Plasma Butyrylcholinesterase Activity Research Articles

Decreased Activity of Circulating Butyrylcholinesterase in Blood Is an Independent Prognostic Marker in Pancreatic Cancer Patients.

Introduction: The activity of butyrylcholinesterase (BChE) in blood reflects liver function and has recently been associated with systemic inflammatory response and tumor cachexia. As these conditions have been previously linked with pancreatic cancer (PC), the purpose of the present study was to evaluate the prognostic impact of plasma BChE in PC. Methods: Data from 574 consecutive PC patients, treated between 2004 and 2018 at a single academic center, was evaluated. The primary endpoint was cancer-specific survival (CSS), analyzed by Kaplan–Meier curve, and both univariate and multivariate Cox proportional models. Results: BChE activity negatively correlated with other liver parameters (bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and C-reactive protein (CRP)), and positively correlated with albumin levels, respectively (p < 0.01). In univariate analysis, a low plasma BChE activity was a factor of poor CSS (hazard ratio: 1.4, 95% confidence interval: 1.129–1.754, p = 0.002). In multivariate analysis, tumor stage, tumor grade, administration of chemotherapy, bilirubin levels and a low BChE activity (hazard ratio: 1.42, 95% confidence interval: 1.10–1.82; p = 0.006) were identified as independent prognostic factors. Conclusion: Decreased activity of BChE in blood plasma predicts shorter survival time in PC patients. Therefore, BChE might be helpful in additional stratification of patients into different prognostic risk groups.

Assessment of DNA damage and cholinesterase activity in soybean farmers in southern Brazil: High versus low pesticide exposure

The aim of this study was to evaluate the DNA damage in soybean growers during two agricultural periods of a crop season (high and low exposure) and a control group, as well as butyrylcholinesterase (BChE) activity during these exposure periods in order to estimate the degree of BChE inhibition for the exposed group. DNA damage in peripheral whole blood was evaluated by the comet assay and plasma BChE activity was accessed as a measure of exposure to cholinesterase inhibitors. None of the soybean growers reported using full Personal Protective Equipment (PPE). BChE was lower in high exposure period than in low exposure period and DNA damage index was significantly increased in the high exposure period than in the low exposure period. In addition, DNA damage in both exposure periods was higher than control group. No correlation was found between exposure time and DNA damage and BChE activity. However, negative correlation was observed between DNA damage in high and low exposure periods. The results indicate that soybean growers are exposed to cholinesterase inhibitors and to pesticides mixtures with genotoxic potential.

A pilot clinical study of the neuromuscular blocker rocuronium to reduce the duration of ventilation after organophosphorus insecticide poisoning

Background: A common manifestation of organophosphorus insecticide self-poisoning is prolonged respiratory failure due to neuromuscular junction dysfunction and likely nicotinic receptor overstimulation. We aimed at collecting preliminary data on whether addition of the competitive nicotinic antagonist rocuronium to standard early therapy might be clinically feasible and associated with reduced duration of ventilation.Methods: A pilot three-arm dose–response phase II trial was set up to compare bolus doses of rocuronium bromide titrated to produce initial >95% or 50% inhibition of neuromuscular function, measured using acceleromyography, plus standard treatment, versus standard treatment alone. After attaining inhibition, patients receiving bolus rocuronium then received rocuronium infusions for a maximum of 120 h. Primary outcome was duration of intubation; secondary outcome was case fatality. Plasma butyrylcholinesterase activity was measured throughout the inpatient stay. Blood was analysed to confirm the organophosphorus insecticide ingested.Results: Forty-five patients were randomised to receive: rocuronium to initially attain 95% inhibition (Roc>95, n = 15), rocuronium to initially attain 50% inhibition (Roc50, n = 14), or no rocuronium (control, n = 16). The most commonly ingested pesticide was profenofos (29/45, 64.4%). Butyrylcholinesterase activity remained severely inhibited for the duration of the study for most patients. Case fatality was 9/45 (20%) and similar across study arms: control 3/16 (18.8%), Roc50 4/14 (28.6%) and Roc>95 2/15 (13.3%) (p = .5842). When excluding patients who died, median [IQR] duration of intubation was significantly longer in the Roc50 (259.5 [176–385] h) and Roc>95 (226.8 [186–355] h) groups compared to controls (88.5 [47–160] h, p = .0162 and p = .0016, respectively).Conclusions: In this pilot dose–response study, we found no evidence that rocuronium in addition to standard therapy reduced the duration of intubation. It is possible that it worsened neuromuscular junction function. Further clinical research, including testing of shorter duration regimens, needs to be performed before nicotinic antagonists can be used in the clinical management of OP poisoning.

Repeated bifenthrin exposure alters hippocampal Nurr-1/AChE and induces depression-like behavior in adult rats

Exposure to insecticides has been associated with depression-like symptoms, especially among occupationally exposed populations, such as farmers. Although the neurotoxicity of pyrethroids such as bifenthrin (BF) is well established, it is still unclear whether exposure to BF may have deleterious effects on the hippocampus and thus behavior. We verified the hypothesis that repeated exposure to BF in a rat model elicits neurochemical and behavioral alterations, the latter of which reflects depression-related symptoms. Adult male Wistar rats (n = 12 per group) were orally administered with different doses of BF (0.6 or 2.1 mg/kg body weight (b.w.)) on a daily basis for 60 days; control rats received the vehicle (corn oil). Different biochemical changes were assessed in the hippocampus, a region of the brain regulating spatial memory; behavioral tests were also conducted. Our results revealed depressive-like behaviors that were expressed by increased despair behavior in the Forced-swimming test. Repeated exposure to BF also decreased acetylcholinesterase (AChE) activity in the hippocampus and butyrylcholinesterase (BuChE) activity in plasma. A significant reduction in the activities of hippocampal membrane-bound ATPases (Na+/K+-ATPase and Mg2+-ATPase) was also observed in BF-treated rats compared to controls. Furthermore, a significant decrease in mRNA expression and protein synthesis of both AChE and orphan nuclear receptor (Nurr-1), as well as in the expression of muscarinic–cholinergic receptor (M1 mAchR) and nicotinic–cholinergic receptor (nAchR2α) was observed in the hippocampus of treated rats compared to controls. Also, BF exposure induced apoptosis as assessed by hippocampal Casp-3 protein levels. Our findings suggest that repeated exposure to BF affects hippocampal signaling and Nurr-1/AChE, and this was accompanied by depression-like state in adult rats.

Assessment of genotoxicity and cholinesterase activity among women workers occupationally exposed to pesticides in tea garden

To assess the effects of exposure to pesticides in tea garden women workers, the present study evaluated the activities of erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) as biomarkers of pesticide exposure and DNA damage by comet assay as a biomarker of genotoxicity in peripheral blood lymphocytes. We examined 143 women subjects including 77 women workers exposed to pesticide in tea garden (exposed) and 66 women subject with no history of occupational exposure to pesticides (non-exposed). The two groups had similar mean ages, BMI and personal habits. The results revealed that exposed group had lower activity of AChE (2.86 ± 0.75 vs. 3.93 ± 0.87 U/ml) BChE (2.02 ± 0.74 vs. 2.60 ± 0.74 U/ml, p < 0.001) than those of non-exposed group. The mean comet parameters such as tail length (TL), % DNA in tail, tail moment (TM) and olive tail moment (OTM) used to measure DNA damage were significantly elevated in exposed workers compared to non-exposed (p < 0.001). There was no variation observed in Cholinesterase (ChEs) activity and Comet assay parameter based on age, personal habits, years of exposure and use of personal protective equipments (PPEs) except BChE activity. The multiple regression analysis showed no association of confounding factors on end points measured except slight negative association of BMI with tail length. Therefore this study suggests that the workers in tea garden might have exposed to pesticide through their occupation on a regular interval. Although this study could able to associate it with their occupational exposure, the role of other DNA damaging factors cannot be ruled out. Our study finding indicate the necessity of periodic monitoring of these biomarkers along with imparting education and training to minimise the risk.

Effects of simvastatin and fenofibrate on butyrylcholinesterase activity in the brain, plasma, and liver of normolipidemic and hyperlipidemic rats.

The study objective was to test the hypothesis that simvastatin and fenofibrate should cause an increase in butyrylcholinesterase (BuChE) activity not only in the plasma and liver but also in the brain of normolipidemic and hyperlipidemic rats. Catalytic enzyme activity was measured using acetylthiocholine (ATCh) and butyrylthiocholine (BTCh) as substrates. Normolipidemic and hyperlipidemic rats were divided in four groups receiving 50 mg/kg of simvastatin a day or 30 mg/kg of fenofibrate a day for three weeks and three control groups receiving saline. Simvastatin and fenofibrate caused an increase in brain BuChE activity in both normo- and hyperlipidemic rats regardless of the substrate. The increase with BTCh as substrate was significant and practically the same in normolipidemic and hyperlipidemic rats after simvastatin treatment (14-17% vs controls). Simvastatin and fenofibrate also increased liver and plasma BuChE activity in both normolipidemic and hyperlipidemic rats regardless of the substrate. In most cases the increase was significant. Considering the important role of BuChE in cholinergic transmission as well as its pharmacological function, it is necessary to continue investigations of the effects of lipid-lowering drugs on BuChE activity.

Assay optimisation and age-related baseline variation in biochemical markers in Lesser Black-backed gulls

Free-ranging animals are often used as bioindicators of both short- and long-term changes in ecosystem health, mainly to detect the presence and effects of contaminants. Birds, and gulls in particular, have been used as bioindicators over a broad range of marine and terrestrial ecosystems. In this study, we standardise the conditions for the use of a suite of biochemical markers in non-destructive matrices of Lesser Black-backed Gull (Larus fuscus) to facilitate future biomonitoring of marine and terrestrial contaminants. We characterized cholinesterase (ChE) in plasma and optimized assay conditions for ChE activity as a marker of neurotoxic damage. Moreover, we quantified variation in activity of ChE, lactate dehydrogenase (LDH), glutathione-S-transferase (GST) and catalase (CAT) as well as variation ranges of lipid peroxidation (LPO), in free-ranging adults and captive chicks. The main ChE form present in plasma of both adults and chicks was butyrylcholinesterase (BChE) followed by acetylcholinesterase (AChE), whose relative proportion in plasma tended to decrease with increased chick age. LPO levels and GST activity in blood cells (BCs) decreased significantly with increasing chick age, while BChE and LDH activity in plasma were not age-dependent. CAT in BCs tended to decline non-significantly in older chicks. Results of this study underscore the importance of standardising assay conditions and assessing intrinsic baseline variation in biochemical markers, before biochemical quantification. Data presented here provide a foundation for future use of BChE and LDH activity in plasma, as well as oxidative stress markers (LPO, CAT and GST) in BCs, to monitor environmental stress effects in Lesser Black-backed gulls.

Atropine counteracts the depressive-like behaviour elicited by acute exposure to commercial chlorpyrifos in rats

Acute organophosphate (OP) poisoning induces well-known signs of toxicosis related to acetylcholinesterase (AChE) inhibition. However, the relationship between acute OP poisoning and the onset of psychiatric disorders remains unclear. Thus, we investigated behavioural and biochemical consequences of acute exposure to the OP chlorpyrifos in male rats and also the effectiveness of the antidotes atropine and pralidoxime on reversing these changes. A sub-lethal dose of commercial chlorpyrifos (20 mg/kg, i.p.) elicited signs of acute toxicosis during the first hours after its injection in rats. Twenty-four hours after treatment, this single dose of chlorpyrifos induced a depressive-like behaviour in the rat forced swimming test without impairing locomotor activity. At this time (24 h), chlorpyrifos decreased plasma butyrylcholinesterase (BChE) activity and hippocampal, striatal and prefrontal cortical AChE activity in rats. The behavioural and biochemical consequences of acute chlorpyrifos poisoning do not seem to be long lasting, since 30 days later they were absent. We evaluated whether these behavioural and biochemical consequences of acute chlorpyrifos treatment would be reversed by the antidotes atropine (10 mg/kg i.p.) and/or pralidoxime (40 mg/kg; i.p.) given 1 h after poisoning. Pralidoxime partially reactivated the AChE activity in the prefrontal cortex, but not in the hippocampus and striatum. Atropine attenuated the depressive-like behaviour induced by chlorpyrifos in rats. Our results suggest that acute chlorpyrifos poisoning induces a transient depressive-like behaviour possible related to hippocampal AChE inhibition. They suggest that treatment with atropine and pralidoxime seems to be insufficient to counteract all the effects of OP acute poisoning, at least in rats.

Blood Plasma Pseudocholinesterase as a Potential Biomarker of Autoimmune Diseases

We studied the blood plasma butyrylcholinesterase (BChE, pseudocholinesterase) activity as a potential marker for differentiating such autoimmune pathologies as type 1 diabetes mellitus (DM1), autoimmune thyroiditis (AIT) and rheumatoid arthritis (RA) from diseases having similar symptoms but different etiology. The blood plasma pseudocholinesterase activity was analyzed for patients with different types of diabetes mellitus. We showed its fivefold increase in DM1 compared to the control group, while in the second type of diabetes, which is metabolic pathology, it decreases two times. It was demonstrated that the activity of blood plasma BChE in patients with AIT and RA also increased fivefold compared to the group of patients without autoimmune disorders. Thus, the butyrylcholinesterase activity increases in diseases of an autoimmune nature, whereas in metabolic pathology it has the tendency to decrease; it indicates the adequacy of the selected criterion for the further development of a screening test-system that would allow differentiation of autoimmune diseases from the diseases of another origin, but with similar symptoms.

Chimeric mice with humanized liver as a model for testing organophosphate and carbamate pesticide exposure.

BACKGROUNDDiagnosis of acute intoxication with organophosphate (OP) or carbamate (CM) pesticides in humans is achieved by measuring plasma butyrylcholinesterase (BuChE) activity. However, BuChE activity is not an ideal biomarker in experimental animal models. The aim of this study was to establish an experimental mouse model for evaluating exposure to OP and CM pesticides by monitoring BuChE activity using chimeric mice in which the liver was reconstituted with human hepatocytes.RESULTSA single oral administration of acephate (300 mg/kg), chlorpyrifos (10 mg/kg), fenobucarb (300 mg/kg) or molinate (250 mg/kg) in chimeric mice led to inhibition of >95%, > 95%, 28% and 60% of plasma BuChE activity after 7, 0.5, 0.5 and 7 h, respectively. Dose‐dependent decreases in plasma BuChE activity were also observed for acephate and chlorpyrifos. A 5‐day repeated‐dose study with 10 or 30 mg/kg acephate found a constitutive reduction in plasma BuChE activity to 80% and 70% of pre‐dose levels, respectively.CONCLUSIONChanges in plasma BuChE activity in chimeric mice with humanized liver clearly reflected the exposure levels of OP and CM pesticides. These results suggest that the humanized‐liver mouse model may be suitable for estimating levels of exposure to these pesticides in humans. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Alterations in acetylcholinesterase and butyrylcholinesterase activities in chronic obstructive pulmonary disease: relationships with oxidative and inflammatory markers.

This work focused on finding a relationship between acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities and the development and severity of COPD. The possible link of these enzymes to oxidative and inflammatory processes was also investigated. The study included 229 healthy controls and 153 COPD patients. Erythrocyte AChE and plasma BChE activities were determined using spectrophotometric methods. Markers related to the oxidative status including thiobarbituric acid-reactive substances (TBARS), total protein carbonyls (PCs), advanced oxidation protein products (AOPP), reduced glutathione, nitric oxide, and peroxynitrite were measured. We also evaluated the activity of glutathione peroxidase, catalase, and superoxide dismutase in the plasma and erythrocytes. Serum levels of IL-6 and TNF-α were measured by the enzyme-linked immunosorbent assay. COPD patients showed increased AChE and BChE activities in comparison to healthy controls. Interestingly, AChE activity was higher in COPD smokers than in nonsmokers, while no difference was revealed for BChE. In addition, our results showed an inverse correlation between AChE activity and the levels of IL-6 in COPD smokers. Positive correlations were found, in COPD smokers, between plasma BChE activity and the levels of several biomarkers of protein oxidative damage including AOPP and PC. Our findings suggest that the alterations in AChE and BChE activities may be related to the oxidative and inflammatory processes in COPD patients rendering these enzymes as markers of COPD disease.

Evaluation of chlorpyrifos toxicity through a 28-day study: Cholinesterase activity, oxidative stress responses, parent compound/metabolite levels, and primary DNA damage in blood and brain tissue of adult male Wistar rats

In this 28 day-study, we evaluated the effects of the insecticide chlorpyrifos orally administered to Wistar rats at doses 0.160, 0.015, and 0.010 mg/kg b. w./day. Following treatment, total cholinesterase activity and activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were measured. Oxidative stress responses were evaluated using a battery of endpoints to establish lipid peroxidation, changes in total antioxidant capacity, level of reactive oxygen species (ROS), glutathione (GSH) level and activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase. Using HPLC-UV DAD analysis, levels of the parent compound and its main metabolite 3,5,6-trichloro-2-pyridinol in plasma and brain tissue were measured. The genotoxic effect was estimated using alkaline comet assay in leukocytes and brain tissue. The exposure did not result in significant effects on total cholinesterase, AChE and BChE activity in plasma and brain tissue. Lipid peroxidation slightly increased both in plasma and brain tissue. Total antioxidant capacity, ROS and GSH levels were marginally influenced by the exposure. Treatment led to significant increases of GSH-Px activity in blood, SOD activity in erythrocytes and a slight increase of catalase activity in plasma. HPLC-UV DAD analysis revealed the presence of both the parent compound and its main metabolite in the plasma of all of the experimental animals and brain tissue of the animals treated at the two higher doses. All of the tested doses of chlorpyrifos were slightly genotoxic, both to leukocytes and brain tissue. Our results call for further research using other sensitive biomarkers of effect, along with different exposure scenarios.

Subacute pyridostigmine exposure increases heart rate recovery and cardiac parasympathetic tone in rats.

Heart rate recovery (HRR) describes the rapid deceleration of heart rate after strenuous exercise and is an indicator of parasympathetic tone. A reduction in parasympathetic tone occurs in patients with congestive heart failure, resulting in prolonged HRR. Acetylcholinesterase inhibitors, such as pyridostigmine, can enhance parasympathetic tone by increasing cholinergic input to the heart. The objective of this study was to develop a rodent model of HRR to test the hypothesis that subacute pyridostigmine administration decreases cholinesterase activity and accelerates HRR in rats. Ten days after implantation of radiotelemetry transmitters, male Sprague Dawley rats were randomized to control (CTL) or treated (PYR; 0.14mg/mL pyridostigmine in the drinking water, 29days) groups. Rats were exercised on a treadmill to record HRR, and blood samples were collected on days 0, 7, 14, and 28 of pyridostigmine administration. Total cholinesterase and acetylcholinesterase (AChE) activity in plasma was decreased by 32%-43% and 57%-80%, respectively, in PYR rats on days 7-28, while plasma butyrylcholinesterase activity did not significantly change. AChE activity in red blood cells was markedly reduced by 64%-66%. HRR recorded 1minute after exercise was higher in the PYR group on days 7, 14 and 28, and on day 7 when HRR was estimated at 3 and 5minutes. Autonomic tone was evaluated pharmacologically using sequential administration of muscarinic (atropine) and adrenergic (propranolol) blockers. Parasympathetic tone was increased in PYR rats as compared with the CTL group. These data support the study hypothesis that subacute pyridostigmine administration enhances HRR by increasing cardiac parasympathetic tone.

The C5 Variant of the Butyrylcholinesterase Tetramer Includes a Noncovalently Bound 60 kDa Lamellipodin Fragment.

Humans with the C5 genetic variant of butyrylcholinesterase (BChE) have 30–200% higher plasma BChE activity, low body weight, and shorter duration of action of the muscle relaxant succinylcholine. The C5 variant has an extra, slow-moving band of BChE activity on native polyacrylamide gel electrophoresis. This band is about 60 kDa larger than wild-type BChE. Umbilical cord BChE in 100% of newborn babies has a C5-like band. Our goal was to identify the unknown, 60 kDa protein in C5. Both wild-type and C5 BChE are under the genetic control of two independent loci, the BCHE gene on Chr 3q26.1 and the RAPH1 (lamellipodin) gene on Chr 2q33. Wild-type BChE tetramers are assembled around a 3 kDa polyproline peptide from lamellipodin. Western blot of boiled C5 and cord BChE showed a positive response with an antibody to the C-terminus of lamellipodin. The C-terminal exon of lamellipodin is about 60 kDa including an N-terminal polyproline. We propose that the unknown protein in C5 and cord BChE is encoded by the last exon of the RAPH1 gene. In 90% of the population, the 60 kDa fragment is shortened to 3 kDa during maturation to adulthood, leaving only 10% of adults with C5 BChE.

Effects of energetic restriction diet on butyrylcholinesterase in obese women from southern Brazil - A longitudinal study.

Butyrylcholinesterase (BChE) activity has been associated with obesity, lipid concentrations, and CHE2 locus phenotypes. This, the aim of this study was to evaluate the effects of an energetic restriction diet intervention on anthropometrical and biochemical variables and on absolute and relative BChE activity in CHE2 C5+ and CHE2 C5- individuals. One hundred eleven premenopausal obese women from Southern Brazil participated in an energetic restriction diet intervention (deficit of 2500 kJ/day) for 8 weeks. Their anthropometric and biochemical parameters were evaluated before and after the intervention. Plasma BChE activity was measured, and BChE bands in plasma and CHE2 locus phenotypes were detected by electrophoresis. The dietetic intervention decreased anthropometric and biochemical parameters as well as absolute BChE activity and relative activity of the G4 band. The CHE2 C5+ phenotype presented a different effect when compared with the CHE2 C5- phenotype. The CHE2 C5+ phenotype showed an effect in absolute BChE activity and in the relative activity of the G4 form, maintaining higher BChE activity regardless of the metabolic changes. In our study, 8 weeks was not sufficient time to lower the body mass index to normal, but it was enough to significantly reduce the absolute BChE activity, which became similar to the levels in nonobese individuals. CHE2 C5+ individuals were resistant to the decrease in BChE activity compared to CHE2 C5- individuals. This shows that the diet did not affect the CHE2 and G4 fraction complex and that the products of the CHE2 locus in association with BChE have a role in energy metabolism, maintaining high levels of enzymatic activity even after dietary intervention.

Anticeramide antibody and butyrylcholinesterase in peripheral neuropathies

Ceramide is a glycosphingolipid, a component of nerve and non neuronal cell membrane and plays a role in maintaining the integrity of neuronal tissue. Butyrylcholinesterase (BChE) is a multifunctional enzyme, its involvement in neurodegenerative diseases has been well established. Anticeramide antibody (Ab-Cer) and enzyme BChE have been implicated in peripheral neuropathies. The present study investigates whether there is an association between Ab-Cer and BChE activities and peripheral neuropathies. Patients included: human immunodeficiency virus associated peripheral neuropathy (HIV-PN, n=39), paucibacillary leprosy (PB-L, n=36), multibacillary leprosy (MB-L, n=52), diabetic neuropathy (DN, n=22), demyelinating sensory motor polyneuropathy (DSMN, n=13) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=10). Plasma Ab-Cer was measured by indirect enzyme linked immune assay (ELISA) and BChE activity in plasma was measured by colorimetric method. Ab-Cer levels were significantly elevated in MB-L and DN as compared to healthy subjects (HS). BChE levels were significantly higher in MB-L and DN as well as in HIV and HIV-PN. There is no significant difference in either Ab-Cer or BChE levels in DSMN and CIDP. Elevated plasma Ab-Cer and BChE levels may be considered significant in the pathogenesis of neuropathies. The variation in concurrent involvement of both the molecules in the neuropathies of the study, suggest their unique involvement in neurodegenerative pathways.

Plasma butyrylcholinesterase activity: a possible biomarker for differential diagnosis between Alzheimer's disease and dementia with Lewy bodies?

ABSTRACTButyrylcholinesterase (BChE) is an enzyme encoded by BCHE gene, responsible for secondary hydrolysis of the acetylcholine. K and −116A BCHE variants were associated with decrease in plasma BChE activity, and their influence has been investigated in diseases with a cholinergic deficit such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). In order to check the influence of BCHE genetic variants on enzymatic activity, all patients and controls were genotyped for K and −116A variants. We found lower plasma BChE activity in DLB patients compared to elderly controls and to AD independent of the presence of K or −116A variants. Our results suggest that the reduction of total plasma BChE activity is probably associated with a feedback mechanism and provides a future perspective of using this enzyme as a possible plasmatic marker for differential diagnosis between AD and DLB.

Butyrylcholinesterase as a Blood Biomarker in Neuroblastoma.

Blood-based biomarkers are important in the detection of the disease and in the assessment of responses to therapy. In this study, butyrylcholinesterase was evaluated as a potential biomarker in newly diagnosed neuroblastoma (NB) patients at diagnosis and longitudinally during treatment. Plasma butyrylcholinesterase activities in age-matched and sex-matched children were used as controls. Pretreatment butyrylcholinesterase levels in NB subjects are on an average 2 times lower than butyrylcholinesterase levels in healthy subjects. Significantly, butyrylcholinesterase activities are ∼40% lower in MYCN-amplified as compared with nonamplified disease. As the course of chemotherapy progresses, butyrylcholinesterase activities recover and normalize to control values. The evident response to treatment indicates that plasma butyrylcholinesterase is a good biomarker of tumor response to therapy. Depressed butyrylcholinesterase levels in NB subjects are not caused by hepatic deficits suggesting a specific role for butyrylcholinesterase in NB. Further examination of the mechanism of altered butyrylcholinesterase production require an animal model that best approximates human condition. Studies in mice show that murine NB allografts significantly reduce butyrylcholinesterase activity in plasma. This finding correlates with changes observed in NB patients. In contrast, human NB xenografts produce the opposite effect, that is, butyrylcholinesterase plasma levels rise as the xenograft size increases. In the absence of any liver damage, dissimilarities between butyrylcholinesterase production in murine and human NB models suggest species-specific signaling pathways. This disparity also suggests that human NB xenograft mouse models do not approximate the human disease.

Activity of cholinesterases in a young and healthy middle-European population: Relevance for toxicology, pharmacology and clinical praxis

The activity of human cholinesterases, erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7) and plasma butyrylcholinesterase (BChE; EC 3.1.1.8) represents an important marker when monitoring exposure to pesticides/nerve agents, and may also be used in occupational medicine in diagnosis and prognosis of some diseases. In this study “normal/baseline” AChE and BChE activity has been investigated in a young and healthy population, with subsequent evaluation of several intra-population factors including sex, age (categories 18–25, 26–35 and 36–45 years old) and smoker status.The modified Ellman's method was used for enzyme activity assessment in 387 young and healthy individuals (201 males and 186 females aged 18–45). A significant inter-sexual difference in AChE and BChE activity was found (AChE: 351±67 for males and 377±65 for females, (μmol/min)/(μmol of hemoglobin), p<0.001; BChE: 140±33 for males and 109±29 for females, μkat/l, p<0.001; mean±SD). Despite the finding that mean AChE activity somewhat decreased whereas BChE activity grew within the age categories of the tested subjects, no significant effect of age on cholinesterase activity was found (p>0.05). Smoking influenced cholinesterase activity – AChE activity in smokers was elevated (approx. 3% in males; 8% in females) relative to that in non-smokers (p<0.05). Smoking was found not to have any effect on BChE activity.Reference values based on confidence intervals for AChE and BChE activity were established. The presented results might be useful in routine clinical practice where the monitoring of blood AChE and plasma BChE activity is crucial for prognosis and diagnosis of organophosphate poisoning, in occupational medicine and in relevant mass casualty scenarios.

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.

Acetylcholinesterase (AChE) is the physiologically important target for organophosphorus toxicants (OP) including nerve agents and pesticides. Butyrylcholinesterase (BChE) in blood serves as a bioscavenger that protects AChE in nerve synapses from inhibition by OP. Mass spectrometry methods can detect exposure to OP by measuring adducts on the active site serine of plasma BChE. Genetic variants of human AChE and BChE do exist, but loss of function mutations have been identified only in the BCHE gene. The most common AChE variant, His353Asn (H322N), also known as the Yt blood group antigen, has normal AChE activity. The most common BChE variant, Ala567Thr (A539T) or the K-variant in honor of Werner Kalow, has 33% reduced plasma BChE activity. The genetic variant most frequently associated with prolonged response to muscle relaxants, Asp98Gly (D70G) or atypical BChE, has reduced activity and reduced enzyme concentration. Early studies in young, healthy males, performed at a time when it was legal to test nerve agents in humans, showed that individuals responded differently to the same low dose of sarin with toxic symptoms ranging in severity from minimal to moderate. Additionally, animal studies indicated that BChE protects from toxicants that have a higher reactivity with AChE than with BChE (e.g., nerve agents) but not from toxicants that have a higher reactivity with BChE than with AChE (e.g., OP pesticides). As a corollary, we hypothesize that individuals with genetic variants of BChE may be at increased risk of toxicity from nerve agents but not from OP pesticides.