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PubMed1983

Carboxylesterases in rat and human sera and their relationship of serum aryl acylamidases and cholinesterases.

The three enzyme activities, carboxylesterase, aryl acylamidase and cholinesterase activities, have been found in rat and human sera. Rat serum carboxylesterase associated with serum aryl acylamidase activity, but not with serum cholinesterase activity, was purified by ammonium sulfate precipitation, followed by successive chromatographies on DEAE-cellulose, blue Sepharose and QAE-Sephadex, and then electrophoresis. Evidence for the identity of the two enzymes, carboxylesterase and aryl acylamidase, was their co-elution profiles and co-purification in the different steps, including electrophoresis, with constant ratios of specific activities and percentage recoveries. Human serum carboxylesterase associated with serum cholinesterase, purified earlier, was compared with the rat serum esterase. Human serum carboxylesterase and aryl acylamidase activities were inhibited by serotonin and neostigmine, whereas rat serum carboxylesterase and aryl acylamidase activities were not affected by these compounds. Tyramine activated human but not rat aryl acylamidase. Rat and human serum esterase activities were both strongly inhibited by the diisopropylfluorophosphate. Both esterases catalyzed the hydrolysis of short-chain triacylglycerols, such as tributyrin, and medium-chain monoacylglycerols, such as monocaprin, but not the hydrolysis of long-chain triacylglycerols.

Amidohydrolases↗
PubMed1982

Substance P hydrolysis by human serum cholinesterase.

Highly purified human serum cholinesterase (EC 3.1.1.8, also known as pseudocholinesterase and butyrylcholinesterase) had peptidase activity toward substance P. Digestion of substance P was monitored by high performance liquid chromatography, which separated three product peptides. The cleavages occurred sequentially. The first peptide to appear as Arg1-Pro2. The Km for this hydrolysis was 0.3 mM; maximum activity was 7.9 nmol min-1 mg-1 of protein, which corresponded to a turnover number of 0.6 min-1. A second cleavage yielded Lys3-Pro4. A third cleavage occurred at the C-terminal, where the amide was removed from Met11 to yield a peptide containing residues 5-11. Both the peptidase and esterase activities of the enzyme were completely inhibited by the anticholinesterase agent, diisopropylfluorophosphate. Substance P inhibited the hydrolysis of benzoylcholine (a good ester substrate) with a KI of 0.17 mM, indicating that substance P interacted with cholinesterase rather than with a trace contaminant. Peptidase and amidase activities for serum cholinesterase are novel activities for this enzyme. It was demonstrated previously that the related enzyme acetylcholinesterase (EC 3.1.1.7) catalyzed the hydrolysis of substance P, but at entirely different cleavage sites from those reported in the present work. Since butyrylcholinesterase is present in brain and muscle, as well as in serum, it may be involved in the physiological regulation of substance P.

Amino Acids↗
PubMed1960

Maximal inhibition of cholinesterase in the central nervous system.

In experiments on mice treated with pralidoxime iodide (pyridine-2-aldoxime methiodide; PAM) and atropine, the cholinesterase activity in the brain was assayed after poisoning with very high doses of organophosphorous anticholinesterases. Acetylcholine was added to the buffer solution in which the brains were homogenized. This precaution reduced the combination between free inhibitor present in the tissue and active enzyme, and the cholinesterase activity found was below 0.5% of controls. When the experimental data were corrected for spontaneous reactivation in vitro during incubation, the calculated activities in vivo were even less. It is concluded that mice can survive complete inactivation of the cholinesterase in the central nervous system, if enough atropine is given to protect the animals against the toxic effects of the accumulating acetylcholine.

Acetylcholine↗
PubMed1989

Electrophysiological estimation of the actions of acetylcholinesterase inhibitors on acetylcholine receptor and cholinesterase in physically isolated Aplysia neurones.

1. The actions of representative cholinesterase inhibitors on the acetylcholine responses of physically isolated single neurones from the pedal ganglion of Aplysia californica were studied, using electrophysiological techniques and rapid agonist application to analyse both the inhibitory actions on the acetylcholine receptor-channel complex and the degree of inhibition of acetylcholinesterase activity on the same neurone. The inhibitors used were physostigmine, edrophonium and diisopropylfluorophosphate (DFP). 2. When selected neurones were suddenly exposed to 50 microM acetylcholine by a 'concentration clamp' technique a large Na-dependent inward current was initiated, and decayed in the continued presence of acetylcholine without external perfusion. However, if perfusion of the acetylcholine solution was reinitiated the current increased somewhat, indicating that the decay of current was due to some combination of receptor desensitization and local depletion of acetylcholine at the membrane by acetylcholinesterase. 3. With simultaneous application of acetylcholine (50 microM) and physostigmine (0.1 to 100 microM) there was a dose-dependent reduction of peak amplitude of the acetylcholine response. However, physostigmine at low concentrations (0.1 to 10 microM) caused a time-dependent increase in the current amplitude alone with a time- and dose-dependent inhibition of acetylcholinesterase activity. At the highest concentration of physostigmine (100 microM) acetylcholinesterase activity was abolished but the current peak was very depressed. After removal of physostigmine from the bathing solution, the current amplitude decreased toward the control at the two lower concentrations as the inhibitory actions on acetylcholinesterase activity were almost reversible, while at the two higher concentrations (10 and 100 microM) the current increased and the inhibition of acethylcholinesterase remained. 4. When acetylcholine (50 microM) and edrophonium (0.1 to 10 microM) were applied simultaneously, edrophonium caused a dose-dependent increase in the peak amplitude that was correlated with a dose-dependent inhibition of acetylcholinesterase activity. Prolonged exposure to edrophonium did not change the peak amplitude and there was no time-dependent change in the inhibition of acetylcholinesterase activity. At the highest concentration of edrophonium used (100 microM), simultaneous application with acetylcholine augmented the peak amplitude relative to control, but to a lesser extent than 10 microM. Prolonged exposure to the highest concentration of edrophonium caused a time-dependent reduction in the peak amplitude. The effects of edrophonium were quickly reversible after the removal of the drug from the bathing solution. 5. DFP (1 and 10mM), similar to 1OO microM physostigmine, caused a dramatic reduction of the peak current on simultaneous application with ftetylcholine. During exposure to DFP the current amplitude and acetylcholinesterase activity were very depressed. After removing DFP from the bathing solution the current amplitude increased to more than the control level after 1 mm DFP, while it did not recover to the control level after 10mM DFP. The inhibition of acetylcholinesterase activity remained at both concentrations. 6. These results indicate that all three cholinesterase inhibitors have dose-dependent actions both at the acetylcholine receptor-channel complex and at acetylcholinesterase. The methods we have developed may be useful in the evaluation of various cholinesterase inhibitors.

Animals↗
PubMed1974

Experience with a cholinesterase histochemical technique for rectal suction biopsies in the diagnosis of Hirschsprung's disease.

Cryostat sections from 160 rectal suction biopsies were stained for cholinesterases by the method of Karnovsky and Roots (1964) in an attempt to facilitate the diagnosis of Hirschsprung's disease. The method proved at least as reliable as experienced assessment of paraffin haematoxylin-eosin sections, and appeared to offer the advantages of reduced scanning fatigue and superior demonstration of the increased cholinesterase-positive nerves in Hirschprung's disease. Contrary to the findings of Meier-Ruge (1971) it was not possible to base a diagnosis on mucosal cholinesterase activity.

Adolescent↗
PubMedDate not supplied

The origin of the molecular diversity and functional anchoring of cholinesterases.

Vertebrates possess two cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which both hydrolyze acetylcholine, but differ in their specificity towards other substrates, and in their sensitivity to inhibitors. In mammals, the AChE gene produces three types of coding regions through the choice of 3' splice acceptor sites, generating proteins which possess the same catalytic domain, associated with distinct C-terminal peptides. AChE subunits of type R ('readthrough') produce soluble monomers; they are expressed during development and induced by stress in the mouse brain. AChE subunits of type H ('hydrophobic') produce GPI-anchored dimers, but also secreted molecules; they are mostly expressed in blood cells. Subunits of type T ('tailed') exist for both AChE and BChE. They represent the enzyme forms expressed in brain and muscle. These subunits generate a variety of quaternary structures, including homomeric oligomers (monomers, dimers, tetramers), as well as hetero-oligomeric assemblies with anchoring proteins, ColQ and PRiMA. Mutations in the four-helix bundle (FHB) zone of the catalytic domain indicate that subunits of type H and T use the same interaction for dimerization. On the other hand, the C-terminal T peptide is necessary for tetramerization. Four T peptides, organized as amphiphilic alpha helices, can assemble around proline-rich motifs of ColQ or PRiMA. The association of AChE(T) or BChE subunits with ColQ produces collagen-tailed molecules, which are inserted in the extracellular matrix, e.g. in the basal lamina of neuromuscular junctions. Their association with PRiMA produces membrane-bound tetramers which constitute the predominant form of cholinesterases in the mammalian brain; in muscles, the level of PRiMA-anchored tetramers is regulated by exercise, but their functional significance remains unknown. In brain and muscles, the hydrolysis of acetylcholine by cholinesterases, in different contexts, and their possible noncatalytic functions clearly depend on their localization by ColQ or PRiMA.

Acetylcholinesterase↗
PubMed1998

Lack of inhibition of human plasma cholinesterase and red cell acetylcholinesterase by antimony compounds including stibine.

1. The toxic gas hypothesis proposes exposure to stibine (antimony trihydride) generated from microbial contamination of cot mattress materials as a possible cause of unexplained death in infancy (SIDS) as a consequence of cholinesterase inhibition. We have measured the direct effects of antimony compounds including stibine on the activity of plasma cholinesterase, red blood cell acetylcholinesterase (AChE) and mouse neuronal AChE in vitro. 2. Colorimetric assays for the different esterases with potassium antimonyl tartrate or antimony trichloride at concentrations up to 10(-3) M in the presence of substrate concentrations sufficient to produce 80% of the maximum reaction rate produced no inhibition of enzyme activity. Exposure of enzyme preparations to stibine gas at concentrations sufficient to cause denaturation of red cell haemogloblin caused no measurable inhibition of esterase activity. 3. We conclude that stibine gas or soluble antimony compounds are not capable of inhibiting cholinesterase activity at toxicologically relevant concentrations.

Acetylcholinesterase↗
PubMed1976

Reactivation studies on organophosphate inhibited human cholinesterases by pralidoxime (P-2-AM).

There is biochemical and clinical evidence that P-2-AM (Pyridine-2-Aldoxime Methiodide, Pralidoxime) does not reactive human acetylcholinesterase inhibited by either Malathion or Malaoxon. In vitro studies using Pralidoxime iodide up to ten times the recommended concentrations, produced insignificant reactivation of cholinesterases inhibited by Malathion or Malaoxon. This was observed inspite of prolonged exposure of the inhibited cholinesterases to the oxime. The value of Pralidoxime as a reactivator of phosphorylated cholinesterases is therefore in doubt, and should not be used in preference to large doses of atropine and other supportive treatment in poisoning by organophosphate pesticides.

Acetylcholinesterase↗
PubMed1975

Presynaptic effects of neuromuscular cholinesterase inhibition.

Paraoxon, an irreversible organophosphorus inhibitor of cholinesterase, produces a myopathy beginning at the neuromuscular junction in rat diaphragm muscles. Thirty minutes after paraoxon was injected i.p. (0.5 mg/kg), neuromuscular cholinesterase activity was reduced to 36% of control. The frequency of miniature end-plate potentials (MEPPs) in diaphragms from paraoxon-treated rats was 109/sec compared with 2.9/sec in saline-injected controls. The faster frequency was seen after paraoxon gradually declined to control rates within 6 hours after injection. The quantum content of end-plate potentials was reduced to 66% of that seen in saline controls. Spontaneous and impulse-related antidromic activity was observed along the phrenic nerve after paraoxon which also gradually diminished with time. When the phosphorylated acetylcholinesterase was reactivated with 10(-3) pyridine-2-aldoxime methiodide, MEPP frequency was reduced significantly and antidromic activity was abolished. Block of axonal excitability with 10(-6) M tetrodotoxin reduces the effects of paraoxon on MEPP frequency and antidromic activity, while acetylcholinesterase remains inhibited. In vitro perfusion with 6 times 10(-8) M paraoxon increases MEPP frequency and initiates antidromic activity. It is concluded that inhibition of neuromuscular cholinesterase by paraoxon leads to an alteration of transmitter release, and this may be associated with ultrastructural abnormalities observed at the motor endplate.

Action Potentials↗
PubMed1976

[Cholinesterases (acetyl and pseudocholinesterase) in human amniotic fluid].

Study on 41 cases. The cholinesterasic activity of human amniotic fluid, free from blood, is very weak, in average 0,10 microkatal, approximatively 300 times weaker than mother's serum. In this "total cholinesterase", we find a large amount (about 40%) of acetylcholinesterase. Amniotic cholinesterases have an prominent placentary origin, with, in addition, a likely activity proceeding from cellular elements.

Acetylcholinesterase↗
PubMedDate not supplied

[Study of the cholinesterase active site using a fluorescent probe].

We studied fluorescence of 9-amino-1,2,3,4-tetrahydroacridine hydrochloride (tacrine) in the presence of serum cholinesterase. Quenching of tacrine fluorescence dependent on cholinesterase activity has been revealed. A quenching mechanism is proposed; it includes formation of a complex and charge transfer mediated by excited tacrine molecule as well as indole of tryptophan residue from the periphery of cholinesterase active site.

Aminoacridines↗
PubMed1990

Metrifonate in healthy volunteers: interrelationship between pharmacokinetic properties, cholinesterase inhibition and side-effects.

Metrifonate concentrations in plasma, its inhibition of blood cholinesterase, and side-effects were studied in 16 healthy volunteers who received a single oral dose of 2.5, 5, 7.5 or 15 mg/kg in a randomized double-blind study (4 subjects for each dose). Metrifonate was determined by a gas chromatographic method. Peak plasma levels were reached within 2 hours; the half-life in plasma, oral clearance, and normalized Cmax and AUCs did not differ significantly between the four groups. Plasma cholinesterase (BuchE) was inhibited to low levels in all subjects, while erythrocyte cholinesterase (AchE) was affected in a dose-dependent fashion. The occurrence of side-effects correlated strongly with peak plasma levels but not with maximum AchE inhibition or with increase in salivation. This study shows that the absorption of metrifonate was not significantly different for doses between 2.5 and 15 mg/kg. The plasma levels of this drug correlated with the occurrence of side-effects.

Adult↗
PubMedDate not supplied

[A comparative study of the effect of vinyl phosphoric acid esters on cholinesterase and carboxylesterase activities in mammals and arthropods].

Studies have been made of the effect of organophosphorus inhibitors on cholinesterase and carboxylesterase from various mammals (human erythrocytes, mouse brain, blood serum of mouse and rat, blood serum of horse) and arthropods (Calliphora vicina, Schizaphis graminum, Myzus persicae, Sitophilus oryzae, Pseudococcus maritimus, Tetranychus urticae). Organophosphorus inhibitors were presented by esters of vynylphosphoric acid containing normal and branched alkyls in the phosphoryl part of the molecule. The increase of the radical up to a propyl one increased the effect of organophosphorus inhibitors with respect to cholinesterase from the majority of the arthropods investigated. Organophosphorus compound with an isopropyl radical was found to be weaker for all the enzymes studied. Extremely high sensitivity of carboxylesterase from all arthropods to all organophosphorus inhibitors was noted; in some of the cases, anticarboxylesterase activity of all drugs was 2-3 orders higher than anticholinesterase one (P. maritimus, T. urticae). Regularities established for cholinesterase practically completely were confirmed on carboxylesterase. This finding evidently reveals similar structure of catalytic surface at the vicinity of esterase center in both enzymes.

Animals↗
PubMed1978

Effect of benzodiazepine derivatives on human blood cholinesterase in vitro.

The in vitro effect of ten benzodiazepine derivatives on the cholinesterases of human plasma and red cells was determined. Flurazepam, temazepam, lorazepam, flunitrazepam and diazepam had an inhibitory effect on plasma cholinesterase of 60--90 per cent and, with the exception of lorazepam, an inhibitory effect of 40--50 per cent on red cell cholinesterase. Clonazepam, oxazepam, chlordiazepoxide, nitrazepam and bromazepam had comparatively minor effects on both enzymes

Anti-Anxiety Agents↗
PubMedDate not supplied

[Organophosphorus compounds as tools for the pharmaco-histochemical study of cholinesterase in the rat striatum].

A series of organophosphorous compounds (OP) was tested using a pharmacohistochemical method applied in vitro on the rat striatum, the central structure which contains the highest levels of acetylcholine and its metabolic enzymes; the OP showed a great variety of action towards the specific cholinesterase (AChE) and non-specific cholinesterase (BuChE). Except for iso-OMPA which is specific for BuChE localized in the microvessels endothelium, all the OP doses used in the present study were more or less potent inhibitors of cholinesterases (ChE). 15 mn after LD 50 doses of OP administered by subcutaneous route, a partial inhibition of the neurophile AChE occurred, revealing some striatal neurons which displayed high residual activity, i.e. the cholinergic interneurons. During the recovery phase following the inhibition of AChE by 1.5 LD 50 doses (the animals being treated with atropine) the AChE reaction product was detected almost simultaneously in some axo-spinous synapses probably non-cholinergic. The partial inhibition and the de novo synthesis of AChE also revealed the presence of small and less reactive non-cholinergic neurons. Among all the OP tested, soman was remarkable for its patchy inhibition of AChE in the striatum. The significance of the alternation of reactive and non-reactive areas is discussed.

Acetylcholinesterase↗
PubMed1987

Benzamides and cholinesterases.

At certain doses metoclopramide (MT), sulpiride and bromopride produce anti-cholinesterase effects as shown by studies on the serum and erythrocyte cholinesterases of the rabbit and the dog, and by those on the hypotensive effect of ACh incubated with rabbit serum in the presence or absence of MT. The anti-cholinesterase effect of MT was more intensive than that of sulpiride, bromopride, procainamide or procaine, but less pronounced than that of prostigmine.

Acetylcholine↗
PubMedDate not supplied

[Estimation of anticholinesterase activity in reversible inhibitors of cholinesterase hydrolysis].

The kinetic analysis of cholinesterase interaction with reversible inhibitors was carried out. It has shown that the existing methods for definition of the type of reversible inhibition of enzyme reactions are not reliable. For example, mixed inhibition with the correlation between the competitive inhibition constant (Kl) and noncompetitive inhibition constant (K'i) less than 0.04, is identified as competitive inhibition. Apparently the ideal competitive inhibition with Ki/Ki = 0 does not exist in reality, because it is unlikely for a reversible inhibitor to decrease the process of the substrate sorption on a catalytical centre of cholinesterase not affecting the deacetylation rate. For objective evaluation of efficiency of reversible inhibitors it is suggested to determine the generalized inhibitory constant Ki at the cholinesterase hydrolysis in acetylcholine or acetylthiocholine. The data about anticholinesterase activity of carbonic and sulfoesters of lupinin are adduced.

Binding Sites↗
PubMedDate not supplied

[The interaction of organosilicon bisammonium compounds with the cholinesterases of Far-Eastern squids and vertebrates. The comparative enzymological, kinetic and conformational aspects].

The research of interaction of cholinesterases from human erythrocytes, horse blood serum, brain of the frog Rana temporaria, optical ganglia of the Pacific squid Todarodes pacificus, as well as optical ganglia of specimens of the Comandor squid Berryteuthis magister from different areas in the Bering sea with 13 organosilicon bis (trimethylammonium) compounds (silane and siloxane rows) as reversible cholinesterase inhibitors have been first studied and generalized. Calculations of the effector structure using the method of theoretical conformational analysis showed higher rigidity of interonium chain of siloxane derivatives and gave grounds to accept the asymmetry of hydrate envelope for these compounds. The data of conformational and kinetic analysis allowed to propose that specificity of antienzymic effect of organosilicon compounds was mainly due to conformational flexibility of interonium chain and the nature of hydration of effector molecule. The new information on the mechanism of catalytic reactions effected by cholinesterases from animals at different evolutionary stages was obtained.

Animals↗