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:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study sought to determine if ozone at levels known to induce bronchial hyperreactivity in guinea pigs would inhibit tissue cholinesterase activity. Male, Hartley guinea pigs were exposed to filtered air, 0.1 ppm ozone, or 0.8 ppm ozone for 1 hr. Two hours after exposure, brain, lung, and diaphragm tissue samples were frozen for assay of cholinesterase activity. Brain cholinesterase activity was only minimally inhibited in either ozone exposure group. Both levels of ozone significantly inhibited lung cholinesterase activity compared to control animals' activity: a 17% decrease in activity in the 0.1 ppm ozone group (P less than .05) and a 16% decrease in the 0.8 ppm ozone group (P less than .05). Ozone at 0.8 ppm also inhibited activity in the diaphragm by 14% (P less than .02). To determine the degree of involvement of cholinesterase inhibition in bronchial hyperreactivity, parathion pretreated animals were challenged with histamine and the pulmonary function changes monitored. Parathion-treated animals had a peak resistance increase of 330 +/- 104% (mean +/- SE), while the control vehicle animals' increase was 165 +/- 48%. The differences were not statistically significant, but show that cholinesterase inhibition may contribute to ozone-induced bronchial hyperreactivity.
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PMID:Ozone inhibition of tissue cholinesterase in guinea pigs. 731 65

We previously reported similar levels of brain cholinesterase inhibition but marked differences in toxicity following acute maximum tolerated doses of the organophosphate pesticides parathion and chlorpyrifos. Because extensive acetylcholinesterase inhibition often induces compensatory changes in cholinergic receptor populations, we compared the effects of parathion and chlorpyrifos on brain muscarinic receptors. Adult male rats were treated with vehicle or the maximum tolerated dose of parathion (18 mg/kg, sc) or chlorpyrifos (279 mg/kg, sc) and observed for signs of acute toxicity. Similarly treated animals were sacrificed at 2, 7, or 14 days after treatment for measurement of cholinesterase activity and binding to the nonselective muscarinic antagonist [3H]quinuclidinyl benzilate, the M2-preferential antagonist [3H]AFDX-384, and the high-affinity agonist [3H]cis-methyldioxolane. More acute toxicity was noted after parathion treatment. Both insecticides caused similar levels (> 85%) of maximal cholinesterase inhibition and reductions (up to 55%) in atropine-sensitive quinuclidinyl benzilate binding (i.e., total muscarinic receptors) and [3H]AFDX-384 binding in cortex and striatum. Parathion also reduced, whereas chlorpyrifos increased, total muscarinic receptor binding and [3H]AFDX-384 binding in the cerebellum. When tissues were preincubated with paraoxon (10 microM), radiolabeling of a subset of quinuclidinyl benzilate binding sites was blocked and the apparent densities of these organophosphate-sensitive receptors in all three tissues were decreased (16% maximal) by parathion but increased (up to 37%) by chlorpyrifos. Similarly, parathion decreased whereas chlorpyrifos increased [3H]cis-methyldioxolane binding sites in all three brain regions. We propose that differential modulation of these organophosphate-sensitive muscarinic receptors contributes to differences in acute toxicity following exposure to these pesticides.
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PMID:Differential modulation of organophosphate-sensitive muscarinic receptors in rat brain by parathion and chlorpyrifos. 750 14

A series of dipeptides which contained phosphonate analogs of proline and piperidine-2-carboxylic acid (homoproline) have been synthesized and tested as inhibitors of DPP-IV. The rates of inhibition of DPP-IV by these compounds are moderate, but the inhibitors are quite specific. The best inhibitor in the series is Ala-PipP(OPh-4-Cl)2 (13), which has a k(inact) of 0.353 s-1 and KI of 236 microM. The DPP-IV inhibitors Ala-ProP(OPh)2 (6), Ala-ProP(OPh-4-Cl)2 (12), and Ala-PipP(OPh-4-Cl)2 (13) do not inhibit trypsin, human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), acetylcholinesterase, papain, and cathepsin B. However, compounds 12 and 13 inhibited chymotrypsin slowly. Most of these dipeptides containing a homoproline phosphonate residue (PipP) or a Pro phosphonate residue (ProP) at the P1 site are stable in a pH 7.8 buffer with half-lives of several hours to several days. DPP-IV inhibited by 6, 7 (Ala-PipP(OPh)2), 12, or 13 is quite stable, and no enzyme activity was recovered after removal of excess inhibitor and incubation in buffer for 1 day. Since the phosphonate inhibitors are specific toward DPP-IV and the inhibited enzymes are stable, they should be useful in establishing the biological functions of DPP-IV and may be useful therapeutically in the prevention of the rejection of transplanted tissue.
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PMID:Dipeptide phosphonates as inhibitors of dipeptidyl peptidase IV. 796 57

Neonatal rats were exposed to parathion, an acetylcholinesterase inhibiting organophosphorus pesticide, during a rapid phase of cholinergic receptor development. Rats were given subcutaneous injections of 1.5 mg/kg/day from postnatal days 8-20. The immediate effects of subchronic developmental exposure were assessed in 21-day-old animals and more persistent effects assessed in 36-day-old animals. There was a 61% inhibition of acetylcholinesterase and a 27% decrease of muscarinic receptor density in 21-day-old treated rats. The reduction in receptor density was dose-dependent and a significant correlation was found between the level of acetylcholinesterase inhibition produced by parathion and the reduction in receptor density. It was estimated that a minimum of at least 15% prolonged inhibition of forebrain acetylcholinesterase by parathion was necessary to reduce receptor density. Regional analyses of receptor autoradiograms of 21-day-old animals indicated muscarinic receptors in the cortex and hippocampus were preferentially lost. The anterior thalamus was notable in having a high density of cholinergic receptors which were unaffected by parathion treatment. No changes were found in the affinity of [3H]QNB for the receptor or in the binding of the agonist, acetylcholine, n competition binding studies. AChE activity and muscarinic receptor density returned to normal after a 16 day recovery period. Parathion treated animals were growth inhibited but, growth retardation induced by undernutrition did not alter receptor density or affinity of QNB for muscarinic receptors. Thus, the transient decrease in receptor density in parathion exposed animals was similar to the response previously observed in adults and was not secondary to growth retardation or undernutrition. Receptor densities and acetylcholinesterase levels were regulated back to normal values after a 16 day recovery period in spite of the perturbation of cholinergic function during cholinergic synapse and receptor development.
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PMID:Muscarinic cholinergic receptor regulation and acetylcholinesterase inhibition in response to insecticide exposure during development. 801 Jan 61

Paraoxon (O,O-diethyl O-p-nitrophenyl phosphate) is the neurotoxic metabolite of the insecticide parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate). The effects of organophosphorus compounds on peripheral synapses have been attributed to inhibition of cholinesterase and to direct actions on muscarinic and nicotinic receptors, but less is known about the actions of organophosphorus compounds, including paraoxon, in the central nervous system. We investigated initially the effects of paraoxon on spontaneous transmitter release by recording miniature postsynaptic currents (MPSCs) from cultured rat hippocampal neurons using the whole-cell mode of the patch-clamp technique. Paraoxon (0.3 microM) in the presence of tetrodotoxin (0.3 microM) and atropine (1 microM) caused a significant increase in the frequency of gamma-aminobutyric acid- and glutamate-mediated MPSCs, but did not change the peak amplitudes or decay-time constants of these MPSCs. In contrast, application of nicotinic agonists or antagonists did not change the MPSC frequency. The presynaptic effect of paraoxon shown here was not mediated by actions on muscarinic or nicotinic receptors, or by elevated acetylcholine levels secondary to inhibition of cholinesterase. In addition, agonists were applied to assess the postsynaptic effects of paraoxon on excitatory and inhibitory amino acid receptors. Paraoxon (30 microM-1 mM) blocked the ion channels of glycine, gamma-aminobutyric acidA, N-methyl-D-aspartic acid and nicotinic acetylcholine receptors, but not the ion channels of kalnate- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. The combined effects of paraoxon on spontaneous transmitter release and on the functions of several ligand-gated receptors may constitute mechanisms relevant to the neurotoxicity of paraoxon.
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PMID:Paraoxon: cholinesterase-independent stimulation of transmitter release and selective block of ligand-gated ion channels in cultured hippocampal neurons. 881

Parathion (PA) is a phosphorotioate pesticide requiring P-450-mediated oxidations to become activated to paraoxon, or to be metabolised to its less toxic metabolites. On the other hand, sodium arsenite [As(III)] markedly decreases total hepatic P-450 content and dependent monoxygenase activities. Our aim was to determine the effects of As(III) pretreatment on the acute toxicity of PA and its possible relationship with the effects of As(III) on P-450-dependent monooxygenase activities. Adult male Wistar rats were pretreated with As(III) (5.6 mg As(III)/kg, s.c.), and 24 h later given PA (5 to 20 mg/kg, per os). As(III) pretreatment increased the acute toxicity of PA, reducing 38% its median lethal dose (LD50) from 11.68 to 7.21 mg PA/kg. In addition, As(III) pretreatment further decreased the inhibitory effect of PA on brain acetylcholinesterase activity, reducing 33% the median inhibitory dose (ID50) from 3.44 to 2.31 mg PA/kg. whereas As(III) alone had no significant effects. As(III) decreased the P-450 content to 87% of control values, reduced EROD activity to 74% and BROD activity to 41%; PA produced no significant effects on these parameters, whereas the joint administration of As(III)+ PA produced effects similar to those of As(III). PROD activity was reduced to 36% of control value by PA, whereas As(III) alone produced no significant effects. However, As(III) pretreatment apparently protected against the inhibition of CYP2B1-mediated PROD activity produced by PA, since PROD values were similar to those of control animals. Our results also indicated that the increase in PA toxicity caused by As(III) pretreatment, could also be related to the CYP2B2 isoform, since decreases in CYP2B2-dependent BROD activity were observed in both As(III) and As(III) + PA groups, but not in PA-treated animals, suggesting that CYP2B2 is involved in PA detoxification.
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PMID:Effects of arsenite pretreatment on the acute toxicity of parathion. 902 May 7

Displacement of muscarinic radioligands by the cholinesterase inhibitors parathion, paraoxon, physostigmine and phenyl saligenin cyclic phosphate was examined in rat cortex and brain stem, human cortex and brain stem, and in Chinese hamster ovary (CHO) cells expressing human M2 or M4 muscarinic acetylcholine receptors. None of the cholinesterase inhibitors tested significantly affected binding of the antagonist [3H]quinuclinidyl benzilate. However, the agonist [3H]oxotremorine-methiodide (3H]oxo-M) was displaced by all compounds tested in a differential manner. Parathion only marginally displaced [H]oxo-M binding with pKi values < 5 in all tissue or cell types. In rat brain paraoxon, physostigmine and phenyl saligenin cyclic phosphate displaced [3H]oxo-M with pKi values of 7.5, 7.0 and 6.1, respectively. The cholinesterase inhibitors displaced [3H]oxo-M in human brain at 15- to 250-fold higher concentrations, that is with pKi values of 6.3, 4.6 and 4.2, respectively. Maximal displacement of [3H]oxo-M varied between 25% and 95%, depending on the species and the compound. Human receptors in brain and in CHO cells were equally sensitive to displacement of [3H]oxo-M by parathion, physostigmine and phenyl saligenin cyclic phosphate. However, paraoxon displaced [3H]oxo-M at > or = 35-fold lower concentrations from human receptors in brain than in CHO cells. In conclusion, the data show that cholinesterase inhibitors interfere with agonist binding to muscarinic acetylcholine receptors. The species-selectivity of the displacement appears to result from differences between rat and human muscarinic acetylcholine receptors. In addition, for paraoxon marked differences exist between the sensitivity of human muscarinic acetylcholine receptors in brain tissue and of those expressed in clonal CHO cells.
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PMID:Differential muscarinic receptor binding of acetylcholinesterase inhibitors in rat brain, human brain and Chinese hamster ovary cells expressing human receptors. 919 Aug 43

Phosphorothionate insecticides such as parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate) and chlorpyrifos (CPS; O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothioate; Dursban) are metabolically converted by oxidative desulfuration into paraoxon and chlorpyrifos-oxon (CPO). The insecticidal action of chlorpyrifos stems from inhibition of acetylcholinesterase (AChE) by CPO, resulting in severe cholinergic toxicity. Sensory peripheral neuropathy was observed in people exposed environmentally to chlorpyrifos sprayed in confined areas. We have examined the kinetics of inhibition of AChE and butyrylcholinesterase (BChE) by paraoxon and CPO. The bimolecular rate constants (ki) for inhibition by paraoxon of recombinant human (rH) AChE, recombinant mouse (rM) AChE, and fetal bovine serum (FBS) AChE were 7.0, 4.0, and 3.2 x 10(5) M(-1) min(-1). The ki values for the inhibition by CPO of rH AChE, fetal bovine serum AChE, human RBC AChE, Torpedo AChE, and recombinant mouse (rM) AChE were 9.3, 2.2, 3.8, 8.0, and 5.1 x 10(6) M(-1) min(-1), respectively. Inhibition of human serum BChE, rH BChE, and rM BChE by CPO yielded ki values of 1.65, 1.67, and 0.78 x 10(9) M(-1) min(-1), respectively. The ki values obtained for BChE from various species were 160- to 750-fold larger than those of AChE from parallel sources. Inhibition of the single-site mutant A328Y of rH BChE by CPO displayed a 21-fold lower rate than that of wild-type rH BChE (ki, 7.9 x 10(7) vs 1.67 x 10(9) M(-1) min(-1)). The double mutant of acyl pocket residues of rH AChE, F295L/F297V, was inhibited by CPO with a 150-fold larger ki than wild type (1.5 x 10(9) vs 1.0 x 10(7) M(-1) min(-1)). The increased rate obtained with the double mutant displaying characteristics of the BChE active center provides a rationale for higher efficacy of CPO scavenging by BChE, compared with AChE.
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PMID:Inhibition of acetylcholinesterase and butyrylcholinesterase by chlorpyrifos-oxon. 974 65

The effects of the carbamate physostigmine and of the organophosphates (OPs) parathion, paraoxon and phenyl saligenin cyclic phosphate (PSP) were examined on different subtypes of neuronal nicotinic acetylcholine receptors (nAChR). Stimulation with 1 mM ACh induced transient nicotinic inward currents in mouse N1E-115 and human SH-SY5Y neuroblastoma and in locust thoracic ganglion cells. All four acetylcholinesterase (AChE) inhibitors reduced the nicotinic currents in a concentration-dependent manner. Parathion is about 50 times more potent in blocking nAChR, compared to its active AChE inhibiting metabolite paraoxon. The relative blocking potency of the different AChE inhibitors was the same in all cell types, and followed the order parathion > physostigmine > PSP > paraoxon. In N1E-115 cells the IC50 values of block amounted to 2 microM, 30 microM, 39 microM and 96 microM for parathion, physostigmine, PSP and paraoxon, respectively. In all cell types, the nicotinic currents were equally blocked by parathion. Human nAChR in SH-SY5Y cells appeared more sensitive to block by physostigmine, PSP and paraoxon, while these AChE inhibitors similarly inhibited nicotinic currents in insect cells and in mouse neuroblastoma cells. The observation that the concentration-dependence of block is different from that of AChE inhibition, indicates a distinct interaction of AChE inhibitors with nAChR. Only in locust cells physostigmine induced a non-desensitizing inward current, that appeared to originate from nAChR activation. Occasionally, the OPs were able to activate slow ionic currents in mouse, but not in human and locust cells. As the OP-induced agonistic activity in mouse cells was not associated with the blocking action, the target site appeared to be distinct from nAChR. These results show that AChE inhibitors block nAChR with different potencies, dependent on the compound and the receptor subtype, and may activate distinct ion currents in neuronal cells of different species origin.
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PMID:Differential effects of physostigmine and organophosphates on nicotinic receptors in neuronal cells of different species. 986 67

A set of four learning and memory tests (Morris Maze I for reference memory, Morris Maze II for working memory, one-way active avoidance, and passive avoidance) were employed to address the questions whether parathion impaired cognitive functions after low, long-term exposure and could cause persistent changes in cognition. Motor activity and general behavior were investigated in a functional observational battery. Parathion was administered in rat food in low doses which caused no clinical symptoms and no or borderline brain acetylcholinesterase inhibition. Parathion doses of 0.5, 2, or 8 ppm in rat food produced the averaged uptake of 24, 100, or 400 microg/kg body weight per group per day in male rats and 36, 152, or 550 microg/kg per day in female rats in week 13. Learning tests were performed in weeks 1 to 4 and 10 to 14, as well as 30 to 34 weeks after the end of treatment, when the male and female rats were about 13 months old. Low doses of parathion given daily for 13 weeks had no cumulative or adverse effects on learning and memory, either during treatment or after the extended treatment-free period, in any of the tests. A significant improvement of learning compared to control observed in the Morris Water Maze I during the first week of treatment (males dose group 0.5 ppm) shows that parathion can improved cognitive functions in rats. Results of the study indicate that adverse effects changing learning and memory in animals may occur only at higher doses of organophosphates, at which the peripheral and brain acetylcholinesterases are inhibited to a greater extent than those in the present study.
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PMID:Learning and memory of rats after long-term administration of low doses of parathion. 992 73


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