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PubMed1999

Subclinical health effects of environmental pesticide contamination in a developing country: cholinesterase depression in children.

The effect of exposure to pesticides among children in a Nicaraguan community in the path of rain water runoff from a large crop-dusting airport was evaluated by measuring plasma cholinesterase. Mean cholinesterase activity in 17 children in the path of runoff was 2.4 international units/ml blood/min, lower than the 2.9 IU/ml/min measured in a group of 43 children from an unexposed community (difference=0.49 IU/ml/min; 95% C.I. 0.24, 0.76). Six (35%) of the 17 exposed children had abnormally low cholinesterase levels. A possible explanation for this physiological effect of exposure to pesticides is the dermal absorption which may have occurred among children playing barefoot in puddles grossly contaminated by runoff from the airport. Drinking water from a well in the exposed community demonstrated low level residues of cholinesterase-inhibiting pesticides, although contamination with toxaphene (not a cholinesterase inhibitor) exceeded by over 8-fold the United States Environmental Protection Agency maximum permissible concentration in drinking water. The difficulty in measuring health effects resulting from environmental pesticide contamination, and in controlling exposure resulting from the rapidly increasing use of pesticides, is a growing problem for developing countries like Nicaragua.

Child↗
PubMed1984

Cholinesterase activity in the rat superior cervical ganglion: effect of denervation and axotomy.

Cholinesterase activity and its various forms in the superior cervical ganglion of the rat were studied after denervation, axotomy and double section. The response of this activity to various inhibitors was also studied. The specific activity of cholinesterase activity was 323 +/- 25 nmol/mg protein/min in homogenates of normal ganglia and the total enzyme activity was 78 +/- 5 nmol/ganglion/min. Axotomy produced approximately a 40% decrease in total activity in ganglia at 3 days compared to contralateral ganglia. Activity in the contralateral ganglia was also decreased by about 30% compared to normal ganglia. Decentralization alone for 3 days did not affect the specific or total cholinesterase activity. However, decentralization followed by axotomy 3 days later resulted in a greater loss in activity compared to axotomy and a significant change in the forms of cholinesterase. After chromatography on Sepharose 6B-100 columns, 3 forms (a, c, d) of cholinesterase activity could be separated from homogenates of single ganglia. The 3 forms had estimated molecular weights of 1,934,000, 129,000 and 59,000 daltons, respectively. A fourth form (b) presented as a shoulder and had an estimated molecular weight of 404,000 daltons. Decentralization or axotomy decreased forms a and d. A reduction in the proportion of form c was also observed in the axotomized ganglion. Decentralization followed by axomoty resulted in large decreases in forms a, b and c and complete loss of form d. Assay of the separated forms in the presence of the specific inhibitor of acetylcholinesterase, BW284C-51, indicated that the majority of the enzyme recovered after chromatography is acetylcholinesterase.

Acetylcholinesterase↗
PubMed1992

Dose-related inhibition of brain and plasma cholinesterase in neonatal and adult rats following sublethal organophosphate exposures.

Developing mammals are markedly more sensitive to acute toxicity from exposure to a variety of organophosphorus (OP) pesticides. The present study examined dose-related inhibition of both brain and plasma cholinesterase activity in neonatal and adult rats exposed to sublethal doses of one of three common OP pesticides, methyl parathion, parathion and chlorpyrifos. Effective dose 50 (i.e., ED50 or dose which would inhibit 50% of the cholinesterase activity) values were determined and then correlated with an indicator of acute toxicity, the maximal tolerated dose (MTD). It was found that ED50 estimates for both brain and plasma cholinesterase correlated highly (r = 0.932-0.992) with previously derived MTD values. In no case was there a significant difference between in vivo brain and plasma cholinesterase inhibition across doses in neonatal rats was high (r = 0.962-0.975) but lower in adults (r = 0.700-0.943). The results suggest that in vivo inhibitory potency of the three OPs towards either brain or plasma ChE activity is highly correlated with sensitivity to acute toxicity in both neonatal and adult rats. Additionally, under defined experimental conditions, plasma ChE inhibition may be a useful quantitative index for the degree of brain cholinesterase inhibition following OP exposures.

Aging↗
PubMed2003

Cholinesterases: new roles in brain function and in Alzheimer's disease.

The most important therapeutic effect of cholinesterase inhibitors (ChEI) on approximately 50% of Alzheimer's disease (AD) patients is to stabilize cognitive function at a steady level during a 1-year period of treatment as compared to placebo. Recent studies show that in a certain percentage (approximately 20%) of patients this cognitive stabilizing effect can be prolonged up to 24 months. This long-lasting effect suggests a mechanism of action other than symptomatic and cholinergic. In vitro and in vivo studies have consistently demonstrated a link between cholinergic activation and APP metabolism. Lesions of cholinergic nuclei cause a rapid increase in cortical APP and CSF. The effect of such lesions can be reversed by ChEI treatment. Reduction in cholinergic neurotransmission--experimental or pathological, such as in AD--leads to amyloidogenic metabolism and contributes to the neuropathology and cognitive dysfunction. To explain the long-term effect of ChEI, mechanisms based on beta-amyloid metabolism are postulated. Recent data show that this mechanism may not necessarily be related to cholinesterase inhibition. A second important aspect of brain cholinesterase function is related to enzymatic differences. The brain of mammals contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The two forms differ genetically, structurally, and for their kinetics. Butyrylcholine is not a physiological substrate in mammalian brain, which makes the function of BuChE of difficult interpretation. In human brain, BuChE is found in neurons and glial cells, as well as in neuritic plaques and tangles in AD patients. Whereas, AChE activity decreases progressively in the brain of AD patients, BuChE activity shows some increase. To study the function of BuChE, we perfused intracortically the rat brain with a selective BuChE inhibitor and found that extracellular acetylcholine increased 15-fold from 5 nM to 75 nM concentrations with little cholinergic side effect in the animal. Based on these data and on clinical data showing a relation between cerebrospinal fluid (CSF) BuChE inhibition and cognitive function in AD patients, we postulated that two pools of cholinesterases may be present in brain, the first mainly neuronal and AChE dependent and the second mainly glial and BuChE dependent. The two pools show different kinetic properties with regard to regulation of ACh concentration in brain and can be separated with selective inhibitors. Within particular conditions, such as in mice nullizygote for AChE or in AD patients at advanced stages of the disease, BuChE may replace AChE in hydrolizing brain acetylcholine.

Alzheimer Disease↗
PubMed1993

Protease inhibitors and indoleamines selectively inhibit cholinesterases in the histopathologic structures of Alzheimer disease.

Neurofibrillary tangles and amyloid plaques express acetylcholinesterase and butyrylcholinesterase activity in Alzheimer disease. We previously reported that traditional acetylcholinesterase inhibitors such as BW284C51, tacrine, and physostigmine were more potent inhibitors of the acetylcholinesterase in normal axons and cell bodies than of the acetylcholinesterase in plaques and tangles. We now report that the reverse pattern is seen with indoleamines (such as serotonin and its precursor 5-hydroxytryptophan), carboxypeptidase inhibitor, and the nonspecific protease inhibitor bacitracin. These substances are more potent inhibitors of the cholinesterases in plaques and tangles than of those in normal axons and cell bodies. These results show that the enzymatic properties of plaque and tangle-associated cholinesterases diverge from those of normal axons and cell bodies. The selective susceptibility to bacitracin and carboxypeptidase inhibitor indicates that the catalytic sites of plaque and tangle-bound cholinesterases are more closely associated with peptidase or protease-like properties than the catalytic sites of cholinesterases in normal axons and cell bodies. This shift in enzymatic affinity may lead to the abnormal protein processing that is thought to play a major role in the pathogenesis of Alzheimer disease. The availability of pharmacological and dietary means for altering brain indoleamines raises therapeutic possibilities for inhibiting the abnormal cholinesterase activity associated with Alzheimer disease.

5-Hydroxytryptophan↗
PubMed1963

CHOLINESTERASE IN DENERVATED END PLATES AND MUSCLE FIBRES.

Parallel studies were made of cholinesterase activities and localizations in denervated rat and rabbit gastrocnemius muscle. Koelle's histochemical reaction was used for demonstrating the localization of cholinesterases. Enzyme activities in whole sliced muscle were measured by electrometric titration. The Cartesian ampulla-diver technique was used for cholinesterase activity determinations in end plate regions or in small pieces of the muscle fibre itself. No changes in the activity of cholinesterases (ChE) were found in the whole denervated muscle which would account for its chemical supersensitivity. The ChE distribution pattern was changed so that the end plate region became less active in the denervated muscle than in the normal one. The decrease in ChE activity in the end plates seems to be largely compensated for by an increase of this enzyme elsewhere in the muscle. A possible connection between the spatial spread of cholinesterase activity and the enlargement of the acetylcholine-sensitive surface is discussed.

Acetylcholine↗
PubMed1964

THE LOCALIZATION OF CHOLINESTERASE ACTIVITY IN RAT CARDIAC MUSCLE BY ELECTRON MICROSCOPY.

A method has been developed for localizing sites of cholinesterase activity in rat cardiac muscle by electron microscopy. The method utilizes thiocholine esters as substrates, and is believed to be dependent on the reduction of ferricyanide to ferrocyanide by thiocholine released by enzymatic activity. The ferrocyanide thus formed is captured by copper to form fine, electron-opaque deposits of copper ferrocyanide, which sharply delineate sites of enzymatic activity at the ultrastructural level. Cholinesterase activity in formalin-fixed heart muscle was localized: (a) in longitudinal elements of the sarcoplasmic reticulum, but not in the T, or transverse, elements; and (b) in the A band, with virtually no activity noted in the M band, or in the H zone. The I band was also negative. No activity was detected in the sarcolemma, or in invaginations of the sarcolemma at the level of the Z band. The perinuclear element of the sarcoplasmic (endoplasmic) reticulum was frequently strongly positive. Activity at all sites was completely abolished by omitting the substrates, or by inhibition with eserine 10(-4)M and diisopropylfluorophosphate 10(-5)M. Eserine 10(-5)M completely inhibited reaction in the sarcoplasmic reticulum, and virtually abolished that in the A band. These observations, together with the use of the relatively specific substrates and suitable controls to eliminate non-enzymatic staining, indicate that cholinesterase activity was being demonstrated. The activity in rat heart against different substrates was that of non-specific cholinesterases, in accordance with biochemical data. The activity in the A band was considered to be probably due to myosincholinesterase. It is proposed that the localization of cholinesterases in myocardium at the ultrastructural level should be taken into account in considering the possible functions of these myocardial enzymes, and it is hoped that knowledge of their localization will open up new avenues of approach in considering their physiological role in myocardium, which at present is not definitely known.

Animals↗
PubMed2000

The influence of drug-induced low plasma cholinesterase activity on the pharmacokinetics and pharmacodynamics of mivacurium.

BACKGROUND: The short duration of action of mivacurium results from its rapid hydrolysis by plasma cholinesterase. Bambuterol, an oral bronchodilator, has an inhibiting effect on plasma cholinesterase. The purpose of this study was to evaluate the effect of bambuterol-induced low plasma cholinesterase activity on the pharmacokinetics and pharmacodynamics of mivacurium. METHODS: Fourteen patients received 20 mg bambuterol and 14 patients received placebo orally 2 h before induction of anesthesia. During anesthesia the neuromuscular block was monitored at the thumb using train-of-four nerve stimulation every 12 s and mechanomyography. The times to different levels of neuromuscular recovery after 0.2 mg/kg mivacurium were measured. The concentrations in venous blood of the three isomers and the metabolites of mivacurium were measured using high-performance liquid chromatography. RESULTS: Plasma cholinesterase activity was inhibited a median of 90% (range, 67-97%) after bambuterol. The time to first response to train-of-four nerve stimulation was 15 min (range, 9-21 min) and 59 min (range, 32-179 min) in patients receiving placebo and bambuterol, respectively. The estimated clearances of the isomers were significantly lower and the elimination half-lives of all three isomers significantly prolonged in patients receiving bambuterol. No difference was seen in elimination half-lives of the metabolites. The elimination rate constant from the effect compartment and the potency of mivacurium was not affected by bambuterol. CONCLUSION: A 90% inhibition of plasma cholinesterase activity significantly reduced clearance of the isomers of mivacurium. Correspondingly, the duration of action of 0.2 mg/kg mivacurium was prolonged three- to fourfold, compared with patients not administered bambuterol.

Adult↗
PubMed1970

The relationship between the level of cholinesterase in plasma and the action of suxamethonium in animals.

1. The neuromuscular blocking action of suxamethonium, given by intravenous injection, and the effect upon it of iso-OMPA (tetraisopropyl pyrophosphoramide) in doses which produced marked selective inhibition of cholinesterase in blood were studied in anaesthetized rats and cats, and in mice.2. In cats experiments were also carried out in which suxamethonium was given by intravenous infusion until an effect which remained constant with time was achieved. From the degree of neuromuscular block (under equilibrium conditions) obtained with different infusion rates the infusion rate for 50% reduction in twitch tension of the indirectly stimulated soleus and gastrocnemius muscles (IR50) was calculated. The effect on it of raising the suxamethonium hydrolysing capacity of blood and of selectively reducing the level of cholinesterase in blood by various doses of iso-OMPA was then investigated.3. At relevant stages of each experiment cholinesterase activity in blood was determined with butyrylcholine or benzoylcholine and where appropriate with suxamethonium as substrate.4. The results obtained show that in rats and cats the effectiveness of suxamethonium is unrelated to the level of cholinesterase activity in blood and that raising the suxamethonium hydrolysing capacity in the blood up to 22-fold (in cats) only reduces the IR50 by a factor of 1.6.5. The enhancement of the effectiveness of suxamethonium in the three species (2- to 3-fold in rats, 2- to 4-fold in mice and 7- to 8-fold in cats under the conditions used for comparison) which follows the administration of iso-OMPA is attributable to inhibition of cholinesterase in the tissues.6. It is concluded that the results obtained clearly indicate that the species studied do not give information as regards suxamethonium and its metabolism which is applicable to man.

Acetylcholinesterase↗
PubMed1995

Application of brain cholinesterase reactivation to differentiate between organophosphorus and carbamate pesticide exposure in wild birds.

Brain cholinesterase activity was measured to evaluate pesticide exposure in wild birds. Thermal reactivation of brain cholinesterase was used to differentiate between carbamate and organophosphorus pesticide exposure. Brain cholinesterase activity was compared with gas chromatography and mass spectrometry of stomach contents. Pesticides were identified and confirmed in 86 of 102 incidents of mortality from 29 states within the USA from 1986 through 1991. Thermal reactivation of cholinesterase activity was used to correctly predict carbamates in 22 incidents and organophosphates in 59 incidents. Agreement (P < 0.001) between predictions based on cholinesterase activities and GC/MS results was significant.

Animals↗
PubMed2003

[Seminal profile in workers exposed to cholinesterase inhibitor insecticides].

The objective of this study was to determine the physical, chemical and cytomorphologic characteristics of semen obtained from workers exposed to cholinesterase inhibitor insecticides and compare them with samples of the same nature obtained from unexposed subjects, and in addition, to correlate those findings with blood levels of cholinesterase. The study group consisted of 29 adult males, age range 20-54, that were exposed to cholinesterase inhibitor insecticides during 4 hours per day for a variable lapse (one year minimum), whereas the control group consisted of 30 unexposed individuals of the same gender, and similar age range. A thorough medical examination was performed in every individual. It consisted of an occupational medical history and complete physical exam. A blood sample was obtained in all the subjects in order to determine total cholinesterase levels by the modified S. Hestrin Hydroxamate method. Semen analysis was done in specimens collected after recent masturbation following a 3-day abstinence period. The data was processed and analyzed by the SAS computerized statistics program. The results revealed significant differences between both groups (p < 0.05) for the following variables: sperm count per mL., percentage of fast, mobile and immobile, live and dead spermatozoids. Spermatozoa morphology was found to be within normal limits as established by the WHO. Nevertheless, the differences related to the percentage of big head and amorphous spermatozoids was significant (p < 0.05). The results indicate that cholinesterase inhibitor insecticides affect certain variables of the semen analysis and hence the quality of the semen.

Adult↗
PubMedDate not supplied

Bambuterol, a carbamate ester prodrug of terbutaline, as inhibitor of cholinesterases in human blood.

Bambuterol, the bis-dimethyl carbamate prodrug of terbutaline, was tested for its potency in inhibiting cholinesterases in human blood. Preincubation of blood with bambuterol in the absence of thiocholine ester substrate was essential for obtaining maximal inhibition. The inhibition exerted by bambuterol after such preincubation was reversible and noncompetitive. Bambuterol was an extremely effective inhibitor of cholinesterase when butyrylthiocholine was used as substrate (I50 = 1.7 +/- 0.3 x 10(-8) M, N = 10) whereas it was 2400-fold less efficient in inhibiting cholinesterase with acetylthiocholine as substrate (I50 = 4.1 +/- 0.5 x 10(-5) M, N = 10). Because butyrylthiocholine is the preferred substrate for cholinesterase (EC 3.1.1.8) and acetylthiocholine for acetylcholinesterase (EC 3.1.1.7), these results indicate that bambuterol is a remarkably selective and potent inhibitor of cholinesterase.

Acetylcholinesterase↗
PubMed1973

Comparison of methods for measuring cholinesterase inhibition by carbamates.

The Acholest and tintometric methods are used widely for measuring blood cholinesterase activity after exposure to organophosphorus compounds. However, if applied for measuring blood cholinesterase activity in persons exposed to carbamates, the accuracy of the methods requires verification since carbamylated cholinesterases are unstable. The spectrophotometric method was used as a reference method and the two field methods were employed under controlled conditions. Human blood cholinesterases were inhibited in vitro by four methylcarbamates that are used as insecticides. When plasma cholinesterase activity was measured by the Acholest and spectrophotometric methods, no difference was found. The enzyme activity in whole blood determined by the tintometric method was </= 11% higher than when the same sample was measured by the spectrophotometric method.

Carbamates↗
PubMed1969

The effect on cholinesterase activity of storage of undiluted whole blood sampled from men exposed to o-isopropoxyphenyl methylcarbamate (OMS-33).

An observation made during an operational field trial with o-isopropoxyphenyl methylcarbamate (OMS-33) suggested that the cholinesterase in undiluted blood samples from workers exposed to that insecticide was inhibited during the storage of those samples before assay.A laboratory investigation has now shown that rapid falls of whole-blood cholinesterase activity do indeed occur during the storage of undiluted samples collected from workers at different times after exposure to OMS-33, but that no such change occurs during the same period of time in circulating blood.Several possible explanations are put forward to account for the fact that, although the carbamate persists in the circulating blood for several hours after cessation of exposure, it does not appreciably inhibit cholinesterase in vivo but only under storage conditions in vitro. The implications of this phenomenon, in so far as methods for determining cholinesterase activity in persons exposed to carbamate insecticides are concerned, are discussed; and the authors point out that, whenever storage of undiluted samples precedes the assay, the spectrophotometric method should be regarded as giving results reflecting daily fluctuations of inhibitor concentration rather than as measuring the actual whole-blood cholinesterase in the body.

Blood↗
PubMedDate not supplied

[Synthesis of multiple forms of brain cholinesterases].

Highly purified multiple forms of brain cholinesterase were isolated by a new method. Eight forms were identified as acetyl cholinesterases, seven forms--as butyryl cholinesterases, four forms--as mixed acetyl- and butyryl cholinesterases and four forms--as aliesterases. Biosynthesis of multiple forms of brain cholinesterase was monitored by following incorporation of 14C-glycine into the purified fractions. Cats were killed at different periods (3 hrs, 3,6 and 9 days) after intoxication with isopropyl hydroxymethyl fluorophosphate. The restoration of the enzymatic activity after the inhibition did not correspond to the incorporation of the labelled amino acid into the enzyme protein. There was a transcient increase in the incorporation of the label after an increase in acetylcholine concentration.

Acetylcholinesterase↗
PubMed1983

Improved Ellman procedure for erythrocyte cholinesterase.

The procedure of Dietz et al. (Clin. Chem. 19: 1309-1313, 1973) for plasma cholinesterase (EC 3.1.1.7) gives a background absorbance of 1.4 A when extended to erythrocyte cholinesterase (EC 3.1.1.8) measurement, because the peak absorbance of the reaction product, 5-thionitrobenzoate, coincides with the hemoglobin Soret band at 410 nm. Consequently, the precision of erythrocyte cholinesterase measurements is poor, and the test is restricted to laboratories with a spectrophotometer having a high signal-to-noise ratio. Use of the detergent benzethonium chloride (Hyamine 1622) instead of quinidine sulfate to stop enzyme action allows readings to be made at 440 nm because the hemoglobin band is shifted to 405 nm and its peak intensity is decreased. Moreover, detergent micelle interactions shift the peak absorbance of the 5-thionitrobenzoate from 410 to 435 nm. Overall, the blank absorbance is decreased to about 0.4 A. This results in an assay that is twice as precise as the previous version and is suited for use in a routine laboratory with a moderate-quality spectrophotometer. Thus erythrocyte cholinesterase measurements can readily be made, to complement plasma cholinesterase in the investigation of exposure to organophosphates.

Benzethonium↗
PubMed1993

Cholinesterase activity in postmortem blood as a screening test for organophosphate/chemical weapon exposure.

This study was undertaken to determine whether postmortem blood cholinesterase activity could be used as a screening test for exposure to nerve agents. Whole blood cholinesterase activity at 25 degrees C was analyzed for a one week period in order to simulate the battle field collection problems of: hemolyzed blood samples, delayed recovery of the specimen, and unrefrigerated transfer to the testing facility. A total of 53 nonpreserved post-mortem whole blood specimens were analyzed in triplicate for cholinesterase activity by the delta pH method of Michel. There was a negligible loss of cholinesterase activity by the seventh day of the study. The enzyme activities of the specimens had a mean value (range) of 0.48 (0.20 to 0.74) initially and 0.45 (0.07 to 0.70) pH units after one week. Whole blood from five healthy adults remained essentially unchanged during this period, with an initial value 0.59 (0.52 to 0.67) and a final value of 0.52 (0.46 to 0.62) pH units. To compare postmortem and simulated nerve agent values, aliquots from 18 of the original 53 postmortem specimens were frozen during day one of the study, thawed on day seven and a cholinesterase inhibitor added. These specimens were then analyzed with the other specimens. All values from inhibited specimens were essentially zero (0.0 to 0.01) pH units compared to a range of 0.07 to 0.61 pH units for matched, uninhibited, day seven postmortem specimens. Fifteen actual nonpreserved specimens from the battlefield were analyzed as verification of screen performance. Their results fell within the uninhibited postmortem range above.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Preservation↗
PubMedDate not supplied

[Catalytic properties of cholinesterases immobilized in N-phthalylchitosan and gelatin].

Catalytic properties of human blood erythrocyte acetylcholinesterase, horse blood serum butyrylcholinesterase and squid visual cholinesterase nonimmobilized and immobilized in N-phthalylchitozane and in gelatin have been comparatively studied. Immobilization of cholinesterases in N-phthalylchitozane does not change its catalytic properties in respect to substrates and inhibitors but increases the enzyme stability. Cholinesterase immobilization in the gelatin membrane increases the Michaelis constants and decreases the maximum velocities in the reaction of enzyme hydrolysis of thiocholine esters and (for squid visual ganglia cholinesterase) of indophenylacetate. The effect of irreversible inhibitor diisopropylfluorophosphate and reversible inhibitors N-methyl-4-piperidinyl benzylate and tacrine on cholinesterases immobilized in the gelatin is weaker as compared with the effect on nonimmobilized enzymes. The results obtained are discussed for the effect of immobilization on the active enzyme surface.

Acetylcholinesterase↗