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PubMed1989

Regional brain cholinesterase activity in rats injected intraperitoneally with anatoxin-a(s) or paraoxon.

Adult male Long-Evans rats were injected intraperitoneally with 1.5, 3.0 or 9.0 micrograms/kg of anatoxin-a(s) that had been extracted from laboratory-grown Anabaena flos-aquae NRC-525-17, 800 micrograms/kg of paraoxon, or a control solution. Blood, anterior spinal cord, and brain cerebellar, cortical, medullary, midbrain, hippocampal, hypothalamic, olfactory and striatal cholinesterase activity was determined in rats that died prior to 2 hours or were anesthetized and killed at 2 hours. Unlike paraoxon, anatoxin-a(s) did not cause detectable inhibition of cholinesterase in the central nervous system, but did cause inhibition of cholinesterase in blood, suggesting that anatoxin-a(s) is strictly a peripheral cholinesterase inhibitor.

Animals↗

PubMed2005

Cholinesterase inhibition and impacts on behavior of the Asian clam, Corbicula fluminea, after exposure to an organophosphate insecticide.

This study assessed the effects of exposure to an insecticide formulation containing the organophosphate, chlorpyrifos on cholinesterase activity, siphoning and burrowing ability in the Asian clam, Corbicula fluminea. Clams were exposed to concentrations of the pesticide ranging from 0.05 to 50 mg/L (as chlorpyrifos) in a series of 96-h static bioassays. Those organisms exposed to pesticide concentrations at or above 3.13 mg/L avoided exposure through valve closure during the 96-h test period, with no resultant effects on cholinesterase activity or behavior. Similarly, no effect was observed at low-test concentrations ranging from 0.05 to 0.1 mg/L, even though clams actively siphoned in these treatments. Asian clams exposed to the mid-range of concentrations, 0.5-1.0 mg/L, experienced a significant reduction in cholinesterase activity and a reduced capacity to burrow into the substrate. While these data indicate that cholinesterase activity in C. fluminea could be used as a biomarker of organophosphorous pesticide exposure, valve closure can clearly influence exposure profiles and biomarker response.

Analysis of Variance↗

PubMed2005

The diacylglycerol lipase inhibitor RHC-80267 potentiates the relaxation to acetylcholine in rat mesenteric artery by anti-cholinesterase action.

The diacylglycerol lipase inhibitor 1,6-bis(cyclohexyloximinocarbonylamino) hexane (RHC-80267) was tested for its effect on acetylcholine-evoked relaxation in rat mesenteric artery. In artery contracted with either noradrenaline or KCl, RHC-80267 (0.1-10 muM) potentiated the relaxation evoked by acetylcholine. The effect of RHC-80267 was not affected by nitric oxide synthase inhibition or by inhibitors of protein kinase C or of phospholipase A(2). The diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol did not change the relaxation to acetylcholine. RHC-80267 did not affect the relaxation evoked by carbachol, by the nitric oxide donor SNAP (S-nitroso-N-acetylpenicillamine) or by the K(+) channel opener cromakalim. Neostigmine, a cholinesterase inhibitor, produced the same effect as RHC-80267 on acetylcholine-evoked relaxation. When tested on cholinesterase in brain homogenate, RHC-80267 concentration-dependently inhibited cholinesterase activity with an IC(50) of 4 muM. These results indicate that the potentiation of acetylcholine-evoked responses by RHC-80267 in rat mesenteric artery is caused by the inhibition of the cholinesterase activity in the vascular wall.

Acetylcholine↗

PubMed2004

Cholinesterase inhibitors modify the activity of intrinsic cardiac neurons.

Cholinesterase inhibitors used to treat the symptoms of Alzheimer's disease (AD) inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), albeit to different degrees. Because central and peripheral neurons, including intrinsic cardiac neurons located on the surface of the mammalian heart, express both BuChE and AChE, we studied spontaneously active intrinsic cardiac neurons in the pig as a model to assess the effects of inhibition of AChE compared to BuChE. Neuroanatomical experiments showed that some porcine intrinsic cardiac neurons expressed AChE and/or BuChE. Enzyme kinetic experiments with cholinesterase inhibitors, namely, donepezil, galantamine, (+/-) huperzine A, metrifonate, rivastigmine, and tetrahydroaminoacridine, demonstrated that these compounds differentially inhibited porcine AChE and BuChE. Donepezil and (+/-) huperzine A were better reversible inhibitors of AChE, and galantamine equally inhibited both the enzymes. Tetrahydroaminoacridine was a better reversible inhibitor of BuChE. Rivastigmine caused more rapid inactivation of BuChE as compared to AChE. Neurophysiological studies showed that acetylcholine and butyrylcholine increase or decrease the spontaneous activity of the intrinsic cardiac neurons. Donepezil, galantamine, (+/-) huperzine A, and tetrahydroaminoacridine changed spontaneous neuronal activity by about 30-35 impulses per minute, while rivastigmine changed it by approximately 100 impulses per minute. It is concluded that (i) inhibition of AChE and BuChE directly affects the porcine intrinsic cardiac nervous system, (ii) the intrinsic cardiac nervous system represents a suitable model for examining the effects of cholinesterase inhibitors on mammalian neurons in vivo, and (iii) the activity of intrinsic cardiac neurons may be affected by pharmacological agents that inhibit cholinesterases.

Acetylcholine↗

PubMed1998

Purification, molecular characterization and catalytic properties of a Pseudomonas fluorescens enzyme having cholinesterase-like activity.

An enzyme with a cholinesterase (ChE) activity, produced by Pseudomonas fluorescens, was purified to homogeneity in a three-step procedure. Analysis by non-denaturing and SDS-PAGE, and by isoelectric focusing, indicated that the enzyme was a monomer of 43 kDa, with a pI of 6.1. The N-terminal sequence, AEPLKAVGAGEGQLDIVAWPGYIEA, showed some similarities with proteins of the ChE family and a strong similarity with a protein from Escherichia coli with unknown structure and function. Cholinesterase activity at pH 7.0 and 25 degreesC was maximum with propionylthiocholine as substrate (kcat,app=670 min-1), followed by acetylthiocholine, and significantly lower with butyrylthiocholine. Catalytic specificity (kcat/Km) was the same for propionylthiocholine and acetylthiocholine, but was two orders of magnitude lower for butyrylthiocholine. Kinetics of thiocholine ester hydrolysis showed inhibition by excess substrate which was ascribed to binding of a second substrate molecule, leading to non-productive ternary complex (Km=35 microM, KSS=0.49 mM with propionylthiocholine). There was low or no reactivity with organophosphates and carbamates. The enzyme inhibited by echothiophate (kII=0.44x102 M-1 min-1) was not reactivated by pralidoxime methiodide. However, the P. fluorescens enzyme had affinity for procainamide and decamethonium, two reversible ChE inhibitors used as affinity chromatography ligand and eluant, respectively. Although similarity of the N-terminal amino acid sequence of the enzyme with an internal sequence of ChEs is weak, its catalytic activity towards thiocholine esters, and its affinity for positively charged ligands supports the contention that this enzyme may belong to the ChE family. However, we cannot rule out that the enzyme belongs to another structural family of proteins having cholinesterase-like properties. The reaction of the enzyme with organophosphates suggests that it is a serine esterase, and currently this enzyme may be termed as having a cholinesterase-like activity.

Amino Acid Sequence↗

PubMed1972

Effect of temperature and pH on carbamoylation and phosphorylation of serum cholinesterases. Theoretical interpretation of activation energies in complex reactions.

1. The effect of temperature and pH was studied on the kinetics of inhibition of horse serum and human serum cholinesterase by four organophosphorus compounds and five carbamates. 2. For all compounds, and at each pH and temperature, the inhibition followed the kinetics of a bimolecular reaction with the inhibitor in excess, and with a negligible concentration of the Michaelis complex. 3. The second-order rate constants (k(a)) for inhibition of human serum cholinesterase by one organophosphate and one carbamate increased from 5 degrees to 40 degrees C with an apparent activation energy of 46kJ/mol (11kcal/mol). 4. The k(a) constant for inhibition of horse serum cholinesterase increased with temperature from 5 degrees to 30 degrees C, and then decreased from 30 degrees to 40 degrees C. The theoretical interpretation of such an unusual effect of temperature is derived. 5. The increase of k(a) with pH (human serum cholinesterase) followed the dissociation curve for a single group on the enzyme (pK7.5). 6. Rate constants for decarbamoylation (k(+3)) were determined, and the time-course of inhibition was calculated from the k(a) and k(+3) constants.

Animals↗

PubMed2000

Use of whole blood for spectrophotometric determination of cholinesterase activity in dogs.

Whole blood has been compared with erythrocytes and plasma for spectrophotometric cholinesterase determination in the dog. Cholinesterase activity was characterized using two substrates: acetylthiocholine and butyrylthiocholine. Acetylcholinesterase was the only form of cholinesterase present on erythrocytes and hydrolysed only acetylthiocholine. Butyrylcholinesterase (pseudocholinesterase) was predominant in plasma, hydrolysing mainly butyrylthiocholine. Based on these results, a method based on the use of two substrates (acetylthiocholine for monitoring acetylcholinesterase and butyrylthiocholine for determining butyrylcholinesterase) in the same whole blood sample is recommended for canine cholinesterase analysis. This way of monitoring both enzymes can be easily automated, yielding good within (CVs < 5%) and between-run (CVs < 7%) precision.

2,2'-Dipyridyl↗

PubMed1978

"Nonspecific" cholinesterase and acetylcholinesterase in rat tissues: molecular forms, structural and catalytic properties, and significance of the two enzyme systems.

"Nonspecific" cholinesterase (acylcholine acylhydrolase; EC 3.1.1.8) from various rat tissues has been found to exist in several stable molecular forms that appear as exact counterparts of molecular forms of acetylcholinesterase (acetylcholine hydrolase; EC 3.1.1.7). The sedimentation pattern of cholinesterase was similar to that of acetylcholinesterase with a small but significant shift between the sedimentation coefficients of the corresponding forms. Extraction yields in different media also demonstrated a close parallelism between the two enzyme systems. Other properties, such as thermal stability and catalytic characteristics, indicated both differences and similarities. In spite of the structural resemblance implied by their physicochemical properties, cholinesterase did not crossreact with antibodies against acetylcholinesterase. The nature of the relationships revealed by these studies and their bearing on the physiological significance of cholinesterases are discussed.

Acetylcholinesterase↗

PubMed1980

Reduced sensitivity of cholinesterase as a factor of resistance in leptophos selected strain in the Egyptian cotton leafworm.

Larvae of a leptophos resistant strain of the Egyptian cotton leafworm Spodoptera littoralis (Boisd) showed varying levels of cross resistance to several organophosphorus insecticides and to the carbamate matacil. Enzymatic determinations revealed that levels of cholinesterase activity were almost identical in larvae of susceptible and resistant strains. Resistant larvae, which remained susceptible to the carbamate methomyl possessed cholinesterase of nearly normal sensitivity to this compound. On the other hand, there was a considerable degree of insensitivity of cholinesterase to inhibition by leptophos-oxon, methyl paraoxon, cyolane, cytrolane, monocrotophos, and matacil in larvae of the resistant strain. It was concluded that reduced sensitivity of cholinesterase enzyme could be considered as an important factor which complements other variables contributing to the mechanism of resistance in larvae of the Egyptian cotton leafworm.

Animals↗

PubMed1980

A study of the cholinesterases of the canine pancreatic sphincters and the relationship between reduced butyrylcholinesterase activity and pancreatic ductal hypertension.

Previous work from this laboratory revealed in increased canine pancreatic intraductal pressure following cholinesterase inhibitor intoxication. The pressure was negatively correlated with serum butyrylcholinesterase (BChE) activity, suggesting that BChE activity mediated the pressure rise. This study uses a histochemical technique to investigate the tissue cholinesterase activity of the canine pancreatic sphincters and the effect of a cholinesterase inhibitor (ChEI) on tissue cholinesterase activity. In five control dogs, serial sections of the major and minor spincters were stained for acetylcholinesterase (AChE) and BChE activity. Four treated dogs were given the ChEI, O,O-diethyl-O- (2-isopropyl-6-methyl-4-pyrimidinyl) phosphoro-thioate, 25 mg/kg, one hour prior to excising the ampullae. In the control dogs, BChE activity is present in the periampullary nerves and the pancreatic smooth muscle sphincters. AChE activity is present in nerves but not in smooth muscle. In the treated group, following a dose of ChEI known to cause ductal hypertension, BChE activity was absent in the pancreatic sphincters but AChE activity was preserved in the periampullary nerves. These data suggest that the pancreatic ductal hypertension that occurs following ChEI administration is due to a selective reduction in pancreatic smooth muscle BChE activity.

Acetylcholinesterase↗

PubMed1972

Actions of the selective inhibitor of cholinesterase tetramonoisopropyl pyrophosphortetramide on the rat phrenic nerve-diaphragm preparation.

1. Tetramonoisopropyl pyrophosphortetramide (iso-OMPA) added for 15 min to the rat isolated phrenic nerve-diaphragm in a concentration of 30 muM, produced a complete selective and stable inhibition of cholinesterase. A concentration of 3 muM produced near complete inhibition of cholinesterase, and a concentration of 300 muM also inhibited acetylcholinesterase marginally.2. Inhibition of cholinesterase was associated with a sustained increase in the neuromuscular blocking action of exogenous butyrylcholine but not of exogenous acetylcholine. Iso-OMPA, 300 muM, in addition caused transient increases in the sensitivity of the rat diaphragm to exogenous acetylcholine and butyrylcholine. In the same concentration, it had a curare-like action on the frog rectus abdominis muscle preparation.3. Iso-OMPA, 30 muM, caused reversible increases in the amplitude of the twitch response and tetanic responses, which were of a similar magnitude in the indirectly stimulated preparation and the directly stimulated curarized preparation. Caffeine had a similar effect on the twitch response and its effectiveness was increased by iso-OMPA, and vice-versa. Amongst anticholinesterases, octamethyl pyrophosphortetramide and tetraethylpyrophosphate also enhanced the amplitude of the tetanic response, but paraoxon, dyflos, and mipafox did not.4. It is concluded that iso-OMPA, in concentrations (3 and 30 muM) which in 15 min give near maximal or maximal selective inhibition of cholinesterase, has no effect on the transmission of nerve impulses at the neuromuscular junction, but enhances reversibly the amplitude of the contractile response to stimulation by a direct action upon the muscle fibre, which involves a mechanism related to but not identical with that by which caffeine potentiates twitch tension. In higher concentrations, iso-OMPA has a curare-like action at the neuromuscular junction.

Acetylcholine↗

PubMed1975

Distribution and properties of cholinesterases in subcellular fractions from rat jejunum and heart tissue.

Homogenates of rat jejunum and heart tissue in 0.3 M sucrose have been separated into different subcellular fractions by centrifugation. The distribution of cholinesterases in these two tissues is different. Acetylthiocholine (Ac), propionylthiocholine (Pc), and butyrylthiocholine (Bc) iodides were used as substrates. Using 1 mmol/1 Ac in the presence of hexafluorenium, a local anaesthetic drug, inhibition percentages of these subcellular cholinesterases were found to be different. The differences in the effect of hexafluorenium were most marked at a concentration of 5 mumol/1. Four electrophoretically distinct subcomponents of cholinesterase have been identified in different subcellular fractions from both jejunum and heart tissues. The electrophoretic profile, as determined by polyacrylamide disc electrophoresis, of different subcellular cholinesterases in these two tissues also appears to be different.

Acetylthiocholine↗

PubMed1982

Cholinesterase activity of the motor endplate in rat intercostal muscle.

Cholinesterase activity was localized solely in the motor endplate of the membrane in rate intercostal muscle. The diameter of rat motor endplates in the gradient dimension was 31.9 micrometers. The cholinesterase activity per unit protein of the soluble fraction of rat muscle membrane was 35.6% higher than the original membrane. From studies with specific substrates and cholinesterase inhibitors, the cholinesterase activity of rat muscle membrane and its soluble fraction consists of more than 90% acetylcholinesterase and less than 10% pseudocholinesterase.

Animals↗

PubMed1986

Cholinesterase phenotyping: clinical aspects and laboratory applications.

The measurement of cholinesterase activity in human serum is an important investigation, especially in patients suspected of poisoning with organophosphate insecticides, or those experiencing prolonged paralysis following treatment with the short acting muscle relaxant succinylcholine. Appropriate clinical management of affected individuals can only be instituted if enzyme activity is measured using a method capable of clear interpretation and phenotypic ascription of cholinesterase, ascertained by use of selected enzyme inhibitors, is reliable. This review considers factors which lead to significant cholinesterase abnormalities and advises on the techniques most appropriate to their investigation. It is concluded that no one method is suitable both for measurement of activity and determination of genotype. The use of propionyl thiocholine is recommended for the first procedure and benzoyl choline for the latter. Those laboratories in which a request for the assessment of cholinesterase status is an unusual event should make greater use of assistance from colleagues whose experience with the problem is greater.

Animals↗

PubMed1988

Cholinesterases in rabbit serum.

1. Rabbit serum was shown to contain two cholinesterases which hydrolysed acetylthiocholine and butyrylthiocholine and one cholinesterase which hydrolysed only butyrylthiocholine. 2. The three enzymes were identified by the kinetics of heat inactivation and kinetics of phosphorylation by the organophosphate VX. 3. Using selective inhibitors (iso-OMPA, eserine, BNPP and BW-284C51) it was shown that the hydrolysis of acetylthiocholine and butyrylthiocholine in untreated native serum had properties of acetylcholinesterase (EC 3.1.1.7), butyrylcholinesterase (EC 3.1.1.8) and also some properties of carboxylesterase (EC 3.1.1.1). 4. Separation of proteins (on PAA-gels) in untreated native serum gave four bands with acetylthiocholine and three with butyrylthiocholine. 5. The two cholinesterases hydrolysing both substrates corresponded to the slow moving bands on the gel. 6. The fastest moving band hydrolysing only butyrylthiocholine could be attributed to the cholinesterase least sensitive to VX.

Acetylthiocholine↗

PubMedDate not supplied

[The specificity of the interaction of the cholinesterases in Far Eastern squid and certain vertebrates with reversible inhibitors].

Studies have been made of the effect of three groups of ammonia reversible inhibitors on the activity of erythrocyte acetylcholinesterase, serum butyrylcholinesterase, cholinesterase from frog brain, as well as cholinesterases from the optical ganglia of the Pacific and three populations of the commander squids. Determination of kinetic parameters of the reversible inhibition of these enzymes revealed differences resulting from the specific structure of their catalytic centers. Tetramethylammonium assay confirmed different properties of cholinesterases in individuals of the commander squid from various habitats in the Bering Sea; this finding may be taken as an indication of intraspecific differentiation of these cephalopods. Certain similarity was noted in the inhibitory specificity of cholinesterases from the Pacific and "southern" commander squids with the overlapping habitats.

Animals↗

PubMed1971

Distribution of cholinesterases in insects.

The study of toxicology and other related fields has been largely based on in vitro techniques. These methods have provided quantitative information on the effects of inhibitors on enzymes, but none on the localized effects of inhibitors on selected sites of action within the animal. Histochemical study of frozen sections does provide data on the site of action of toxicants. The utility of histochemistry in conjunction with in vitro methods is discussed.The substrates acetylthiocholine and phenyl thioacetate were utilized in demonstrating cholinesterase. Neither substrate penetrated well into freshly dissected nerve cord preparations, but both compounds were hydrolysed by sectioned tissue. The leaving group of phenyl thioacetate was demonstrated to be benzenethiol. In general, acetylthiocholine was hydrolysed slightly more rapidly by insect cholinesterases. A unique cholinesterase was found in motor end-plates of cricket muscle, which hydrolyses acetylthiocholine and which was inhibited by physostigmine. No other insect muscle preparation showed this activity. Topical application of insecticides showed that a vital site of action in flies is the peripheral area of the thoracic ganglia and that in crickets the brain and nerve cord are involved at knock-down. Kinetic data indicate that acetylthiocholine has a greater affinity than does phenyl thioacetate for a variety of enzyme sources. Ultrastructural evidence shows that cholinesterases that hydrolyse acetylthiocholine are membrane-bound. Phenyl thioacetate was found to be useful as a model in designing new insecticides.

Acetylcholine↗

PubMed1980

Prolonged succinylcholine-induced apnea caused by atypical cholinesterase: report of case.

A case of prolonged apnea after administration of succinylcholine in a patient homozygous for the dibucain variant cholinesterase (genotype E1aE1a) has been presented. Knowledge of the patient's medical history, preoperative laboratory tests, and the length of apnea enabled the surgical team to eliminate liver disease, carcinoma, and malnutrition from the differential diagnosis. This, in addition to the patient's failure to respond to an anticholinesterase agent, led to the belief that the patient had an atypical cholinesterase response to succinylcholine and not one secondary to a decreased production of cholinesterase enzyme from an impaired liver or prolonged paralysis for the nondepolarizing agent, pancuronium. Treatment consisted of maintaining adequate pulmonary ventilation nitrous oxide sedation to diminish anxiety until the patient regained spontaneous respiration. Anticholinesterase agents were used after the patient had progressed to a phase II depolarization block. After a cholinesterase assay of the family's serum, all members having the atypical allele were instructed to obtain medical alert identification.

Adult↗