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PubMed1993

Cholinesterases regulate neurite growth of chick nerve cells in vitro by means of a non-enzymatic mechanism.

Cholinesterases present homologies with some cell adhesion molecules; however, it is unclear whether and how they perform adhesive functions. Here, we provide the first direct evidence showing that neurite growth in vitro from various neuronal tissues of the chick embryo can be modified by some, but not all, anticholinesterase agents. By quantifying the neuritic G4 antigen in tectal cell cultures, the effect of anticholinesterases on neurite growth is directly compared with their cholinesterase inhibitory action. BW 284C51 and ethopropazine, inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively, strongly decrease neurite growth in a dose-dependent manner. However, echothiophate which inhibits both cholinesterases, does not change neuritic growth. These quantitative data are supplemented by morphological observations in retinal explant cultures grown on striped laminin carpets, viz., defasciculation of neurite bundles by BW 284C51 and Bambuterol occurs, indicating that these drugs disturb adhesive mechanisms. These data strongly suggest that a) cholinesterases can participate in regulating axonal growth, b) both AChE and BChE can perform such a nonsynaptic function, and c) this function is not the result of the enzyme activity per se, since at least one drug was found that inhibits all cholinesterase activities but not neurite growth. Thus, a secondary site on cholinesterase molecules must be responsible for adhesive functions.

Acetylcholinesterase↗
PubMed1993

Colocalization of cholinesterases with beta amyloid protein in aged and Alzheimer's brains.

The colocalization of beta amyloid protein with the enzymes acetyl- and butyrylcholinesterase was assessed using immunocytochemistry for beta amyloid protein and a sensitive histochemical technique for cholinesterases. In non-demented aged and Alzheimer's disease brains, double-stained sections for cholinesterases and thioflavin-S showed that all thioflavin-S-positive plaques were also positive for cholinesterases, indicating the presence of these enzymes in all plaques with beta-pleated amyloid protein. When amyloid angiopathy was present, cholinesterases were also observed in amyloid-laden vessels walls. Comparison of series of adjacent sections alternatively stained for acetylcholinesterase, beta amyloid protein and butyrylcholinesterase, as well as by double histo-immunocytochemical staining, showed either cholinesterase in a proportion of the preamyloid diffuse plaques. These data indicate that cholinesterases are associated with the amyloid protein from very early stages, when the beta-pleated structure is being formed. Novel functions attributed to acetyl- and butyrylcholinesterase, such us their proteolytic activity either by themselves or in association with heparan sulfate proteoglycans, may play a role in the aggregation or the consolidation processes taking place at the early stages of diffuse plaque formation.

Aged↗
PubMed1991

Interactions of bambuterol with human serum cholinesterase of the genotypes EuEu (normal), EaEa (atypical) and EuEa.

Bambuterol, a carbamate ester prodrug of the bronchodilator terbutaline, was tested as inhibitor and substrate of human serum cholinesterases of the genotypes EuEu (the normal enzyme), EaEa (the atypical enzyme) and EuEa. The IC50 for the normal enzyme was 11 +/- 2.2 nM (mean, SD, N = 10) and for the atypical enzyme 140 +/- 6 nM (N = 13), indicating a much higher affinity of bambuterol to the normal enzyme. The heterozygotes showed a mixed behaviour; the major activity was inhibited like the normal enzyme (IC50 = 9.3 +/- 1.9 nM, N = 9), while a residual activity (10-15%) was inhibited by bambuterol like the atypical enzyme. At a bambuterol concentration of 100 nM each of the three cholinesterase genotypes responded uniquely to bambuterol; the normal enzyme was inhibited to 2.2 +/- 0.9%, the atypical enzyme to 58 +/- 4.6%, and the heterozygote to 10 +/- 1.2% of the basal activity. Bambuterol may therefore be added to the list of inhibitors useful in the genotyping of cholinesterases. Bambuterol was much less efficiently hydrolysed in serum containing the atypical cholinesterase than in serum containing the normal enzyme. The results of the hydrolysis experiments once again illustrate the difference in affinity of bambuterol to the genetic forms of cholinesterase, and also strengthen the evidence that cholinesterase is the major serum enzyme catalysing the hydrolysis of bambuterol.

Cholinesterases↗
PubMed1978

[Cholinesterase, arylesterase and proteinuria. A clinical trial in glomerular and tubular proteinuria (author's transl)].

A study is presented on the activity of cholinesterase (substrate acetylcholine) and of arylesterase (substrate phenylactate) in proteinuria, classified according to the results of electrophoresis of glomerular and tubular proteinuria. Comparison is made with the corresponding serum. The urine is concentrated by dialysis on polyethylene-glycol to 60 g protein per 1000 before determination of the activities. In the presence of equal quantities of protein, cholinesterase is slightly more active in glomerular than in tubular proteinuria. In selective glomerular proteinuria, cholinesterase and arylesterase are less active than in cases with little or no selectivity. Comparison with serum, in each individual case, indicates that the ratio of activity in concentrated urine to that in serum, is higher for cholinesterase and arylesterase in tubular than in glomerular cases, whereas the reverse is true in urine at its natural concentration, on account of the lower degree of proteinuria in tubular cases. The ratio of cholinesterase to arylesterase activity in concentrated urine and serum is determined. Since cholinesterase activity is greatly increased in glomerular cases (nephrosis) this ratio is on average markedly higher in glomerular proteinuria than in serum, whereas it is similar in urine and serum of tubular cases. These results, seen in the light of the molecular weights of the enzymes, are difficult to interpret with certainty, especially as regards tubular proteinuria.

Adult↗
PubMed1984

Multiple regression analysis of the cholinesterase activity with certain physiochemical factors.

Nineteen hundred sixteen agricultural workers who have been living in a rural area in central Japan were studied. Their age, blood pressure, Broca index, hemoglobin content, serum total cholesterol, and activity of serum cholinesterase and transaminase (GOT and GPT) were determined. The relation between the cholinesterase activity and certain physiochemical factors of the subjects was studied. Cholinesterase activity (ChE) is related to certain factors such as age, hemoglobin content (Hb), serum total cholesterol (TCh), transaminase activity (GPT), and Broca index (BI). A multiple regression equation exists between the cholinesterase activity and these factors: ln ChE = a (age) + b (Hb2) + c X ln GPT + d X ln TCh + e BI + f, where a, b, c, d, e, and f are constants. The estimated value of cholinesterase activity agrees with its measured activity. The partial correlation coefficients of the equation can be classified into the following three classes: (1) The partial correlation coefficients of total cholesterol and Broca index are nearly constant without distinction of sex and season. (2) The coefficient of hemoglobin content has a small seasonal and sexual difference. (3) The coefficients of age and GPT have a great seasonal and sexual difference. Using the equation, the most probable value of cholinesterase activity can be estimated. Therefore, the significant changes of its activity may be attributed to the toxic effects of insecticides or the abnormality of liver function.

Adult↗
PubMed1986

Perioral behaviors induced by cholinesterase inhibitors: a controversial animal model.

Perioral behaviors induced by neuroleptic drugs have been interpreted as an animal model of tardive dyskinesia. However, these behaviors have also been induced or enhanced by physostigmine, a cholinesterase inhibitor. The latter result is contradictory to the clinical effect of physostigmine in human tardive dyskinesia. In view of this contradiction and other considerations, perioral behaviors have also been interpreted as a model of acute dystonia. The present experiments replicated an earlier failure to observe spontaneous perioral behaviors after long-term neuroleptic treatment in rats as well as the paradoxical effect of physostigmine. The effect of physostigmine was also compared to phenylmethanesulfonyl fluoride and methanesulfonyl fluoride, irreversible CNS active cholinesterase inhibitors. There were significant differences between the effects of the various cholinesterase inhibitors and their interactions with perioral behaviors and neuroleptic treatment. It is concluded that the effects of cholinesterase inhibitors on perioral behaviors in rodents may not be accounted for entirely by cholinesterase inhibition. Further experiments using additional agonists and antagonists will be required to clarify the behavioral effects of these cholinesterase inhibitors.

Animals↗
PubMed1987

Serum cholinesterase levels after thermal injury. Is treatment required?

Changes in serum cholinesterase (also known as pseudo- or non-specific cholinesterase) activity have been measured in 20 patients after thermal injury. In 19 patients a marked fall was noted at around day 5 post-burn, and recovery to normal levels was variable and in some cases prolonged. A variety of symptoms, for example, dyspnoea and confusion, have been attributed to lowered serum cholinesterase activity and some workers have gone so far as to advocate blood transfusion to treat such a condition (Price et., 1970; Frohlich, 1977). In this study we found 13 patients (65 per cent) with such symptoms coexisting with a low serum cholinesterase activity. However, we do not believe these symptoms were directly attributable to the low enzyme activity for the following reasons: In only three of the 13 patients were symptoms observed at times when the lowest cholinesterase activity was recorded. A conventional explanation for these symptoms was available, except in three cases with abdominal distension. In six cases no symptoms were observed despite very low cholinesterase levels.

Acetylcholinesterase↗
PubMed2006

On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases.

Cholinesterases, in addition to their well-known esterase action, also show an aryl acylamidase (AAA) activity whereby they catalyze the hydrolysis of amides of certain aromatic amines. The biological function of this catalysis is not known. Furthermore, it is not known whether the esterase catalytic site is involved in the AAA activity of cholinesterases. It has been speculated that the AAA activity, especially that of butyrylcholinesterase (BuChE), may be important in the development of the nervous system and in pathological processes such as formation of neuritic plaques in Alzheimer's disease (AD). The substrate generally used to study the AAA activity of cholinesterases is N-(2-nitrophenyl)acetamide. However, use of this substrate requires high concentrations of enzyme and substrate, and prolonged periods of incubation at elevated temperature. As a consequence, difficulties in performing kinetic analysis of AAA activity associated with cholinesterases have hampered understanding this activity. Because of its potential biological importance, we sought to develop a more efficient and specific substrate for use in studying the AAA activity associated with BuChE, and for exploring the catalytic site for this hydrolysis. Here, we describe the structure-activity relationships for hydrolysis of anilides by cholinesterases. These studies led to a substrate, N-(2-nitrophenyl)trifluoroacetamide, that was hydrolyzed several orders of magnitude faster than N-(2-nitrophenyl)acetamide by cholinesterases. Also, larger N-(2-nitrophenyl)alkylamides were found to be more rapidly hydrolyzed by BuChE than N-(2-nitrophenyl)acetamide and, in addition, were more specific for hydrolysis by BuChE. Thus, N-(2-nitrophenyl)alkylamides with six to eight carbon atoms in the acyl group represent suitable specific substrates to investigate further the function of the AAA activity of BuChE. Based on the substrate structure-activity relationships and kinetic studies, the hydrolysis of anilides and esters of choline appears to utilize the same catalytic site in BuChE.

Amides↗
PubMed2006

The impact of aerial application of organophosphates on the cholinesterase levels of rural residents in the Vaalharts district, Northern Cape Province, South Africa.

A cluster of Guillaine-Barre syndrome cases in the Vaalharts region, South Africa prompted an investigation of the impact of aerial organophosphate spraying on cholinesterase levels of residents in the region. A prospective study of cholinesterase levels among residents and workers in the area and a control area was performed. Standardized red blood cell cholinesterase levels amongst participants were monitored before (round 1), during (round 2), and after (round 3) the 1996/1997 aerial spraying season. Participants were assigned environmental exposure categories based on the time since (within 10 or 30 days) and distance from (on farm, on neighboring farm, <10 km from farm) aerial pesticide application. There were 342 participants in round 1, of whom 78% participated in round 2, 62% in round 3, and 56% in all three rounds. There was an increase in cholinesterase levels in round 2 (mean increase = 5.96+/-6.25 IU/g hemoglobin) and then a decrease in round 3 (6.17+/-6.51), significantly associated with environmental exposure (participants living on farm or neighboring farm and <10 km from spraying area) controlling for age, gender, alcohol dependence, and usual and recent domestic and occupational pesticide use (e.g., for round 2-round 1 cholinesterase differences, beta; (exposed group relative to unexposed)=5.72+/-1.21 IU/g hemoglobin, P = 0.000, R2 = 0.27, n = 171). The results show a shift in cholinesterase levels associated with residence in the spraying area, but in the direction opposite to that expected from the spraying of pesticides. Seasonal fluctuations in ambient temperature during the study may have influenced the results.

Adult↗
PubMed1999

Absence of neurovisual effects due to tissue and blood cholinesterase depression in a chronic disulfoton feeding study in dogs.

Technical grade disulfoton (DiSyston) was fed to Beagle dogs (four animals per sex and treatment level) at nominal concentrations of 0, 0.5, 4 and 12 ppm for 1 year. The purpose of this study was to characterize the potential general and neurovisual toxicity according to routine Environmental Protection Agency (EPA) guideline requirements, and by use of ancillary ocular and neurologic tests established in this Laboratory. Ophthalmological tests included: ocular tissue cholinesterase and histopathology, electroretinography (ERG), tracking, refractivity, intraocular pressure and pachymetry (corneal thickness) measurements. Neurological examinations included; peripheral and cranial reflex tests, task performance tests, gait and behavioral observations, and rectal temperature measurements. Plasma, erythrocyte and corneal cholinesterase were significantly depressed at 4 and 12 ppm in both sexes. Brain cholinesterase was depressed at 4 and 12 ppm in females. Retinal cholinesterase was depressed at 4 ppm in females and at 12 ppm in males. Ciliary body cholinesterase was depressed at 12 ppm in both sexes. Despite these cholinergic effects, there were no ophthalmologic findings in measurements of ERG, tracking, refractivity, intraocular pressure or pachymetry. There were no clinical neurology findings related to compound administration. We conclude that 0.5 ppm was a no-observable effect level (NOEL), and effects were limited to cholinesterase changes that had no detectable physiologic impact. This study demonstrates that special mechanistic investigations incorporated within guideline studies, enhances scientific integrity and can minimize the need for dedicated organ system studies.

Animals↗
PubMedDate not supplied

Cholinesterase inhibitors induce growth cone collapse and inhibit neurite extension in primary cultured chick neurons.

Cholinesterase inhibitors are commonly prescribed medicines in neurological and anesthesiological clinical practices at relatively high doses. Recent studies report that cholinesterases, originally described as neurotransmitter degradation enzymes, are expressed in the developing central nervous systems. They are hypothesized to play an important role during the establishment of neuronal cytoarchitecture. In this study, the effects of several clinically utilized cholinesterase inhibitors on one potential aspect of neuronal development were examined using a primary culture system of chick central and peripheral neurons. Three cholinesterase inhibitors, physostigmine, neostigmine, and edrophonium, suppressed the activity of the leading edges of the extending axons (the nerve growth cones) dose dependently. Filopoda and lamellipodia of nerve growth cones were collapsed by the exposure to the cholinesterase inhibitors. This action was quick, mostly within 5 min, and partly irreversible. The lowest concentration that could induce statistically significant growth cone collapse was 10(-5) M for physostigmine, 10(-4) M for neostigmine, and 10(-2) for edrophonium, respectively. The ED50 values for the growth cone collapsing activity were approximately, 10(-3) M for physostigmine. 10(-2.5) M for neostigmine, and 10(-2) M for edrophonium both in dorsal root ganglion culture and in retinal culture. Even though the result of this in vitro study cannot be applied directly to the in vivo situation, physicians should consider the potential detrimental effects of cholinesterase inhibitors to growing and regenerating nervous tissues.

Animals↗
PubMed1989

Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase.

A point mutation in the gene for human serum cholinesterase was identified that changes Asp-70 to Gly in the atypical form of serum cholinesterase. The mutation in nucleotide 209, which changes codon 70 from GAT to GGT, was found by sequencing a genomic clone and sequencing selected regions of DNA amplified by the polymerase chain reaction. The entire coding sequences for usual and atypical cholinesterases were compared, and no other consistent base differences were found. A polymorphic site near the C terminus of the coded region was detected, but neither allele at this locus segregated consistently with the atypical trait. The nucleotide-209 mutation was detected in all five atypical cholinesterase families examined. There was complete concordance between this mutation and serum cholinesterase phenotypes for all 14 heterozygous and 6 homozygous atypical subjects tested. The mutation causes the loss of a Sau3A1 restriction site; the resulting DNA fragment length polymorphism was verified by electrophoresis of 32P-labeled DNA restriction fragments from usual and atypical subjects. Dot-blot hybridization analysis with a 19-mer allele-specific probe to the DNA amplified by the polymerase chain reaction distinguished between the usual and atypical genotypes. We conclude that the Asp-70----Gly mutation (acidic to neutral amino acid substitution) accounts for reduced affinity of atypical cholinesterase for choline esters and that Asp-70 must be an important component of the anionic site. Heterogeneity in atypical alleles may exist, but the Asp-70 point mutation may represent an appreciable portion of the atypical gene pool.

Base Sequence↗
PubMedDate not supplied

Cholinesterase and self-reported pesticide exposure among pregnant women.

Ascertainment of exposure to cholinesterase-inhibiting pesticides in pregnant subjects is complicated by altered enzyme activity that results from metabolic changes associated with pregnancy. Nevertheless, this study found a high correlation (Pearson chi-square = 13.67, p = .008) between classification of pesticide exposure using self-reported interview information and plasma cholinesterase activity for 203 pregnant women for whom three trimester cholinesterase values were available. All plasma cholinesterase activity values were referenced, by trimester, to a larger sample of 1,050 plasma cholinesterase values from 535 pregnant women. Subjects who lived nearest to agricultural land and who reported that they worked with pesticides in agricultural and other occupations tended to have lower plasma cholinesterase activity than those who reported use of household pesticides only.

Adolescent↗
PubMedDate not supplied

Chronic neurologic sequelae to cholinesterase inhibition among agricultural pesticide applicators.

To test the hypothesis that chronic neurologic sequelae are associated with cholinesterase depression short of frank organophosphate poisoning, we compared 45 male subjects who had a history of moderate cholinesterase inhibition with 90 male subjects who had neither past cholinesterase inhibition nor current pesticide exposure. Cholinesterase-inhibited subjects were defined as having had a history of (a) red blood cell cholinesterase at 70% or less of baseline or (b) plasma cholinesterase at 60% or less of baseline absent symptoms of frank poisoning. In the subject comparison evaluation, only 1 of 27 neurologic tests (i.e., serial digit performance) was significant statistically, but it was opposite of the direction hypothesized. In a companion study for which the same battery of neurologic tests and the same subjects were used, neurologic sequelae were related to high exposures among subjects who sought treatment for organophosphate poisoning. The data in the current study, in which the subjects experienced lower exposures short of frank poisoning, provide some evidence that preventing acute organophosphate poisoning also prevents neurologic sequelae.

Adult↗
PubMedDate not supplied

Prevalence of congenital deficiency in serum cholinesterase.

The most economical blood test for the monitoring of workers who are exposed to organophosphate pesticides is serum cholinesterase; however, serum cholinesterase can be affected by conditions other than pesticide exposure. The results of studies in Europe indicate a 4% prevalence of congenital serum cholinesterase deficiency. Prevalence rates in the United States have not been reported. In this study, 127 workers who were part of an employee health program were evaluated. Workers who had decreased serum cholinesterase levels on baseline testing before pesticide exposure were evaluated for a congenital deficit in serum cholinesterase. Five (3.9%) individuals had baseline measurements below the laboratory normal reference value: 4 (3.1 %) were heterozygote for the deficiency, and the remaining individual did not return to test for the genetic deficiency. No one was found to have the homozygote deficiency. The prevalence of congenital deficiency in serum cholinesterase in a midwestern population was 3.1-3.9%. We found it useful to incorporate the knowledge of who has a congenital deficiency into our employee health program, the purpose of which is to monitor workers who spray organophosphates.

Adult↗
PubMed1975

Serum cholinesterase activity in burned patients. I: biochemical findings.

The purpose of the study was to determine the magnitude and the aetiology of alterations in serum cholinesterase activity (pseudocholinesterase) in burned patients. Sixty burned patients with an estimated area of burn between 3 and 72% of body surface were investigated. Serum cholinesterase activity, serum albumin concentration and serum bilirubin were measured at various time intervals. The magnitude as well as the rate of fall of serum cholinesterase activity was found to be closely correlated with the severity of burn injury. Minimum levels were often reached 5 to 6 days after the burn injury, at which time the activity might have been depressed by more than 80 per cent. In the most severely burned patients, the activity sometimes remained low for months despite wound healing. Apart from the severity of the burn injury in the individual patient, several important factors determined the level of serum cholinesterase activity at a given time. These included the presence or absence of local or systemic infections, the event of recent surgery such as slough removal or skin grafting, and blood transfusions. The decrease in serum albumin concentration following the burn injury occurred earlier than the decrease in serum cholinesterase activity. Minimum levels were often reached during the first 24 h, after which time the concentration rose to reach fairly constant but decreased levels after 4 to 5 days. Apart from this initial phase, the changes in serum albumin concentration were roughly proportional to the changes in serum cholinesterase activity. The possible reasons for these findings are discussed.

Adolescent↗
PubMed1985

Substance P in human plasma is degraded by dipeptidyl peptidase IV, not by cholinesterase.

Human serum cleaves two dipeptides from the N-terminus of the neurohormone substance P. It has been suggested that this degrading activity is inherent to serum cholinesterase. We oppose this, because it turned out that highly purified serum cholinesterase contains traces of dipeptidyl peptidase IV, an enzyme known to attack the N-terminus of substance P. The peptidase is incompletely separated from cholinesterase during the procainamide-gel affinity chromatography as the last step of the usual purification procedure. Physostigmine completely inhibits the hydrolysis of butyrylthiocholine by such purified cholinesterase preparations, but not their substance P-degrading activity. Vice versa, epsilon-carbobenzoxy-lysylproline, an inhibitor of dipeptidyl peptidase IV, inhibits the peptidase activity of these preparations more than their esterase activity. After rechromatography on procainamide gel the peptidase is completely separated and the remaining cholinesterase has lost its substance P-degrading activity. We conclude that the N-terminal region of substance P is not degraded by cholinesterase but by the contaminating dipeptidyl peptidase IV, a different serine enzyme.

Cholinesterases↗
PubMedDate not supplied

Predictive value of preoperative serum cholinesterase concentration in patients with liver dysfunction undergoing cardiac surgery.

OBJECTIVE: There are an increasing number of patients with severe liver dysfunction subjected to open heart surgery. This retrospective study was designed to assess operative results and clarify the degree of liver injury in patients with liver dysfunction undergoing open heart surgery. In addition, determinants influencing their prognosis were assessed. METHODS: In a 9-year period from 1988 to 1996, we operated on 31 patients with posthepatitis liver dysfunction and 16 with chronic passive congestion of the liver. This group was 2.3% and 1.6% of the 1368 patients undergoing cardiac surgery in the same period. We compared several perioperative factors between survivors and nonsurvivors to determine risk factors affecting mortality. RESULTS: In the group with posthepatitis liver dysfunction, the postoperative course of 5 patients among 31 (16.1%) was poor. Serum cholinesterase concentration was lower only in the nonsurvivor group (nonsurvivor vs survivor: 1979+/-949 vs 3515+/-1424 IU/I, p < 0.05). All patients with cholinesterase < 2000 IU/L died. The duration of CPB (212+/-53 vs 150+/-54 minutes, p < 0.03) and ACC time (151+/-38 vs 96+/-40 minutes, p < 0.02) was longer in the nonsurvivor group. In the group with chronic passive congestion, the postoperative course of 5 of 16 (31.3%) patients with valvular disease was poor. Serum cholinesterase concentration was lower only in the nonsurvivor group (nonsurvivor vs survivors: 2006+/-435 vs 3483+/-1442 IU/L, p < 0.02), and all patients with cholinesterase < 2000 IU/L died. Postoperative bleeding was greater in the nonsurvivor group (3327+/-2106 vs 1428+/-643 mL, p < 0.05). Multivariate logistic regression analysis including the described pre- and intraoperative factors identified only serum cholinesterase concentration (F = 9.18) as significant. CONCLUSIONS: A low value of preoperative serum cholinesterase (< 2,000 IU/L) is thought to be the predictor of prognosis after open heart surgery in patients with severe posthepatitis and congestive liver dysfunction. Operative factors (cardiopulmonary time in posthepatitis liver dysfunction and postoperative bleeding in the congestive liver dysfunction) also influenced the prognosis.

Adolescent↗