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)

The role of specific cytochrome P450 isoforms in catalysing the oxidative biotransformation of the organophosphorothioate pesticides parathion, chlorpyrifos and diazinon into structures that inhibit cholinesterase has been investigated in human liver microsomes using chemical inhibitors. Pesticides were incubated with human liver microsomes and production of the anticholinergic oxon metabolite was investigated by the inhibition of human serum cholinesterase. Quinidine and ketoconazole at 10 micromol/l inhibited oxidative biotransformation. Compared to control incubations (no inhibitor) where cholinesterase activity was inhibited to between 1 and 4% of control levels, incorporation of the CYP2D6 inhibitor quinidine into the microsomal incubation resulted in cholinesterase activity of 50% for parathion, 38% for diazinon and 30% for chlorpyrifos. Addition of the CYP3A4 inhibitor ketoconazole to microsomal incubations resulted in 66% cholinesterase activity with diazinon, 20% with parathion and 5% with chlorpyrifos. The unexpected finding that CYP2D6, as well as CYP3A4, catalysed oxidative biotransformation was confirmed for chlorpyrifos and parathion using microsomes prepared from a human lymphoblastoid cell line expressing CYP2D6. While parathion has been investigated only as a model compound, chlorpyrifos and diazinon are both very important, widely used pesticides and CYP2D6 appears to be an important enzyme in their bioactivation pathway. CYP2D6 is polymorphic and hence may influence individual susceptibility to exposure to chlorpyrifos and diazinon as well as other structurally similar pesticides.
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PMID:Evidence for the activation of organophosphate pesticides by cytochromes P450 3A4 and 2D6 in human liver microsomes. 1099 83

Acetylcholinesterase in mussel is potentially a useful biomarker of exposure to organophosphates (OP) in the marine environment. This study looked at cholinesterase activity in subcellular fractions of various tissues from the common mussel, Mytilus edulis. Measurement of enzyme rates demonstrated that although highest specific activity was found in foot 'mitochondrial' fraction, recovery of activity was very low. Gill 'microsomal' fraction had the second highest specific activity with a useful level of recovery and therefore was the most suitable tissue fraction for biomarker applications. Comparative studies of alternative alkylthiocholine substrates and competitive inhibitors suggest there is a single cholinesterase enzyme type present in this fraction. Inhibition of alkylcholine hydrolysis by BW284C51, specific to acetylcholinesterase in vertebrates, showed that cholinesterase activity in gill 'microsomal' fraction is inhibited by this compound but to a lesser extent than in vertebrate AChE. Inhibition of cholinesterase activity by azamethiphos in gill 'microsomal' fraction gave an IC50 of approximately 100 microM and showed both time and concentration dependence. However this indicates a lower potency compared to other animals and it is debatable whether mussel cholinesterase activity is useful as a biomarker of exposure in the field.
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PMID:Characterisation of choline esterases and their tissue and subcellular distribution in mussel (Mytilus edulis). 1458 Aug 6

The role of the polymorphic cytochrome P450 (CYP) 2D6 isoform in catalysing the oxidative biotransformation of the organophosphate pesticide chlorpyriphos and the carbamate aldicarb into structures that inhibit cholinesterase and induce genotoxicity has been investigated in microsomal fraction, using quinine as a specific chemical inhibitor of CYP 2D6. Pesticides were incubated with rat liver microsomes and production of anticholinergic active metabolites was investigated by the inhibition of human serum cholinesterase. Compared to microsomes incubated without quinine, where cholinesterase activity was inhibited to a mean 53% (chlorpyriphos) and 57% (aldicarb) of control, the introduction of P450 2D6 inhibitor quinine into microsomal incubation mixture reduced cholinesterase activity to 72% of control for chlorpyriphos and to 27% for aldicarb, suggesting that P450 2D6 is involved in the activation of chlorpyriphos but does not influence aldicarb toxicity on acetylcholinesterase. Moreover, the potential genotoxicity of these compounds was evaluated by single cell gel electrophoresis (comet assay) on human leucocytes. DNA fragmentation compared to control was markedly increased after incubation with aldicarb plus quinine, confirming that the parent compound is more toxic than the products of CYP metabolism; conversely, DNA damage after incubation with chlorpyriphos was sensibly reduced by quinine indicating the metabolic activation of this pesticide by CYP 2D6. These data suggest that polymorphism of CYP 2D6 can influence the toxicity of organophosphate but not of carbamate pesticides.
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PMID:[Genotoxicity and activation of organophosphate and carbamate pesticides by cytochrome P450 2D6]. 1497 94

The aim of this study is to propose a bioindicator organism, the lizard Gallotia galloti, and a nondestructive biomarker assay, utilising serum butyrylcholinesterase, for the assessment of the toxicological impact of organophosphorus (OP) insecticides in the Canary Islands. Laboratory and field studies were performed using the OP insecticide Trichlorphon. In the laboratory study, experimental groups of Gallotia galloti were treated with 5, 50 and 100 mg/kg of Trichlorphon, respectively, and after 24 h the following enzyme activities were assayed: brain acetylcholinesterase (AChE), serum butyrylcholinesterase (BChE), microsomal carboxylesterase (CbE) and microsomal 7-ethoxyresorufin dealkylation (EROD). BChE activity was monitored in two groups of lizards treated with 50 and 100 mg/kg of Trichlorphon, respectively, for a period of 21 and 31 days after treatment. In the field study, BChE activity was detected in Gallotia galloti specimens, 24 and 48 h after treatment of an experimental area with 10 kg/ha of Dipterex sp80 (80% Trichlorphon). Three conclusions can be drawn. (1) Gallotia galloti has the features of an ideal bioindicator: high sensitivity to OPs and extremely slow recovery of serum BChE with respect to other vertebrate species; this property extends the temporal application of this biomarker in field studies. (2) A high correlation was found between the destructive biomarker brain AChE and the nondestructive biomarker serum BChE, 24 h after treatment. (3) The results of the field study show the relative 'non-toxicity' of Trichlorphon for nontarget organisms, such as lizards, at the average concentrations used in agriculture.
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PMID:The lizard Gallotia galloti as a bioindicator of organophosphorus contamination in the Canary Islands. 1509 78

Organic ammonium salts of N-(2-benzoyloxyethyl)-alkyldimethylammonium bromide (BCHn-1) type are formed by the homological series Ar-COO(CH2)2-N+(CH3)2CnH2a + 1.Br-, whose structure contains a biodegradably labile ester bond, on the basis of which they rank among disinfectants and antiseptics of soft character. They are preferentially biotransformed hydrolytically to produce benzoic acid and substituted choline. The rapidity of enzymatic hydrolysis depends on the chemical structure (the length of the aliphatic chain on the ammonium nitrogen), it increases up to the number of 10 nitrogens of the aliphatic chain, and it rapidly decreases with further prolongation. The paper aimed to demonstrate the catalytic activity of butyrylcholinesterase on the enzymatic hydrolysis of selected organic ammonium salts in the medium of the microsomal fraction of the rat liver on the basis of inhibitory kinetic studies with physostigmine, a cholinesterase inhibitor. The product of enzymatic hydrolysis of BCHn-1, benzoic acid, was determined after extraction with chloroform from the acid medium by means of HPLC analysis with the use of the internal standard p-iodobenzoic acid at the wavelength of 228 nm. Kinetic parameters K(M) and VMAX were evaluated following Lineweaver-Burke using the method of linear regression analysis. The specific activity of butyrylcholinesterase (E.C.3.1.1.8) in the enzymatic hydrolytic process of BCHn-1 was significantly influenced by the presence of physostigmine, which was manifested by increased K(M), KI, and IC50 values in the investigated enzymatic process of selected substrates of the homological series BCHn-1, and by decreased VMAX and rate constants.
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PMID:[Catalytic activity of butyrylcholinesterase in biodegradation of organic ammonium salts in vitro]. 1509 77

Human lymphocytes were exposed to the leukemogenic pesticide isofenphos (IFP) to investigate its effects on chromosomal DNA and cholinergic homeostasis using cholinesterase activity as a marker. Isolated peripheral lymphocytes were administered concentrations of IFP ranging from 0.1 ng/ml to 10 microg/ml. The absence (Group 1) and presence (Group 2) of DNA repair inhibitors 4 mM hydroxyurea (HU), 40 microM cytosine arabinoside (ARA-C) and an NADPH regenerating system (NRS) (Group 3) were analyzed at 1, 6 and 24 h by single cell gel electrophoresis using the comet assay. Significant damage to DNA directly from IFP at 1 h by remarkably low concentrations was observed in Group 1, escalating in Group 2 with DNA repair inhibition, while Group 3 disruptions were highest due to the presence of the NRS P-450 microsomal fraction conducive to producing reactive IFP-oxon and N-desalkyl metabolites. The extent of DNA aberrations increased further in parallel within the groups at 6 and 24 h. Male and female chemical sensitivities were similar on average (P < 0.01). Cholinesterase activity measured in a satellite group was inhibited with 0.1 microg/ml IFP by 69, 62, and 48% at 1, 6, and 24 h, respectively, indicating gradual induction of compensatory synthesis. Restoration of cholinergic homeostasis may be exceptionally impaired at higher IFP concentrations from acetyl-CoA depletion [Leuk. Res. 25 (2001) 883]. In summary, these studies reveal that exposure to the organophosphate pesticide isofenphos induces human DNA mutation beyond endogenous repair capacity and disrupts cholinergic nuclear signaling affectively constructing the mutator phenotype of leukemogenesis.
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PMID:Chromosomal aberrations in human lymphocytes exposed to the anticholinesterase pesticide isofenphos with mechanisms of leukemogenesis. 1523 72

This study compared CYP-mediated activation and toxicity of chlorpyrifos (CPF) in male and female rats, since gender difference in CPF toxicity in rats has been reported. A dose of 50 mg/kg of CPF in corn oil was administered ip to 2 groups of male and female rats while the respective control groups received the vehicle alone. Measurement of cholinesterase activity in brain showed no difference in cholinesterase inhibition between male and female rats 3 h following CPF administration. In contrast, inhibition of plasma cholinesterase was significantly greater in females than males. The activities of microsomal CYP 1A1, 2B1, 2E1 and 3AV 2 determined whether CPF, a suicide substrate of cytochrome P450 enzymes, was metabolized by the liver CYP enzymes. The CYP 1A1 and 2B1 activities were significantly decreased in both male and female rats, with the CYP 1A1 decrease in females markedly greater than that in males. CPF produced a significant inhibition of only CYP 3A1/2 activity, but not CYP 2E1 activity, irrespective of gender effect. These results demonstrated that CYP 1A1, 2B1 and 3A1/2 were differentially involved in the metabolism of CPF to CPF-oxon in both genders and the extent of plasma cholinesterase inhibition was significantly greater in female than male rats.
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PMID:Cytochrome P450-mediated activation and toxicity of chlorpyrifos in male and female rats. 1558 41

Ciclesonide (CIC) is an inhaled glucocorticosteroid. This study aimed to identify esterases involved in the metabolism of CIC to the active metabolite desisobutyryl-ciclesonide (des-CIC), and to measure hydrolysis rates in human liver, lung and plasma and normal human bronchial epithelial (NHBE) cells in vitro. Ciclesonide (5 microM and 500 microM) was incubated with microsomal or cytosolic fractions from liver, lung and plasma (n=4 for each) and des-CIC formation was determined by reverse-phase high-performance liquid chromatography with U.V. detection. The roles of carboxylesterase, cholinesterase and A-esterase in CIC hydrolysis were determined using a range of inhibitors. Inhibitor concentrations for liver and NHBE cells were 100 microM and 5 microM, respectively. Liver tissue had a higher activity for 500 microM CIC hydrolysis (microsomes: 25.4; cytosol: 62.9 nmol/g tissue/min) than peripheral lung (microsomes: 0.089; cytosol: 0.915 nmol/g tissue/min) or plasma (0.001 nmol/mL plasma/min), corresponding with high levels of carboxylesterase and cholinesterase in the liver compared with the lung. CIC (5 microM) was rapidly hydrolyzed by NHBE cells (approximately 30% conversion at 4h), with almost complete conversion by 24h. In liver and NHBE cells, major involvement of cytosolic carboxylesterases, with some contribution by cholinesterases, was indicated. The highest level of conversion was found in the liver, the site of inactivation of des-CIC through rapid oxidation by cytochrome P450. Carboxylesterases in bronchial epithelial cells probably contribute significantly to the conversion to des-CIC in the target organ, whereas low systemic levels of des-CIC are a result of the high metabolic clearance by the liver following CIC inhalation.
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PMID:The role of esterases in the metabolism of ciclesonide to desisobutyryl-ciclesonide in human tissue. 1733 75

Chlorpyrifos (CPF) is a broad spectrum organophosphorus insecticide bioactivated in vivo to chlorpyrifos-oxon (CPFO), a very potent anticholinesterase. A great majority of available animal studies on CPF and CPFO toxicity are performed in rats. The use of mice in developmental neurobehavioural studies and the availability of transgenic mice warrant a better characterization of CPF-induced toxicity in this species. CD1 mice were exposed to a broad range of acute (12.5-100.0mg/kg) and subacute (1.56-25mg/kg/day from 5 to 30 days) CPF oral doses. Functional and biochemical parameters such as brain and serum cholinesterase (ChE) and liver xenobiotic metabolizing system, including the biotransformation of CPF itself, have been studied and the no observed effect levels (NOELs) identified. Mice seem to be more susceptible than rats at least to acute CPF treatment (oral LD(50) 4.5-fold lower). The species-related differences were not so evident after repeated exposures. In mice a good correlation was observed between brain ChE inhibition and classical cholinergic signs of toxicity. After CPF-repeated treatment, mice seemed to develop some tolerance to CPF-induced effects, which could not be attributed to an alteration of P450-mediated CPF hepatic metabolism. CPF-induced effects on hepatic microsomal carboxylesterase (CE) activity and reduced glutathione (GSH) levels observed at an early stage of treatment and then recovered after 30 days, suggest that the detoxifying mechanisms are actively involved in the protection of CPF-induced effects and possibly in the induction of tolerance in long term exposure. The mouse could be considered a suitable experimental model for future studies on the toxic action of organophosphorus pesticides focused on mechanisms, long term and age-related effects.
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PMID:Cholinesterase inhibition and alterations of hepatic metabolism by oral acute and repeated chlorpyrifos administration to mice. 1738 47

Diazinon is a widely used pesticide in agriculture. So, the current work aimed to investigate the effects of diazinon exposure on some physiological and biochemical parameters, as well as, histopathological changes and histochemical acetyl-cholinesterase activity (AChE). The red Baladi rabbits were dipped into water (Control Group), diazinon at low concentrations of 0.6 mg diazinon low concentration (DLC) or high concentration of 3mg diazinon high concentration (DHC) dissolved in 1l of water for 10s. Treatment was repeated after 10 days and animals were sacrificed between 0 and 21 days after the second treatment. Blood analysis revealed that Red blood cells (RBC's), hemoglobin (Hb) and plasma total protein (TP) were significantly decreased in both diazinon concentrations (P<0.01), (P<0.05), (P<0.01) respectively. Cholesterol and microsomal protein were increased (P<0.01), while, liver/ body weight and cytochrome P-450 were decreased in both concentrations (P<0.01). Also there was a highly significant effect of concentration X day interaction on all parameters (P<0.01). Histopathological changes of liver, kidney and brain were observed after DHC dipping. Glycogen content was decreased in liver and increased in kidney Bowman's capsule. Furthermore, AChE activity was inhibited in brain tissue, decreased in liver cells, but gradually increased in kidney glomerular cells. Therefore, kidney and brain were highly affected by diazinon exposure compared with the liver. Exposure of animals to diazinon caused extensive changes in physiological, biochemical, and histopathological parameters as well as histochemical AChE. So, contact exposure of diazinon leads to negative response on animal health.
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PMID:Diazinon toxicity affects histophysiological and biochemical parameters in rabbits. 1793 2


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