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PubMedDate not supplied

A structure-activity relationship study of organophosphorus compounds.

Organophosphorus compounds have been shown to exhibit toxic behavior as insecticides, pesticides, and mammalicides. Soman and 21 related compounds were studied for possible structure-activity relationships. Computer-aided methods were used to generate a linear expression relating the activity (ln [1/LD50], rabbit I.V.) of the compounds to three structure-based descriptors (R = 0.96). Principal components regression and jackknife analysis were performed to assess the stability of the model.

Computer Graphics↗
PubMed1994

A comparative study of inhibition of acetylcholinesterase, trypsin, neuropathy target esterase, and spleen cell activation by structurally related organophosphorus compounds.

Organophosphorus (OP) compounds can bind to and inactivate several target molecules other than acetylcholinesterase (AChE). In the present study, five sets of structurally related organophosphorus compounds were used to evaluate the relationships between organophosphorus binding sites of AChE, neuropathy target esterase (NTE), trypsin, and the target molecule(s) involved in inhibition of splenocyte activation by OP compounds. The concentration of each OP compound required to inhibit enzyme activity or splenocyte activation by concanavalin A by 50% was determined. The pattern of IC50 values indicated that AChE, trypsin, NTE, and the molecule(s) involved in inhibition of splenocyte activation are distinct with regard to patterns of inhibition by OP compounds. However, there was a striking similarity in the patterns of inhibition for trypsin and NTE with substantial differences for only 2 of 20 compounds. This pattern suggests similarity in the active sites of these molecules. There were also similarities in the IC50 patterns for lymphocyte activation and trypsin or NTE activity. However, the correlation was not as strong as between NTE and trypsin, and the data suggested the possibility of multiple target molecules for inhibition of splenocyte activation by OP compounds. More importantly, there was essentially no correlation between the pattern of IC50 values for AChE and splenocyte activation. This strongly suggests that acetylcholine and AChE of the type found in the brain are not important in the regulation of splenocyte activation by concanavalin A.

Animals↗
PubMed2003

Neurotoxicity induced in differentiated SK-N-SH-SY5Y human neuroblastoma cells by organophosphorus compounds.

Organophosphorus (OP) compounds used as insecticides and chemical warfare agents are known to cause potent neurotoxic effects in humans and animals. Organophosphorus-induced delayed neuropathy (OPIDN) is currently thought to result from inhibition of neurotoxic esterase (NTE), but the actual molecular and cellular events leading to the development of OPIDN have not been characterized. This investigation examined the effects of OP compounds on the SY5Y human neuroblastoma cells at the cellular level to further characterize cellular targets of OP neurotoxicity. Mipafox and paraoxon were used as OP models that respectively do and do not induce OPIDN. Mipafox (0.05 mM) significantly decreased neurite length in SY5Y cells differentiated with nerve growth factor (NGF) while paraoxon at the same concentration had no effect when evaluated after each of three 4-day developmental windows during which cells were treated daily with OP or vehicle. In contrast, paraoxon but not mipafox altered intracellular calcium ion levels ([Ca(2+)](i)), as seen in three types of experiments. First, immediately following the addition of a single high concentration of OP to the culture, paraoxon caused a transient increase in [Ca(2+)](i), while mipafox up to 2 mM had no effect. Paraoxon hydrolysis products could also increase intracellular Ca(2+) levels, although the pattern of rise was different than it appeared immediately after paraoxon administration. Second, repeated low-level paraoxon treatment (0.05 mM/day for 4 days) decreased basal [Ca(2+)](i) in NGF-differentiated cells, though mipafox had no effect. Third, carbachol, a muscarinic acetylcholine receptor agonist, transiently increased [Ca(2+)](i) in differentiated cells, an affect attenuated by 4-day pretreatment with paraoxon (0.05 mM/day), but not by pretreatment with mipafox. These results indicate that the decrease in neurite extension that resulted from mipafox treatment was not caused by a disruption of Ca(2+) homeostasis. The effects of OPs that cause or do not cause OPIDN were clearly distinguishable, not only by their effects on neurite length, but also by their effects on Ca(2+) homeostasis in differentiated SY5Y cells.

Calcium↗
PubMed2006

Microbial degradation of organophosphorus compounds.

Synthetic organophosphorus compounds are used as pesticides, plasticizers, air fuel ingredients and chemical warfare agents. Organophosphorus compounds are the most widely used insecticides, accounting for an estimated 34% of world-wide insecticide sales. Contamination of soil from pesticides as a result of their bulk handling at the farmyard or following application in the field or accidental release may lead occasionally to contamination of surface and ground water. Several reports suggest that a wide range of water and terrestrial ecosystems may be contaminated with organophosphorus compounds. These compounds possess high mammalian toxicity and it is therefore essential to remove them from the environments. In addition, about 200,000 metric tons of nerve (chemical warfare) agents have to be destroyed world-wide under Chemical Weapons Convention (1993). Bioremediation can offer an efficient and cheap option for decontamination of polluted ecosystems and destruction of nerve agents. The first micro-organism that could degrade organophosphorus compounds was isolated in 1973 and identified as Flavobacterium sp. Since then several bacterial and a few fungal species have been isolated which can degrade a wide range of organophosphorus compounds in liquid cultures and soil systems. The biochemistry of organophosphorus compound degradation by most of the bacteria seems to be identical, in which a structurally similar enzyme called organophosphate hydrolase or phosphotriesterase catalyzes the first step of the degradation. organophosphate hydrolase encoding gene opd (organophosphate degrading) gene has been isolated from geographically different regions and taxonomically different species. This gene has been sequenced, cloned in different organisms, and altered for better activity and stability. Recently, genes with similar function but different sequences have also been isolated and characterized. Engineered microorganisms have been tested for their ability to degrade different organophosphorus pollutants, including nerve agents. In this article, we review and propose pathways for degradation of some organophosphorus compounds by microorganisms. Isolation, characterization, utilization and manipulation of the major detoxifying enzymes and the molecular basis of degradation are discussed. The major achievements and technological advancements towards bioremediation of organophosphorus compounds, limitations of available technologies and future challenge are also discussed.

Bacteria↗
PubMed1975

Chemotherapeutic studies on Litomosoides carinii infection of Mastomys natalensis. 6. The filaricidal activity of organophosphorus compounds.

Several organophosphorus compounds have been evaluated for their efficacy against micro- and macrofilariae in experimental investigations on Litomosoides carinii infection in the multimammate rat Mastomys natalensis. The anthelmintic haloxon proved to be the most effective compound with high activity against microfilariae and a favourable chemotherapeutic range. The organophosphates fenthion, Dursban, metrifonate, coumaphos, crufomate and naphthalophos also showed pronounced microfilaricidal activity but with different and lower chemotherapeutic indices. The preparations chlorfenvinphos, benoxafos, cythioate and imidan proved to be without marked microfilaricidal action at tolerable dose schedules. The organophosphorus compounds did not show any influence on the mobility or viability of the adult worms of Litomosoides carinii.

Animals↗
PubMed2006

Detection of organophosphorus compounds by covalently immobilized organophosphorus hydrolase.

As a consequence of organophosphorus (OP) toxins posing a threat to human life globally, organophosphorus hydrolase (OPH) has become the enzyme of choice to detoxify such compounds. Organophosphorus hydrolase was covalently immobilized onto a quartz substrate for utilization in paraoxon detection. The substrate was cleaned and modified prior to chemical attachment. Each modification step was monitored by imaging ellipsometry as the thickness increased with each modification step. The chemically attached OPH was labeled with a fluorescent dye (7-isothiocyanato-4-methylcoumarin) for the detection of paraoxon in aqueous solution, ranging from 10(-9) to 10(-5) M. UV-visible spectra were also acquired for the determination of the hydrolysis product of para-oxon, namely p-nitrophenol.

Aryldialkylphosphatase↗
PubMed2004

Membrane-assisted solvent extraction of triazines, organochlorine, and organophosphorus compounds in complex samples combined with large-volume injection-gas chromatography/mass spectrometric detection.

The performance of the fully automated membrane-assisted solvent extraction was investigated for 47 environmental contaminants (among them 30 organochlorine compounds, 9 organophosphorus compounds, and 7 triazines). The extraction took place in a 20-mL headspace vial filled with the aqueous sample and containing a polypropylene membrane bag with 1 mL of cyclohexane as extractant. This device was handled by a multipurpose sampler, which enabled the sample to be mixed at a defined temperature with subsequent large-volume injection of the organic extract taken out of the membrane bag. After optimization of extraction parameters, the method was validated for the three compound classes, triazines and organochlorine and organophosphorus compounds, using spiked distilled water. Then, the extraction yield of these analytes from several complex samples such as a natural and a synthetic wastewater, a bacterial culture, and orange juice was determined and compared to a conventional liquid-liquid extraction. Furthermore, the possibility of reducing matrix interference by adding salt, methanol, or detergent during membrane-assisted solvent extraction was investigated.

Gas Chromatography-Mass Spectrometry↗
PubMed1987

Comparative sensitivities of avian neural esterases to in vitro inhibition by organophosphorus compounds.

The inhibitory power of organophosphorus compounds in vitro was compared against neurotoxic esterase (also known as neuropathy target esterase, NTE), acetylcholinesterase and carboxylesterase activities in brains from chickens, turkeys, quail and rats. Brains from the species most susceptible to clinical signs of organophosphorus-induced delayed neuropathy (chicken, turkey) contained more NTE than did rat and quail. Higher concentrations of organophosphorus compounds were required to inhibit rat NTE and quail acetylcholinesterase than were necessary for inhibition of these enzymes in chicken and turkey brains. Total carboxylesterase and acetylcholinesterase activities were less in rats than in the avian species.

Animals↗
PubMed1999

The role of phosphotriesterases in the detoxication of organophosphorus compounds.

The enzymes that hydrolyze organophosphorus compounds are called phosphotriesterases. The presence of phosphotriesterases has been described in a variety of tissues. The physiological role of these enzymes is not known, although a clear correlation exists between the levels of phosphotriesterases and susceptibility of the species to the toxic effects of organophosphorus compounds. Thus, mammals that possess high levels of phosphotriesterases in serum and liver are more tolerant to the toxic effects of these compounds than birds and insects - these being species considered lacking of phosphotriesterases. Because most of these enzymes are not well characterized, they are usually differentiated according to their different patterns of response to activators and/ or inhibitors. Phosphotriesterases usually depend of divalent cations and therefore EDTA usually inhibits them. A peculiar EDTA-resistant phosphotriesterase has been described in serum albumin. The biotechnological and therapeutical applications of phosphotriesterases are currently subject to study.

Animals↗
PubMed1987

Organophosphorus compounds. II. Metabolic considerations.

Organophosphorus compounds are esters of alcohols with phosphoric acids or anhydrides of phosphoric acids with some other acids. The most important groups are the phosphates, phosphorothionates, phosphorothioates, phosphoroamidates, phosphorochloridate and phosphonates. The metabolism of phosphorothionates and phosphorothioates involves initial activation (oxidative desulphuration) followed by hydrolysis of the active metabolites. Activation is carried out by the action of microsomal oxidases, and degradation is performed by different types of hepatic and plasma esterases.

Animals↗
PubMed1984

Spontaneous reactivation of mouse plasma cholinesterase after inhibition by various organophosphorus compounds.

We investigated the spontaneous reactivation of mouse plasma cholinesterase (ChE) after inhibition by various organophosphorus compounds. The remarkable spontaneous reactivations during storage at 24 degrees C were observed in plasma ChE prepared 30 min after oral administration of three O,O-dimethyl organophosphorus compounds, i.e. malathion, methylparathion and cyanox; while the spontaneous reactivation did not occur after inhibition by tolclofos-methyl, one of O,O-dimethyl organophosphorus compounds. The plasma ChEs inhibited by surecide, salithion and leptophos, which contain no O,O-dimethyl moiety, were not reactivated or only slightly so. These results suggest that a more sufficient attention should be paid in the determination of activity of plasma ChE inhibited by O,O-dimethyl organophosphorus compounds than that of plasma ChE inhibited by organophosphorus compounds without O,O-dimethyl moiety, since plasma ChE inhibited by the organophosphorus compounds with O,O-dimethyl moiety, except for tolclofos-methyl, was more easily reactivated, and the correct activity of inhibited plasma ChE can not be obtained without attention to the spontaneous reactivation. Furthermore, these spontaneous reactivations were examined by using butyrylthiocholine as well as acetylthiocholine as a substrate, and results showed that there was little difference between the spontaneous reactivations observed in using acetylthiocholine and butyrylthiocholine. So, it is concluded that these spontaneous reactivations take place only in pseudo ChE.

Animals↗
PubMed1971

Toxic effects produced in insects by organophosphorus compounds.

This paper reviews the toxicity of organophosphorus compounds in relation to cholinesterase inhibition in insects. It covers anticholinesterase effects on different stages of the life cycle and the relationship between cholinesterase inhibition and lethality. Other effects of organophosphorus compounds, which may account for anomalies in insecticidal action, are also considered.

Animals↗
PubMed1971

Side effects of organophosphorus compounds: delayed neurotoxicity.

Many organophosphorus compounds produce a chronic toxicity that has been classified as a dying-back process in which the long axons are particularly affected. Recent evidence indicates that an essential first step in the production of the lesion is the phosphorylation of a protein that is able to hydrolyse substrates such as phenyl phenylacetate. The esterase activity of the protein is inhibited by this phosphorylation, presumably at the active site. However, the toxic effect is related only to phosphorylation and not to loss of esterase activity.

Animals↗
PubMed1960

The relationship between the chemical structure and neurotoxicity of alkyl organophosphorus compounds.

Thirty-six alkyl organophosphorus compounds have been tested for neurotoxicity in the chicken. The individual compounds were chosen to enable the importance of each portion of the molecule to be assessed in relation to the property of neurotoxicity. Seventeen substances were found to be neurotoxic, fifteen for the first time. All of these contained fluorine. On the basis of the results reported, certain predictions have been made about the chemical structure of compounds which would be expected to be neurotoxic. The importance of fluorine suggests that it plays a direct role in the development of the biochemical lesion, and this may occur as the result of its being carried by the molecule as a whole to specific areas in the nervous system. By the action of cholinesterase, the P-F bond may be ruptured and ionic fluorine liberated where it blocks some metabolic cycle.

Animals↗
PubMed2003

Optical biosensor for simultaneous detection of captan and organophosphorus compounds.

The optical biosensor consisting of GST and acetylcholinesterase (AChE)-immobilized gel film was developed to detect captan and organophosphorus compounds simultaneously in contaminated water. The sensing scheme was based on the measurement of decrease of products formation (s-(2,4-dinitrobenzene) glutathione and alpha-naphthol by GST and AChE, respectively) due to the inhibition by captan and organophosphorus compounds. The absorbance of s-(2,4-dinitrobenzene) glutathione and alpha-naphthol was detected at 400 and 500 nm, respectively, by a proposed optical biosensor system. It was observed that AChE was inhibited by both captan and organophosphorus compounds, and GST was inhibited only by captan. The simultaneous detection and quantification of captan and organophosphorus compounds could be successfully achieved by the proposed sensor system. The proposed biosensor could successfully detect the captan and organophosphorus compounds concentration from 0 to 2 ppm.

Acetylcholinesterase↗
PubMed2004

[Neuroimmunomodulatory effect of highly toxic organophosphorus compound on the development of Trichinella spiralis infection].

The highly toxic organophosphorus compound (isopropylmethylphosphonofluoridate--IMPF) belonging to the group of the so called toxic of warfare agents can impair immune effector mechanisms determining the development of parasitic infection. Preliminary studies have demonstrated that IMPF delays elimination of adults Trichinella spiralis forms from the intestine of C57B1/6 mice and B6C3F1 hybrids. Besides, the studied compound modifies the proliferative activity of T-cells in the above mentioned mice and reduces the production of anti-SRBC antibodies in C57B1/6 strain. The mechanisms are discussed of the organophosphorus compound effect on neuroimmunological processes connected with antiparasitic immunity, paying attention also to the function of these processes by the parasitic infection itself, in host-parasite relationship. The probability is also considered of increased sensitivity to Leishmania infection in humans poisoned with IMPF and/or other organophosphorus compounds.

Animals↗
PubMed1996

Effect of activated charcoal and atropine on absorption and/or exsorption of organophosphorus compounds in rats.

Effects of activated charcoal and atropine for the removal of organophosphorus compounds, which remain in the gastrointestinal tract or have already been absorbed into the systemic circulation, were investigated in rats. Activated charcoal extensively adsorbed the organophosphates fenitrothion, tolelofos methyl, piperophos and salithion, and its immediate administration after oral ingestion of fenitrothion remarkably reduced serum fenitrothion levels, but had no effect on the serum levels of the compound which had been absorbed from the gastrointestinal tract. Thus, all of the organophosphorus compounds were poorly exsorbed (0.002-0.39% of the dose in 120 min) from the blood into the intestinal lumen probably due to their extensive protein binding and large distribution volumes. Atropine inhibited absorption of fenitrothion in the perfusion in-situ and also delayed the absorption of the compound in-vivo, but had no significant effect on exsorption of fenitrothion. The serum fenitrothion levels on treatment with both atropine and charcoal significantly decreased compared with those of the control. We conclude that, oral activated charcoal will not be able to enhance the elimination of organophosphorus compounds which have already been absorbed into the systemic circulation, but constituted useful method for the removal of the compounds remaining in the gastrointestinal tract because of its excellent adsorptive capacity.

Animals↗
PubMed1997

Identification of the contents and the shelf-life of indicator tubes from field kits for detection of organophosphorus compounds in the air.

Indicator tubes from field kits for detection of organophosphorus compounds in the air were found on the territory of Croatia, in barracks liberated during the war years of 1991/1992, and were analysed during 1993/95. The detection kit consisted of glass indicator tubes with two sealed vials within each tube, a device for opening the tubes and breaking the vials, and an air sampling pump. The tubes were marked with serial numbers and expiry dates (1974-1992), but the description as to their contents was unavailable. The aim of this study was to identify the contents of the indicator tubes and to establish whether they were still suitable for detection of organophosphorus compounds. One vial was found to contain a cholinesterase (EC 3.1.1.7) preparation, while the other vial contained a non-thiocholine substrate and a pH-sensitive indicator (most probably cresol red). Applying DDVP as an organophosphorus cholinesterase inhibitor, it was found that all sets of indicator tubes were suitable for use regardless of the indicated expiry dates. Furthermore, the same tubes were found suitable for detection of organophosphorus compounds in water.

Air↗