Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertriglyceridaemia is a risk factor for cardiovascular disease in patients suffering from Type II diabetes mellitus, and is due to enhanced synthesis and/or impaired clearance of triacylglycerol-rich lipoproteins. In the present study we investigated whether pseudocholinesterase (PChE) activity could serve as a marker for the rate of triacylglycerol synthesis in these patients. Patients were stratified according to their apolipoprotein E (apoE) phenotype, i.e. E3E2, E3E3 or E3E4. In study I, the relationship between PChE activity and serum triacylglycerols was investigated in 224 insulin-treated patients with Type II diabetes. In study II, which had a cross-over design, PChE activity was measured in 45 dyslipidaemic, insulin-treated patients with Type II diabetes that were treated with bezafibrate or pravastatin. In study I, PChE activity was correlated positively with serum triacylglycerol concentrations, but did not differ significantly between apoE phenotypes. The strongest relationship was found in the E3E4 group (r=0.50; P=0.001), the phenotype for which hypertriglyceridaemia is expected to be the result of increased triacylglycerol synthesis. In a stepwise multiple regression analysis, serum triacylglycerol concentrations were found to be the strongest predictor of PChE activity in the E3E4 group. In study II, PChE activity decreased as a result of bezafibrate treatment in all three apoE groups. The decrease in PChE activity with bezafibrate treatment paralleled the decrease in serum triacylglycerol concentrations in the apoE subgroups. Pravastatin treatment did not significantly affect PChE activity. Thus the present study suggests an association between PChE activity and the rate of triacylglycerol synthesis. Measurement of PChE activity may therefore be a useful tool in the choice of drug for treatment of hypertriglyceridaemia in patients with Type II diabetes.
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PMID:Is pseudocholinesterase activity related to markers of triacylglycerol synthesis in Type II diabetes mellitus? 1141 Jan 11

Amyloid beta peptide implicated in Alzheimers disease is cleaved by insulin degrading enzyme (IDE). Abnormal cholinesterases similar to butyrylcholinesterase (BChE) are found in Alzheimer brain. The similarities between IDE and BChE (which is known to have an arylacylamidase and a metallocarboxypeptidase-like activity) such as their zinc metalloenzyme nature, their localization in glia and their ability to bind amyloid peptide in Alzheimers disease raise interesting questions.
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PMID:Amyloid beta peptide processing, insulin degrading enzyme, and butyrylcholinesterase. 1149 57

Elevated levels of butyrylcholinesterase activity occur under a number of hypertriglyceridemic conditions, including diabetes and obesity. This study examines whether butyrylcholinesterase activity has a direct effect on triglyceride production, using Caco-2 cells, a human intestinal adenocarcinoma cell line. Caco-2 cells were incubated with 500 microM oleate to stimulate triglyceride production, and butyrylcholinesterase activity was measured in the cellular homogenate. Butyrylcholinesterase activity was approximately 3 x 10(-3) micromol/min per milligram protein. Although triglyceride production increased by almost five-fold after 18 h of stimulation with oleate, butyrylcholinesterase activity was not increased. Furthermore, inhibition of butyrylcholinesterase activity using 1 mM tetraisopropylpyrophosphoramide did not significantly affect triglyceride production or secretion. Human insulin (100 microU/ml) increased the production of butyrylcholinesterase without increasing triglyceride production. This demonstrates that stimulation of fatty acid production and butyrylcholinesterase activity occur by independent mechanisms and suggests that their correlation in hyperlipidemic conditions is not due to a direct relationship in production in situ.
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PMID:Production of butyrylcholinesterase by Caco-2 cells: lack of relationship with triglyceride production. 1157 88

In adverse drug reactions, effects accounted for by the pharmacological profile of the drug may be distinguished from sometimes bizarre, unpredictable events ("idiosyncrasies"). In the majority of cases, the latter are due to reactive intermediates formed by members of the cytochrome P450 family of enzymes. These products are usually formed at very low quantities. However, genetic disposition (e.g. by enhanced expression of the catalyzing enzyme or failure of protective factors such as glutathione) or certain external conditions (for example comedication of inducers of drug metabolism) may lead to toxic intermediates being available at relevant quantities. Once generated, these metabolites will react with macromolecules and finally cause cell necrosis. Necrosis may result from direct damage to functions essential to the cell or be secondary to harmful immune reactions activated by recognition of the new structures as neoantigens. As the principal site of drug metabolism, the liver is most frequently affected by idiosyncratic reactions, which often enough are recognized only after large numbers of patients have been treated. The idiosyncratic potential of a drug relates to its chemical structure rather than its pharmacological mechanism. Risks are evident if biotransformation yields products with chemical substructures such as quinones, phenoles, acyl halides, aromatic and hydroxyl amines. There are numerous cases of precursor drugs with idiosyncratic potential that have been replaced or marginalized by agents with more favorable chemical properties. Examples include beta 1-preferential beta-adrenoceptor antagonists (toxic precursor: practolol) and the choline esterase inhibitors used in treatment of Alzheimer's disease. In the latter group, tacrine (CAS 321-64-2) gives rise to high liver enzyme levels in about 30% of the patients, an effect not shared with more recent, chemically different entities. A similar case can be made for the insulin sensitizer troglitazone (CAS 97322-87-7) (marketed, now withdrawn in the USA) and its successors rosiglitazone (CAS 122320-73-4) and pioglitazone (CAS 111025-46-8). Due to its different chemical structure, only troglitazone can be transformed into a reactive quinone metabolite, a process that may be accelerated by the drug inducing its own metabolism. In agreement with this view, there is no evidence of specific hepatic toxicity with the two successor drugs. Ongoing progress in molecular toxicology may aid in minimizing idiosyncratic hazards already at early stages of drug development.
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PMID:From toxic precursors to safe drugs. Mechanisms and relevance of idiosyncratic drug reactions. 1210 41

Elevated serum butyrylcholinesterase (BChE) activity in the diabetic rat, mouse and human is very evident. The source of the increased level of BChE in the diabetic condition is not known. The effect of diabetes on cardiac BChE has not been studied so far, in spite of high BChE levels in the heart. In the present study, we investigated the effect of alloxan-induced diabetes on serum and on the soluble as well as the membrane-bound form of cardiac BChE activity and their substrate kinetics. We included rats of both sexes in the study. Serum BChE activity increased only in male diabetic rats (2.3-fold), while the activities of the soluble as well as the membrane-bound form of cardiac BChE activity increased 2.2- to 2.8-fold in male diabetic rats. A smaller increase (30%) was observed in the activity of the membrane-bound form of cardiac BChE in female diabetic rats. A slight reduction in BChE activity was observed in male and female rats after insulin treatment. The activity ratio of the soluble to the membrane-bound form of cardiac BChE was higher in diabetic and insulin-treated diabetic rats as compared with controls. The K(m) values of component II of the serum and soluble forms of cardiac BChE were comparable. In conclusion, the diabetes-induced increase in serum and cardiac BChE activity was sex dependent. Insulin was not able to rectify the diabetes-induced abnormalities in serum and cardiac BChE activity. The heart could be one of the possible sources of the increased level of serum BChE.
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PMID:Effect of alloxan-induced diabetes on serum and cardiac butyrylcholinesterases in the rat. 1237 9

Brain insulin receptor and ERK I/II are suggested to play a role in memory formation. We designed a series of experiments to explore if Asiasari radix (AR) extracts could display memory enhancing actions possibly via the activation of insulin receptor and ERK I/II in mice and rats. Methanol extract of AR had significantly increased survival time in the NaNO(2) intoxication assay in mice. Methanol extract of Asiasari radix (fraction 1) and its subfractions, chloroform-soluble fraction (fraction 2) and chloroform-insoluble, methanol-soluble fraction (fraction 4) were further tested for memory formation. In eight-arm radial maze experiments, both reference memory errors and working memory errors were significantly decreased in mice by fractions 1, 2 and 4. In addition, these fractions were also effective in promoting memory in the passive avoidance test in mice and rats. To gain insight into the mechanism of memory enhancing effects by Asiasari radix extracts, the activities of hippocampal insulin receptors and ERK I/II were tested in mice and rats. Fraction 1 significantly stimulated tyrosine phosphorylation of the insulin receptor, whereas ERK I/II were stimulated by fractions 1, 2 and 4. These fractions also inhibited cholinesterase activities in rats. These results suggest that Asiasari radix extracts may exert memory enhancing effects via activation of insulin receptor and ERK I/II as well as decreasing cholinesterase activity.
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PMID:Memory enhancing actions of Asiasari radix extracts via activation of insulin receptor and extracellular signal regulated kinase (ERK) I/II in rat hippocampus. 1274 37

The central role of the intracellular enzyme hormone-sensitive lipase (HSL) in regulating fatty acid metabolism makes it an interesting pharmacological target for the treatment of insulin resistant and dyslipidemic disorders where a decrease in delivery of fatty acids to the circulation is desirable, e.g., in individuals with type 2 diabetes, metabolic syndrome, or impaired glucose tolerance. On the basis of a lead structure from high throughput screening, we have identified a very potent type of carbamoyl-triazole inhibitors of HSL. As part of the lead optimization program, four new classes of carbamoyl-triazoles were synthesized and tested with respect to potency, efficacy and selectivity. Methyl-phenyl-carbamoyl-triazoles were identified as potent and efficacious HSL inhibitors. These compounds do not inhibit other hydrolases such as hepatic lipase, lipoprotein lipase, pancreatic lipase, and butyrylcholine esterase. However, the inhibitors 4b and 4g with IC(50) values for HSL of 0.17 and 0.25 microM, respectively, were the only inhibitors selective against acetylcholine esterase. A reversible pseudosubstrate inhibition mechanism is proposed for this class of inhibitors.
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PMID:Synthesis and structure-activity relationship for a novel class of potent and selective carbamoyl-triazole based inhibitors of hormone sensitive lipase. 1471 11

Treating dementia has become a major challenge in clinical practice. Presently, acetylcholinesterase inhibitors are the first-line drugs in the treatment of Alzheimer's disease (AD). These options are now complemented by memantine, which is approved for the treatment of moderate-to-severe AD. Altogether, a minimum of six agent classes already exist, all of which are approved for clinical use and are either already being tested or ready for phase III clinical trials for the treatment of AD. These include cholinesterase inhibitors, blockers of the NMDA receptor, antioxidants or blockers of oxidative deamination (including Gingko biloba), anti-inflammatory agents, neurotrophic factors (including hormone replacement therapy and drugs acting on insulin signal transduction) and antiamyloid agents (including cholesterol-lowering therapy). These approaches hold promise for disease modification and have a potential to be used as combination therapy for cognitive enhancement. Presently, only nine clinical studies have been published that have investigated the effects of a combination regimen on cognitive performance or AD. Among those, one study was conducted in elderly cognitively intact persons; the others involved patients with AD. Only five of the treatment studies followed a randomised, controlled design. Not all studies favoured the superior efficacy of combination therapy over monotherapy. Some studies, however, showed some evidence for synergistic combination effects of symptomatic therapy, including delay or prevention of disease progression in AD patients. In addition, six studies investigated the effects of AChE inhibitor in combination with antipsychotic or antidepressant therapy on behavioural aspects of AD symptomatology. In four of those studies there were indications that combination therapy had greater efficacy over monotherapy. The treatment of AD patients requires optimised options for all stages of illness based on the available drugs. There is a great need for further well designed studies on combination therapy in AD.
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PMID:Combination therapy in Alzheimer's disease: a review of current evidence. 1552 88

Coagulation factor XIII is a transglutaminase catalysing the crosslinking of fibrin chains as well as the formation of covalent links between several extracellular matrix proteins such as fibronectin, vitronectin and collagen. By mediating the incorporation of alpha2 antiplasmin into the fibrin network, this factor also interferes with fibrinolysis. Increased plasma factor XIII activity was reported by our laboratory 30 years ago in hypertriglyceridemic subjects who also displayed increased activity of serum cholinesterase, a marker of hepatic protein synthesis, and a delayed diluted, blood clot lysis time. Recent data in the literature emphasize a relationship between insulin resistance (metabolic syndrome) and increased plasma levels of factor XIII, confirming our results. It was also reported that a faster activation of this factor related to the Val 34 leu polymorphism provides protective effect against myocardial infarction and stroke, this effect being however negated in patients with insulin resistance and high plasma levels of plasminogen activator inhibitor-1. The pathogenic role of factor XIII in atherothrombosis seems to be bivalent. On the one side, an increased activity would favor the persistence of fibrin depositions and increase plaque burden, while on the other side it would reduce plaque vulnerability and the risk of downstream embolization.
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PMID:Coagulation factor XIII and atherothrombosis. A mini-review. 1552 18

When compared with values recorded in 14 control subjects, the 15 overweight patients with type 2 diabetes displayed significantly increased activities of serum alanineaminotransferase (172% of mean values in controls), gamma-glutamyltransferase (253%) and cholinesterase (139%). A much wider dispersion of individual values for the two firstly mentioned enzymes was however noted so that their correlation with serum triglycerides levels were weaker (r = 0.373; p < 0.05 and r = 0.451; p < 0.05 respectively) than the same correlation obtained for serum cholinesterase (r = 0.760; p < 0.001). In two other studies including 28 controls and 30 diabetic patients serum cholinesterase was found to be significantly correlated with serum levels of insulin (r = 0.622; p < 0.001), C-peptide (r = 0.652; p < 0.001) and free fatty acid (r = 0.821; p < 0.001). Circumstantial evidence is provided that insulin resistance and an increased flux of free fatty acids from adipose tissue to the liver would stimulate the hepatic synthesis of serum cholinesterase.
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PMID:Serum cholinesterase activity correlates with serum insulin, C-peptide and free fatty acids levels in patients with type 2 diabetes. 1552 39


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