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PubMedDate not supplied

Enzymes hydrolyzing organophosphates as potential catalytic scavengers against organophosphate poisoning.

Enzymes hydrolyzing organophosphates could be used as catalytic scavengers for treatment of organophosphate poisoning and for decontamination. Two organophosphorus hydrolases (OPH) were selected: the Flavobacterium sp/Pseudomonas diminuta phosphotriesterase (PTE) and human paraoxonase (HuPON). Genes encoding these enzymes were cloned and functional recombinant enzymes expressed. PTE was expressed in E. coli. Natural HuPON was purified from human plasma; recombinant HuPON was expressed in human embryonic kidney 293 T cells. Although HuPON displays interesting catalytic properties, a site-directed mutagenesis program was undertaken to improve its catalytic efficiency. PTE has high efficiency in hydrolysis of organophosphates, including nerve agents. PTE injected in rat has a half-life of 100 min. However, to overcome pharmacokinetic problems of injected OPH and/or immunological incompatibility, the model enzyme (recombinant PTE) was immobilized onto a hollow-fiber reactor. This reactor designed for extracorporeal blood circulation is under experimentation for post-exposure detoxification.

Animals↗
PubMed2004

Organophosphates, serine esterase inhibition, and modeling of organophosphate toxicity.

The highlighted article in this issue (Ashani and Pistinner, "Estimation of the Upper Limit of Human Butyrylcholinesterase Dose Required for Protection against Organophosphates toxicity: A Mathematically Based Toxicokinetic Model") is an innovative approach to modeling the amount of protective enzyme, human butyrylcholinesterase, that could be administered to humans to protect them from the lethal effects of organophosphate nerve agents. The threat of nerve agent exposures at lethal level regrettably remains a threat to military as well civilian populations, and the authors of this article have used their previous experimental data along with new in vitro data to devise and calibrate a mathematical model that could have practical utility in the prophylaxis of military personnel against chemical warfare agents.

Animals↗
PubMed2002

[Study on monitoring and clearing of organophosphate in blood in organophosphate poisoned rats].

OBJECTIVE: To study the new method of monitoring and clearing organophosphate in blood during single or mixed organophosphate(OP) poisoning. METHOD: (1) Mixed equal volumes of blood of OP poisoned rat and healthy rat, then determine whole blood cholinesterase (ChE) activity. The descending range of ChE activity represents the level of residual OP in blood. (2) Poisoned rats by single or mixed OP pesticides were injected with 5% NaHCO3 15 ml/kg intraperitoneally, then the level of OP in blood was detected. RESULTS: (1) The monitoring results of blood residual OP by gas chromatography were similar to that by "Mixes blood method", which showed significant difference(P < 0.05) from that before OP administration. (2) NaHCO3 injection could not improve the toxic symptoms and whole blood or brain ChE inhibition in 10 CP poisoned rats, blood residual OP level was also not affected, but lung pathological changes by OP such as interstitial inflammation and oedema showed some relief. CONCLUSION: The monitoring of blood ChE by "mixed blood method" may reflect the general level of the blood residual OP within the range of exposure dose. The effect of NaHCO3 was not satisfactory, but it may improve OP-induced lung pathological changes.

Animals↗
PubMed1999

Development of sensors for direct detection of organophosphates. Part I: Immobilization, characterization and stabilization of acetylcholinesterase and organophosphate hydrolase on silica supports.

Biosensors for organophosphates in solution may be constructed by monitoring the activity of acetylcholinesterase (AChE) or organophosphate hydrolase (OPH) immobilized to a variety of microsensor platforms. The area available for enzyme immobilization is small (< 1 mm2) for microsensors. In order to construct microsensors with increased surface area for enzyme immobilization, we used a sol-gel process to create highly porous and stable silica matrices. Surface porosity of sol-gel coated surfaces was characterized using scanning electron microscopy; pore structure was found to be very similar to that of commercially available porous silica supports. Based upon this analysis, porous and non-porous silica beads were used as model substrates of sol-gel coated and uncoated sensor surfaces. Two different covalent chemistries were used to immobilize AChE and OPH to these porous and non-porous silica beads. The first chemistry used amine-silanization of silica followed by enzyme attachment using the homobifunctional linker glutaraldehyde. The second chemistry used sulfhydryl-silanization followed by enzyme attachment using the heterobifunctional linker N-gamma-maleimidobutyryloxy succinimide ester (GMBS). Surfaces were characterized in terms of total enzyme immobilized, total and specific enzyme activity, and long term stability of enzyme activity. Amine derivitization followed by glutaraldehyde linking yielded supports with greater amounts of immobilized enzyme and activity. Use of porous supports not only yielded greater amounts of immobilized enzyme and activity, but also significantly improved long term stability of enzyme activity. Enzyme was also immobilized to sol-gel coated glass slides. The mass of immobilized enzyme increased linearly with thickness of coating. However, immobilized enzyme activity saturated at a porous silica thickness of approximately 800 nm.

Acetylcholinesterase↗
PubMed2002

Analysis of the sequence and expression of a second putative acetylcholinesterase cDNA from organophosphate-susceptible and organophosphate-resistant cattle ticks.

The cattle tick, Boophilus microplus, is a major pest of cattle in Australia, Central and South America, and parts of Africa and Asia. Control of ticks with organophosphates (OPs) and carbamates, which target acetylcholinesterases (AChE), led to evolution of resistance to these pesticides. Alleles at the locus studied here, AChE2, from OP-susceptible female ticks from Australia and Mexico differed at 46 of 1689 nucleotide positions (20 putative amino acid differences) whereas alleles from three strains of OP-resistant ticks from Australia differed with the allele from the Australian susceptible ticks at six to 13 nucleotide positions (three to six putative amino acid differences). However, the role, if any, of these polymorphisms in the OP-resistance phenotype is unknown. Certainly none of the polymorphisms correspond to sites in AChE that are involved in catalysis or binding of acetylcholine in other organisms. Both of the AChE loci of B. microplus, AChE1 and AChE2, are apparently expressed in synganglia; AChE1 is also expressed in salivary glands and ovaries, in OP-susceptible and OP-resistant ticks. This seems to contradict studies of enzyme kinetics, which indicated that only one form of AChE was present in the synganglia, the site of the action of OPs, in this species of tick.

Acetylcholinesterase↗
PubMed2006

Asymmetric fluorogenic organophosphates for the development of active organophosphate hydrolases with reversed stereoselectivity.

In order to enhance the enzymatic detoxification rate of organophosphorus (OP) nerve agents we have searched for more active variants of recombinant mammalian paraoxonase (PON1). We have previously identified three key positions in PON1 that affect OP hydrolysis: Leu69, Val346 and His115, that significantly enhance the hydrolysis of cyclosarin (GF), soman, chlorpyrifos-oxon (ChPo), O-isopropyl-O-(p-nitrophenyl)methylphosphonate (IMP-pNP) and diisopropyl fluorophosphate (DFP). GC/FPD analysis compared to residual AChE inhibition assay displayed stereoselective hydrolysis of GF, soman and IMP-pNP, indicating that wild type PON1 and its variant V346A are more active toward the less toxic P(+) optical isomer. In order to obtain new PON1 variants with reversed stereoselectivity, displaying augmented activity toward the more toxic isomer P(-) of nerve agents, we synthesized new asymmetric fluorogenic OPs (Flu-OPs). Six Flu-OPs were prepared containing either ethyl (E), cyclohexyl (C) or pinacolyl (P) alkyl radicals attached to methyl-phosphonyl (MP) moiety analogous to the structure of VX, GF and soman, respectively. The fluorescent moieties are either 3-cyano-4-methyl-7-hydroxy coumarin (MeCyC) or 1,3-dichloro-7-hydroxy-9,9-dimethyl-9H-acridin-2-one (DDAO). The kinetics of AChE and BChE inhibition by these new Flu-OPs display k(i) values 8.5x10(4) to 8.5x10(7) and 5x10(4) to 2x10(6)M(-1)min(-1), respectively. EMP-MeCyC and EMP-DDAO are the most active inhibitors of AChE whereas CMP-MeCyC and CMP-DDAO are better inhibitors of BChE than AChE, indicating accommodation of bulky cyclohexyl group inside the active site of BChE. PMP-MeCyC and PMP-DDAO are the least active inhibitors of both AChE and BChE. CMP-MeCyC and CMP-DDAO were significantly detoxified only by the five-site mutations PON1 variant L69V/S138L/S193P/N287D/V346A. Degradation kinetics of Flu-OPs measured by increase in absorbance of the released fluorogenic group was fit by a two exponential function, indicating faster hydrolysis of the less toxic optical isomer. Interestingly, wt PON1 caused only 50% degradation of racemic EMP-MeCyC, CMP-MeCyC and CMP-DDAO indicating complete hydrolysis of P(+) isomer. This remarkable stereoselectivity was used for the enzymatic separation of the P(-) isomer of CMP-MeCyC. The bimolecular rate constant k(i) for human AChE inhibition by the isolated P(-) isomer of CMP-MeCyC is five-fold larger than that of its P(+) isomer. The marked preference of wt PON1 toward P(+) stereo-isomer of CMP-MeCyC and CMP-DDAO renders their P(-) stereo-isomers suitable for the selection of new OP hydrolase variants with reversed stereoselectivity.

Acetylcholinesterase↗
PubMed2003

Sources of exposure to and public health implications of organophosphate pesticides.

OBJECTIVE: To review the public health significance of organophosphate pesticide exposure in the United States of America. Since the situation of high organophosphate pesticide exposure and the concomitant health risks in the developing countries of the world is well known, this article seeks to highlight the public health significance of organophosphate exposure in the United States, where it is less common than in many other nations. Looking at the situation in the United States would serve to further emphasize the seriousness of organophosphate pesticide-related health issues in developing countries. METHODS: A search for journal articles on organophosphate pesticides and organophosphate exposure was done on the PubMed electronic bibliographic database system of the National Library of Medicine of the United States. To supplement that search, information on organophosphate toxicity, biological monitoring, and regulation of pesticides was obtained from other published articles, textbooks, and relevant Internet sites. RESULTS: Organophosphate pesticides are a group of chemicals that are mainly used in agriculture. Organophosphates inhibit the activity of both the cholinesterase (ChE) enzymes-red blood cell (RBC) ChE and serum ChE-resulting in the cholinergic features of organophosphate toxicity. A 50% reduction in serum ChE activity from the baseline is an indication of acute organophosphate toxicity. The RBC ChE activity, which is less rapidly depressed than the serum ChE activity, is a measure of chronic exposure to organophosphates. Exposures to organophosphates are broadly classified into two categories: occupational and environmental. Occupational exposures occur among agricultural workers (including migrant farmworkers), industrial workers, pest control exterminators, and other workers. Nonoccupational exposure affects a large segment of the general population in the United States. Residential exposures come from organophosphate pesticide use by exterminators and by household residents as well as from dietary and accidental exposures. Other environmental exposures occur in public places and areas close to farms, and exposures could also happen from organophosphate use in chemical warfare or terrorism. In the United States some organophosphate pesticides are restricted by the Environmental Protection Agency in order to protect humans, animals, and the environment. In addition, the Food Quality Protection Act regulates dietary exposure to pesticides, particularly for infants and children. CONCLUSIONS: Organophosphate pesticides continue to pose a risk to human health in the United States. Biological monitoring should be used to strictly regulate occupational exposures to organophosphates and thus protect the health and safety of workers. Among the public there should be an increased awareness of environmental exposure to organophosphates as well as of the threat of chemical warfare or terrorism.

Cholinesterases↗
PubMed2002

Negative correlations between resistance to three organophosphate insecticides and productivity within a natural population of Drosophila melanogaster (Diptera: Drosophilidae).

To investigate the relationship between resistance to organophosphate insecticides and fitness components, we first measured resistance to three organophosphates, malathion, prothiophos, and fenitrothion, and productivity, a measure of fitness components, for each of the isofemale lines from the same natural population of Drosophila melanogaster (Meigen). Pearson correlation coefficients indicated that positive correlations among resistance to the organophosphates and negative correlations between resistance to each of the organophosphates and the productivity existed within the natural population. We further investigated the genetic basis of the correlations among resistance to the organophosphates and the productivity, by using chromosome-substituted lines between a resistant and a susceptible inbred line established from the same natural population. Chromosomal analyses indicated that the third chromosome from the resistant line exhibited not only significant, positive effects on resistance to all of the organophosphates tested but also a significant negative effect on the productivity, suggesting positive genetic correlations between resistance to each organophosphate and negative genetic correlations between resistance to each organophosphate and the productivity. In addition, a significant negative effect on the productivity was also detected from the second chromosome, which did not exhibit significant major effects on resistance to the organophosphates. This suggests that fitness components of resistant lines could be also affected by factors independent of insecticide resistance. The dynamics of genetic variation in resistance to the organophosphates within the natural population of D. melanogaster are discussed from the standpoint of negative genetic correlations between resistance to the organophosphates and the productivity.

Animals↗
PubMed1988

Effects of organophosphates and nerve growth factor on muscarinic receptor binding number in rat pheochromocytoma PC12 cells.

Muscarinic receptor binding in PC12 cells is influenced by both nerve growth factor (NGF) and organophosphates. Treatment of PC12 cells with a single dose of NGF (50 ng, 7S NGF/ml) increased [3H]N-methylscopolamine ([3H]-NMS) binding sites approximately two-fold at 48 hr but did not change the Kd for this ligand. Exposure of PC12 cells to soman, 50 microM, decreased [3H]-NMS binding in both undifferentiated and NGF-treated cells; however, decreases in muscarinic binding induced by the organophosphate were only minimal after the first hour after treatment and were maximal at about 24 hr. Other organophosphates including sarin, tabun, and VX as well as the carbamate, pyridostigmine, also reduced [3H]-NMS binding in PC12 cells measured 24-48 hr after treatment. The order of potency of organophosphates in lowering [3H]-NMS binding was soman greater than sarin greater than VX greater than tabun greater than DFP. High amounts of VX (200 microM) but not the other organophosphates inhibited [3H]-NMS binding when added to cells during the course of binding assays. Decreases in muscarinic receptor binding induced by the organophosphates differed markedly from that produced by carbamylcholine, which decreased [3H]-NMS binding maximally 30 min after addition to the cells. Decreases in [3H]-NMS binding produced by carbamylcholine were antagonized by atropine, but reductions in muscarinic binding produced by the organophosphates were not reversed by atropine. Thus, decreases in muscarinic receptor binding induced in PC12 cells by organophosphates occur via a novel mechanism that does not involve agonist-induced receptor desensitization.

Animals↗
PubMed1987

Action of organophosphates on GABAA receptor and voltage-dependent chloride channels.

The effects of several organophosphates were studied on the binding of t-[35S]butyl-bicyclophosphorothionate ([35S]TBPS) to rat brain GABAA receptor and receptor function as assayed by GABA-induced 36Cl-influx into membrane vesicles and on the binding of [35S]TBPS to a voltage-dependent Cl-channel in Torpedo californica electric organ. The organophosphate anticholinesterases diisopropylphosphorofluoridate, soman, sarin, tabun, and VX had little or no effect on GABA-regulated chloride channels. They also had no effect on [35S]TBPS binding to the voltage-dependent chloride channel, except for soman which inhibited it with an IC50 of 24 microM. Triphenyl phosphate was the only one of three organophosphate flame retardants tested that inhibited both GABA-regulated chloride channel and binding of [35S]TBPS to the voltage-dependent chloride channel with IC50s of 18 and 13 microM, respectively. The industrial organophosphate tri-o-cresyl phosphate and the anticholinesterase organophosphate insecticides leptophos, leptophos oxon, and O-ethyl O-4-nitrophenyl phenylphosphonothioate inhibited GABA-regulated chloride channels and bound with high affinity to the voltage-dependent chloride channels (IC50 = 0.3 to 8.7 microM). There was no apparent correlation between the affinities of the GABAA receptor chloride channel or the voltage-dependent chloride channel for the different organophosphates and their potencies in inhibiting acetylcholinesterase or in inducing delayed neurotoxicity. Nevertheless, although the voltage-dependent chloride channel and/or GABAA receptor are not primary targets for organophosphate anticholinesterases and flame retardants, it is suggested that the inhibition of these two proteins by certain organophosphates may contribute to their toxicities.

Animals↗
PubMed2000

Occupational exposure limits for 30 organophosphate pesticides based on inhibition of red blood cell acetylcholinesterase.

Toxicity and other relevant data for 30 organophosphate pesticides were evaluated to suggest inhalation occupational exposure limits (OELs), and to support development of a risk assessment strategy for organophosphates in general. Specifically, the value of relative potency analysis and the predictability of inhalation OELs by acute toxicity measures and by repeated oral exposure NOELs was assessed. Suggested OELs are based on the prevention of red blood cell (RBC) acetylcholinesterase (AChE) inhibition and are derived using a weight-of-evidence risk assessment approach. Suggested OEL values range from 0.002 to 2 mg/m(3), and in most cases, are less than current permissible exposure levels (PELs) or threshold limit values(R) (TLVs(R)). The available data indicate that experimental data for most organophosphates evaluated are limited; most organophosphates are equally potent RBC AChE inhibitors in different mammalian species; NOELs from repeated exposure studies of variable duration are usually equivalent; and, no particular grouping based on organophosphate structure is consistently more potent than another. Further, relative potency analyses have limited usefulness in the risk assessment of organophosphates. The data also indicated that equivalent relative potency relationships do not exist across either exposure duration (acute vs. repeated) or exposure route (oral vs. inhalation). Consideration of all variable duration and exposure route studies are therefore usually desirable in the development of an OEL, especially when data are limited. Also, neither acute measures of toxicity nor repeated oral exposure NOELs are predictive of weight-of-evidence based inhalation OELs. These deviations from what is expected based on the common mechanism of action for organophosphates across exposure duration and route - AChE inhibition - is likely due to the lack of synchrony between the timing of target tissue effective dose and the experimental observation of equivalent response. Thus, comprehensive interpretation of all toxicity data in the context of available toxicokinetic, toxicodynamic and exposure information for each individual organophosphate in a weight-of-evidence based risk assessment is desirable when deriving inhalation OELs.

Animals↗
PubMed1997

Pralidoxime continuous infusion in the treatment of organophosphate poisoning.

OBJECTIVE: To report a case of organophosphate poisoning treated with a continuous infusion of pralidoxime chloride. CASE SUMMARY: A 27-year-old white man presented with extreme agitation, muscle weakness and fasciculations, and respiratory failure after ingesting an organophosphate pesticide (Dursban, active ingredients chlorpyrifos and xylene) as a suicide attempt. Atropine sulfate and pralidoxime chloride were administered intermittently, but the patient continued to be extremely agitated and have muscle fasciculations. Subsequently, a continuous intravenous infusion of pralidoxime (8 mg/mL concentration) at 500 mg/h was initiated to help control breakthrough nicotinic symptoms. Therapy with atropine and pralidoxime was continued for approximately 72 hours. Therapy was discontinued due to the predominance of anticholinergic symptoms and the patient's increased awareness. DISCUSSION: Severe organophosphate poisoning with nicotinic and/or central manifestations should be treated with pralidoxime in addition to atropine. The rationale supporting the use of pralidoxime as a continuous infusion in this case includes: (1) slow absorption of organophosphate compounds following exposure to large quantities, (2) unknown quantity ingested, (3) delayed nicotinic effects from redistribution of lipid-soluble organophosphate and metabolic activation of phosphorothioates such as chlorpyrifos, and (4) intensive care monitoring. There is limited documentation in the literature of continuous infusions of pralidoxime used to treat organophosphate poisoning and the stability of the admixture is unknown. CONCLUSIONS: A continuous pralidoxime infusion successfully managed the prolonged nicotinic symptoms seen after ingestion of an organophosphate. A continuous infusion of pralidoxime may be particularly useful in cases of organophosphate poisoning when the extent of chemical exposure or quantity of chemical ingested is unknown but potentially toxic and the therapy must be symptomatically managed.

Adult↗
PubMed2006

Seasonal fluctuation in susceptibility to insecticides within natural populations of Drosophila melanogaster. II. Features of genetic variation in susceptibility to organophosphate insecticides within natural populations of D. melanogaster.

To elucidate genetic variation in susceptibility to organophosphate insecticides within natural populations of Drosophila melanogaster, we conducted an analysis of variance for mortality data sets of isofemale lines (10-286 lines) used in the previous studies. Susceptibility of isofemale lines to the three organophosphate insecticides was continuously distributed within each natural population, ranging from susceptible to resistant. Analysis of variance showed highly significant variation among isofemale lines in susceptibility to each insecticide for each natural population. Significant genetic variances in susceptibility to the three chemicals were estimated for the Katsunuma population; 0.0529-0.2722 for malathion, 0.0492-0.1603 for prothiophos, and 0.0469-0.1696 for fenitrothion. Contrary to the consistent seasonal tendency towards an increase in mean susceptibility in the fall, reported in the previous study, genetic variances in susceptibility to the three organophosphates did not change significantly in 1997 but tended to increase by 2- to 5-times in 1998. We tested whether both the observed situations, maintenance and increase in genetic variance in organophosphate resistance, can be generated under circumstances in which the levels of resistance to the three organophosphates tended to decrease, by conducting a simulation analysis, based on the hypothesis that resistant genotypes have lower fitnesses than susceptible ones under the density-independent condition. The simulation analysis generally explained the pattern in the mean susceptibility and genetic variances in susceptibility to the three organophosphates, observed in the Katsunuma population of D. melanogaster. It was suggested that the differences in the frequencies of resistance genes in the summer population could affect the patterns in genetic variance in organophosphate resistance in the fall population.

Animals↗
PubMedDate not supplied

Effects of organophosphates on the visual system of rats.

The possibility that exposure to organophosphate insecticides can lead to ocular damage is suggested by Japanese studies from the 1960s and 1970s indicating that exposed humans developed chronic ocular degeneration, in addition to showing more commonly accepted effects of cholinesterase-inhibiting compounds. Other papers reported ocular lesions in laboratory animals treated with organophosphates. More recently, retinal degeneration following chronic organophosphate treatment has been reported to the Environmental Protection Agency by pesticide manufacturers in studies conducted in compliance with good laboratory practice regulations. Several factors, however, have prompted scepticism regarding organophosphate-induced ocular toxicity, including the widespread use of organophosphate compounds for both agricultural and ophthalmological practices without numerous additional reports of comparable ocular toxicity. We are developing a research program to address these issues involving electrophysiological, biochemical and histological investigations of rats treated with organophosphate insecticides. The research program is young, but early results are available. Notably, retinas from rats treated with a single subcutaneous injection of 100 mg kg-1 fenthion showed decreases in carbachol-stimulated release of inositol phosphate, an indicator of cholinergically-mediated intracellular second messenger systems. These effects persisted at least 56 days after fenthion administration. This could indicate several different toxicological actions, which are currently under investigation. It is concluded that the possible association between exposure to organophosphates and ocular toxicity cannot be dismissed, and that several important research issues need to be resolved.

Animals↗