy. In previous studies we observed that phenyl valerate esterase (PVase) activity of an enzymatic fraction in chicken brain might be due to a butyrylcholinesterase protein (BuChE), and it was suggested that this enzymatic fraction could be related to the potentiation/promotion phenomenon of the organophosphate-induced delayed neuropathy (OPIDN). In this work, PVase activity of purified human butyrylcholinesterase (hBuChE) is demonstrated and confirms the novel observation that a relationship of BuChE with PVase activities is also relevant for humans, as is, therefore the potential role in toxicity for humans. The KM and catalytic constant (kcat) were estimated as 0.52/0.72 microM and 45,900/49,200 min(-1) respectively. Furthermore, this work studies the inhibition by preincubation of PVase and cholinesterase activities of hBuChE with irreversible inhibitors (mipafox, iso-OMPA or PMSF), showing that these inhibitors interact similarly in both activities with similar second-order inhibition constants. Acethylthiocholine and phenyl valerate partly inhibit PVase and cholinesterase activities, respectively. All these observations suggest that both activities occur in the same active center. The interaction with a reversible inhibitor (ethopropazine) showed that the cholinesterase activity was more sensitive than the PVase activity, showing that the sensitivity for this reversible inhibitor is affected by the nature of the substrate. The present work definitively establishes the capacity of BuChE to hydrolyze the carboxylester phenyl valerate using a purified enzyme (hBuChE). Therefore, BuChE should be considered in the research of organophosphorus targets of toxicity related with PVase proteins.

Title:

Estevez J, Selva V, Benabent M, Mangas I, Sogorb MA, Vilanova E

Ref:

259

PubMed

ESTHER: Estevez_2016_Chem.Biol.Interact_259_374
PubMedSearch: Estevez 2016 Chem.Biol.Interact 259 374
PubMedID: 27507601
no abstract

Title:

Mangas I, Taylor P, Vilanova E, Estevez J, Franca TCC, Komives E, Radic Z

Ref:

PubMed

ESTHER: Mangas_2016_Arch.Toxicol_90_603
PubMedSearch: Mangas 2016 Arch.Toxicol 90 603
PubMedID: 25743373
Inhibitor(s) related to this paper: IMP-MeCyC, Mipafox

Abstract

The hydroxyl oxygen of the catalytic triad serine in the active center of serine hydrolase acetylcholinesterase (AChE) attacks organophosphorus compounds (OPs) at the phosphorus atom to displace the primary leaving group and to form a covalent bond. Inhibited AChE can be reactivated by cleavage of the Ser-phosphorus bond either spontaneously or through a reaction with nucleophilic agents, such as oximes. At the same time, the inhibited AChE adduct can lose part of the molecule by progressive dealkylation over time in a process called aging. Reactivation of the aged enzyme has not yet been demonstrated. Here, our goal was to study oxime reactivation and aging reactions of human AChE inhibited by mipafox or a sarin analog (Flu-MPs, fluorescent methylphosphonate). Progressive reactivation was observed after Flu-MPs inhibition using oxime 2-PAM. However, no reactivation was observed after mipafox inhibition with 2-PAM or the more potent oximes used. A peptide fingerprinted mass spectrometry (MS) method, which clearly distinguished the peptide with the active serine (active center peptide, ACP) of the human AChE adducted with OPs, was developed by MALDI-TOF and MALDI-TOF/TOF. The ACP was detected with a diethyl-phosphorylated adduct after paraoxon inhibition, and with an isopropylmethyl-phosphonylated and a methyl-phosphonylated adduct after Flu-MPs inhibition and subsequent aging. Nevertheless, nonaged nonreactivated complexes were seen after mipafox inhibition and incubation with oximes, where MS data showed an ACP with an NN diisopropyl phosphoryl adduct. The kinetic experiments showed no reactivation of activity. The computational molecular model analysis of the mipafox-inhibited hAChE plots of energy versus distance between the atoms separated by dealkylation showed a high energy demand, thus little aging probability. However, with Flu-MPs and DFP, where aging was observed in our MS data and in previously published crystal structures, the energy demand calculated in modeling was lower and, consequently, aging appeared as a more likely reaction. We document here direct evidence for a phosphorylated hAChE refractory to oxime reactivation, although we observed no aging.

Title:

Mangas I, Estevez J, Vilanova E

Ref:

259

PubMed

ESTHER: Mangas_2016_Chem.Biol.Interact_259_358
PubMedSearch: Mangas 2016 Chem.Biol.Interact 259 358
PubMedID: 27087132

Abstract

OPs are a large diverse class of chemicals used for several purposes (pesticides, warfare agents, flame retardants, etc.). They can cause several neurotoxic disorders: acute cholinergic toxicity, organophosphorus-induced delayed neuropathy, long-term neurobehavioral and neuropsychological symptoms, and potentiation of neuropathy. Some of these syndromes cannot be fully understood with known molecular targets. Many enzyme systems have the potential to interact with OPs. Since the discovery of neuropathy target esterase (NTE), the esterases that hydrolyze phenyl valerate (PVases) have been of interest. PVase components are analyzed in chicken tissue, the animal model used for testing OP-delayed neurotoxicity. Three enzymatic components have been discriminated in serum, and three in a soluble fraction of peripheral nerve, three in a soluble fraction of brain, and four in a membrane fraction of brain have been established according to inhibitory kinetic properties combined with several inhibitors. The criteria and strategies to differentiate these enzymatic components are shown. In the brain soluble fraction three enzymatic components, namely Ealpha, Ebeta and Egamma, were found. Initial interest focused on Ealpha activity (highly sensitive to paraoxon and spontaneously reactivated, mipafox and resistant to PMSF). By protein separation methods, a subfraction enriched in Ealpha activity was obtained and 259 proteins were identified by Tandem Mass Spectrometry. Only one had the criteria for being serine-esterase identified as butyrylcholinesterase, which stresses the relationship between cholinesterases and PVases. The identification and characterization of the whole group of PVases targets of OPs (besides AChE, BuChE and NTE) is necessary to clarify the importance of these other targets in OPs neurotoxicity or on detoxication pathways. A systematic strategy has proven useful for the molecular identification of one enzymatic component, which can be applied to identify them all.

Title:

Benabent M, Vilanova E, Mangas I, Sogorb MA, Estevez J

Ref:

230

PubMed

ESTHER: Benabent_2014_Toxicol.Lett_230_132
PubMedSearch: Benabent 2014 Toxicol.Lett 230 132
PubMedID: 24576786

Abstract

Organophosphorus compounds (OPs) induce neurotoxic disorders through interactions with well-known target esterases, such as acetylcholinesterase and neuropathy target esterase (NTE). However, OPs interact with other esterases of unknown biological function. In soluble chicken brain fractions, three components of enzymatic phenylvalerate esterase activity (PVase) called Ealpha, Ebeta and Egamma, have been kinetically discriminated. These components are studied in this work for the relationship with acetylcholine-hydrolyzing activity. When Ealpha PVase activity (resistant PVase activity to 1500muM PMSF for 30min) was tested with different acetylthiocholine concentrations, inhibition was observed. The best-fitting model to the data was the non-competitive inhibition model (Km=0.12, 0.22mM, Ki=6.6, 7.6mM). Resistant acetylthiocholine-hydrolyzing activity to 1500muM PMSF was inhibited by phenylvalerate showing competitive inhibition (Km=0.09, 0.11mM; Ki=1.7, 2.2mM). Ebeta PVase activity (resistant PVase activity to 25muM mipafox for 30min) was not affected by the presence of acetylthiocholine, while resistant acetylthiocholine-hydrolyzing activity to 25muM mipafox showed competitive inhibition in the presence of phenylvalerate (Km=0.05, 0.06mM; Ki=0.44, 0.58mM). The interactions observed between the substrates of AChE and PVase suggest that part of PVase activity might be a protein with acetylthiocholine-hydrolyzing activity.

Title:

Mangas I, Vilanova E, Benabent M, Estevez J

Ref:

225

PubMed

ESTHER: Mangas_2014_Toxicol.Lett_225_167
PubMedSearch: Mangas 2014 Toxicol.Lett 225 167
PubMedID: 24355587

Abstract

Low level exposure to organophosphorus esters (OPs) may cause long-term neurological effects and affect specific cognition domains in experimental animals and humans. Action on known targets cannot explain most of these effects by. Soluble carboxylesterases (EC 3.1.1.1) of chicken brain have been kinetically discriminated using paraoxon, mipafox and phenylmethyl sulfonylfluoride as inhibitors and phenyl valerate as a substrate. Three different enzymatic components were discriminated and called Ealpha, Ebeta and Egamma. In this work, a fractionation procedure with various steps was developed using protein native separation methods by preparative HPLC. Gel permeation chromatography followed by ion exchange chromatography allowed enriched fractions with different kinetic behaviors. The soluble chicken brain fraction was fractionated, while total esterase activity, proteins and enzymatic components Ealpha, Ebeta and Egamma were monitored in each subfraction. After the analysis, 13 fractions were pooled and conserved. Preincubation of the soluble chicken brain fraction of with the organophosphorus mipafox gave rise to a major change in the ion exchange chromatography profile, but not in the molecular exchanged chromatography profile, which suggest that mipafox permanently modifies the ionic properties of numerous proteins.

Title:

Estevez J, Mangas I, Sogorb MA, Vilanova E

Ref:

203

PubMed

ESTHER: Estevez_2013_Chem.Biol.Interact_203_245
PubMedSearch: Estevez 2013 Chem.Biol.Interact 203 245
PubMedID: 23200747

Abstract

Organophosphorus compounds (OPs) cause neurotoxic disorders through interactions with well-known target esterases, such as acetylcholinesterase and neuropathy target esterase (NTE). However, the OPs can potentially interact with other esterases of unknown significance. Therefore, identifying, characterizing and elucidating the nature and functional significance of the OP-sensitive pool of esterases in the central and peripheral nervous systems need to be investigated. Kinetic models have been developed and applied by considering multi-enzymatic systems, inhibition, spontaneous reactivation, the chemical hydrolysis of the inhibitor and "ongoing inhibition" (inhibition during the substrate reaction time). These models have been applied to discriminate enzymatic components among the esterases in nerve tissues of adult chicken, this being the experimental model for delayed neuropathy and to identify different modes of interactions between OPs and soluble brain esterases. The covalent interaction with the substrate catalytic site has been demonstrated by time-progressive inhibition during ongoing inhibition. The interaction of sequential exposure to an esterase inhibitor has been tested in brain soluble fraction where exposure to one inhibitor at a non inhibitory concentration has been seen to modify sensitivity to further exposure to others. The effect has been suggested to be caused by interaction with sites other than the inhibition site at the substrate catalytic site. This kind of interaction among esterase inhibitors should be considered to study the potentiation/promotion phenomenon, which is observed when some esterase inhibitors enhance the severity of the OP induced neuropathy if they are dosed after a non neuropathic low dose of a neuropathy inducer.

Title:

Mangas I, Vilanova E, Estevez J

Ref:

297

PubMed

ESTHER: Mangas_2012_Toxicology_297_17
PubMedSearch: Mangas 2012 Toxicology 297 17
PubMedID: 22503708

Abstract

Some effects of organophosphorus compounds (OPs) esters cannot be explained by action on currently recognized targets. In this work, we evaluate and characterize the interaction (inhibition, reactivation and "ongoing inhibition") of two model compounds: paraoxon (non-neuropathy-inducer) and mipafox (neuropathy-inducer), with esterases of chicken brain membranes, an animal model, tissue and fractions, where neuropathy target esterase (NTE) was first described and isolated. Four enzymatic components were discriminated. The relative sensitivity of time-progressive inhibition differed for paraoxon and mipafox. The most sensitive component for paraoxon was also the most sensitive component for mipafox (EPalpha: 4.4-8.3% of activity), with I(50) (30 min) of 15-43 nM with paraoxon and 29 nM with mipafox, and it spontaneously reactivated after inhibition with paraoxon. The second most sensitive component to paraoxon (EPbeta: 38.3% of activity) had I(50) (30 min) of 1540 nM, and was practically resistant to mipafox. The third component (EPgamma: 38.6-47.6% of activity) was paraoxon-resistant and sensitive to micromolar concentrations of mipafox; this component meets the operational criteria of being NTE (target of organophosphorus-induced delayed neuropathy). It had I(50) (30 min) of 5.3-6.6 muM with mipafox. The fourth component (EPdelta: 9.8-10.7% of activity) was practically resistant to both inhibitors. Two paraoxon-resistant and mipafox-sensitive esterases were found using the sequential assay removing paraoxon, but only one was paraoxon-resistant and mipafox-sensitive according to the assay without removing paraoxon. We demonstrate that this apparent discrepancy, interpreted as reversible NTE inhibition with paraoxon, is the result of spontaneous reactivation after paraoxon inhibition of a non-NTE component. Some of these esterases' sensitivity to OPs suggests that they may play a role in toxicity in low-level exposure to organophosphate compounds or have a protective effect related with spontaneous reactivation. The kinetic characterization of these components will facilitate further studies for isolation and molecular characterization.

Title:

Mangas I, Vilanova E, Estevez J

Ref:

PubMed

ESTHER: Mangas_2012_Chem.Res.Toxicol_25_2393
PubMedSearch: Mangas 2012 Chem.Res.Toxicol 25 2393
PubMedID: 23009703

Abstract

Phenylmethylsulfonyl fluoride (PMSF) is a protease and esterase inhibitor that causes protection or potentiation/promotion of organophosphorus delayed neuropathy (OPIDN) depending on whether it is dosed before or after an inducer of delayed neuropathy. The molecular target of promotion has not yet been identified. Kinetic data of esterase inhibition were first obtained for PMSF with a soluble chicken brain fraction and then analyzed using a kinetic model with a multienzymatic system in which inhibition occurred with the simultaneous chemical hydrolysis of the inhibitor and ongoing inhibition (inhibition during the substrate reaction). The best fitting model was a model with resistant fraction, Ealpha (28%), and two sensitive enzymatic entities, Ebeta (61%) and Egamma (11%), with I(50) at 20 min of 70 and 447 muM, respectively. The estimated constant of the chemical hydrolysis of PMSF was kh = 0.23 min(-1). Ealpha, which is sensitive to mipafox and resistant to PMSF, became less sensitive to mipafox when the preparation was preincubated with PMSF. Its Ealpha I(50) (30 min) of mipafox increased with the PMSF concentration used to preincubate it. Egamma is sensitive to both PMSF and mipafox, and after preincubation with PMSF, Egamma became less sensitive to mipafox and was totally resistant after preincubation with 10 muM PMSF or more. The sensitivity of Ealpha to paraoxon (I(50) 30 min from 9 to 11 nM) diminished after PMSF preincubation (I(50) 30 min 185 nM) and showed no spontaneous reactivation capacity. The nature of these interactions is unknown but might be due to covalent binding at sites other than the substrate catalytic center. Such interactions should be considered to interpret the potentiation/promotion phenomenon of PMSF and to understand the effects of multiple exposures to chemicals.

Title:

Mangas I, Vilanova E, Estevez J

Ref:

256

PubMed

ESTHER: Mangas_2011_Toxicol.Appl.Pharmacol_256_360
PubMedSearch: Mangas 2011 Toxicol.Appl.Pharmacol 256 360
PubMedID: 21600909

Abstract

Some published studies suggest that low level exposure to organophosphorus esters (OPs) may cause neurological and neurobehavioral effects at long term exposure. These effects cannot be explained by action on known targets. In this work, the interactions (inhibition, spontaneous reactivation and "ongoing inhibition") of two model OPs (paraoxon, non neuropathy-inducer, and mipafox, neuropathy-inducer) with the chicken brain soluble esterases were evaluated. The best-fitting kinetic model with both inhibitors was compatible with three enzymatic components. The amplitudes (proportions) of the components detected with mipafox were similar to those obtained with paraoxon. These observations confirm the consistency of the results and the model applied and may be considered an external validation. The most sensitive component (Ealpha) for paraoxon (11-23% of activity, I(50) (30 min)=9-11 nM) is also the most sensitive for mipafox (I(50) (30 min)=4 nM). This component is spontaneously reactivated after inhibition with paraoxon. The second sensitive component to paraoxon (Ebeta, 71-84% of activity; I(50) (30 min)=1216 nM) is practically resistant to mipafox. The third component (Egamma, 5-8% of activity) is paraoxon resistant and has I(50) (30 min) of 3.4 muM with mipafox, similar to NTE (neuropathy target esterase). The role of these esterases remains unknown. Their high sensitivity suggests that they may either play a role in toxicity in low-level long-term exposure of organophosphate compounds or have a protective effect related with the spontaneous reactivation. They will have to be considered in further metabolic and toxicological studies.

Send your questions or comments to :Mail to: Nicolas Lenfant, Thierry Hotelier, Yves Bourne, Pascale Marchot and Arnaud Chatonnet.Please cite: Lenfant 2013 Nucleic.Acids.Res. or Marchot Chatonnet 2012 Prot.Pept Lett.

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