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)

Exposure of rat brain Na+ + K+-ATPase (ATP phosphohydrolase E.C. 3.6.1.3) to concentrations of cassaine greater than 1 x 10(-4) M resulted in a poorly reversible inhibition of this enzyme. Inhibition did not require the presence of ATP and developed rapidly, but the final amount of inhibition observed was independent of time. The amount of inhibition observed at a given concentration of cassaine was reduced by increasing the concentration of membranes in the system. The inhibition of Na+ + K+-ATPase activity was associated with equivalent inhibition of the phosphorylation and (3H)-ouabain binding reactions of this enzyme, while the uninhibited enzyme was apparently kinetically normal. Concentrations of cassaine which produced this stable inhibition of Na+ + K+-ATPase had no effect on the Mg2+-activated ATPase or the NADH cytochrome-c-reductase activities of crude rat brain microsomal preparations. Cassaine inhibited the cholinesterase activity of rat brain microsomes with a Ki of about 5 x 10(-5) M, but his inhibition was fully reversible. The poorly reversible inhibitory actions of cassaine, thus, appeared specific for Na+ + K+-ATPase. Because this stable pattern of inhibition of the Na+ + K+-ATPase by cassaine required drug concentrations at least one hundred-fold greater than those which produce positive inotropic effects, it appears unlikely that this pattern of Na+ + K+-ATPase inhibition is involved in the cardiotonic actions of this drug.
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PMID:Studies on the stable inhibition of Na+ + K+-ATPase by cassaine. 13 Feb 44

1. The inhibition of cholinesterase and carboxylesterase activities in the diisopropyl fluorophosphate (DFP) intoxication, and the inducibility of organophosphate (OP) detoxicating enzymes was studied in rats. 2. In phenobarbital (PB)-, but not in beta-naphthoflavone (NF)-pretreated rats, the activities of DFP-inhibited cholinesterases were 70-120% higher than in non-pretreated rats. Also the inhibition of the microsomal and cytosolic carboxylesterase activity in liver was efficiently antagonized by BP, but not by NF. 3. In vitro the microsomes from PB-treated rats detoxicated DFP probably by O-dealkylation, since no fluoride was released from DFP. Glutathione S-transferase did not detoxicate DFP. 4. 7-Pentoxyresorufin O-dealkylase, a specific enzyme of cytochrome P450IIB subfamily, was induced by PB, flumecinol, isosafrole and NF by 167- 61-, 26- and 1.6-fold, respectively. 7-Ethoxyresorufin O-deethylase, a marker enzyme of cytochrome P450IA subfamily, was induced by those agents 5-, 4-, 31- and 94-fold, given in the same order. Glutathione S-transferase, paraoxonase and DFPase activities were increased 0-72% by the tested inducers. 5. The results suggest that the cytochrome P450IIB subfamily, inducible by PB, participates in DFP detoxication by O-dealkylation. Its induction probably causes the protection against the cholinesterase inhibition by OPs.
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PMID:Inhibition of cholinesterases by DRP and induction of organophosphate-detoxicating enzymes in rats. 216 59

Rats were injected intraperitoneally with phenobarbital (PB) and 3-methylcholanthrene (MC) which are microsomal enzyme inducers, and methyl iodide (MeI), cobalt chloride (CoCl2) and tri-o-cresyl phosphate (TOCP) which are inhibitors of the enzymes glutathione transferase, cytochrome (cyt) P-450 and carboxylesterase, respectively, and then challenged with soman (i.p.) to know its LD50. Pretreatment with PB and MC increased and TOCP decreased, whereas MeI as well as CoCl2 did not alter the LD50 value of soman in rats. The 1/2 LD50 dose of soman did not affect the liver microsomal cyt P-450 level, but significantly lowered carboxylesterase (CaE) and cholinesterase (ChE) activities in liver microsomes and in blood plasma. Induction of plasma CaE was more important than microsomal CaE in PB-mediated protection against soman toxicity. Gel filtration of plasma into four protein fractions for their relative soman binding capacity showed that a high-molecular-weight protein fraction (180,000 daltons on SDS-PAGE) which had no CaE activity could bind soman 6 times more than the low-molecular-weight CaE-containing protein fraction (60,000 daltons on SDS-PAGE).
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PMID:Role of carboxylesterase in protection against soman toxicity. 276 74

Pretreatment of rats with chloramphenicol (CAP) (100 mg/kg, ip) 30 min prior to a single oral LD50 dose of malathion (MTH) at 340 mg/kg completely protected against MTH-induced signs of cholinergic toxicity. Pretreatment with CAP also decreased the extent and duration of MTH-induced inhibition of cholinesterase (ChE). It was previously established that CAP inhibits (1) the cytochrome-P-450-catalyzed oxidative desulfuration of methylparathion to the much more toxic oxygen analog methylparaoxon (MOX) and (2) the carboxyesterase in rat liver. Since carboxyesterases account for 60% or more of the catabolism of MTH in the rat, the present results were surprising. Thus it appears that the inhibition of MTH toxicity by CAP pretreatment is attributable to inhibition by CAP of the metabolic activation of MTH to MOX.
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PMID:Effect of chloramphenicol pretreatment on malathion-induced acute toxicity in the rat. 662 Apr 20

Rats were pretreated with phenobarbitol [PB (75 mg/kg, IP)] for 3 days and subsequently injected with parathion, an organophosphorous insecticide, which requires microsomal activation for its anticholinesterase effect or with dichlorovos, a cholinesterase (ChE) inhibitor as such. The difference in the mortality and spontaneous regeneration of inhibited plasma ChE by IP administration of the two insecticides was compared. A single dose of 10 mg/kg parathion caused 100% mortality in PB-untreated rats, but effected no mortality in PB-pretreated rats. A lower dose (7.5 mg/kg) of parathion resulted in plasma ChE levels which were 5, 5, 17, and 93% of initial values in PB-untreated rats and 85, 97, and 92% of initial values in PB-pretreated rats at 2-hr, 1-3-, and 5-day periods, respectively. Mortality resulting from single dose of 30 mg/kg dichlorovos was 30% in PB-pretreated, as well as untreated rats. A lower dose of dichlorovs (20 mg/kg) resulted in plasma ChE activity which was 48, 82, 90, and 97% of initial levels in PB-untreated rats, and 60, 100, 100, and 130% in PB-pretreated rats at 2 hr, 1, 3, and 5 day's, respectively. Administration of 2 mg/kg parathion for 3 days did not affect cytochrome P-450 levels in liver microsomes, but administration of 6 mg/kg dichlorovos for 3 days caused greatly lowered levels of liver microsomal cytochrome P-450, resulting from its inactivation to cytochrome P-420. Phenobarbital caused accelerated in vitro ChE regeneration in the case of dichlorovos-inhibited enzyme in the plasma, but not in the case of parathion-inhibited enzyme.
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PMID:Effect of phenobarbitol pretreatment on regeneration of plasma cholinesterase activity inhibited by parathion or dichlorovos. 705 32

Cholinesterase inhibitors (ChEIs) are dosed in two phases for the treatment of dementia, an initial dose-escalation phase to achieve a therapeutic dose and a maintenance phase where the therapeutic dose is given for long-term therapy. ChEIs are associated with a range of side effects as a result of cholinergic stimulation in different areas of the brain and the periphery Acute, centrally-mediated gastrointestinal events (mostly nausea and vomiting) are class effects of all ChEIs, and are reported mostly during the dose-escalation phase of therapy. These events have been associated more with the dual acetylcholinesterase/butyrylcholinesterase (AChE/BuChE) inhibitor rivastigmine than with the AChE-selective inhibitors donepezil and galantamine, probably due to rivastigmine's higher potency. However, these events can be minimised using slow dose escalation with small dose graduations and administration with food. Other side effects associated with ChEIs include central nervous system events, extrapyramidal symptoms, sleep disturbances and cardiorespiratory events, associated with cholinergic activity in the cortex, caudate nucleus, brainstem and medulla, respectively, and muscle cramps and weakness, cardiorespiratory events and urinary incontinence, associated with peripheral cholinergic activity. These symptoms are mostly reported during the maintenance phase of therapy. They are more frequently reported with donepezil, but are rarely reported with rivastigmine, and galantamine may not have been marketed long enough to make an adequate assessment. These differences are due to the drugs' respective pharmacology. For example, donepezil and rivastigmine are active centrally, in contrast to galantamine, which is more active peripherally. Furthermore, rivastigmine preferentially inhibits the G1 isoform of cholinesterase, predominantly located in the cortex, hippocampus and in neuritic plaques, while donepezil and galantamine are not selective for any cholinesterase isoforms and have wide cholinergic activity both centrally and peripherally The cholinergic activity of rivastigmine, in contrast to donepezil and galantamine, is apparently more targeted at clinically relevant brain sites. The pharmacological profile of rivastigmine results in it having a low potential to interact with other drugs and it may be used with a high margin of safety in patients having a wide variety of concomitant diseases. Donepezil and galantamine may have significant interactions with other drugs that are metabolised by the hepatic cytochrome system and therefore need to be used with caution in patients with many concomitant illnesses. When dosed with care, ChEIs are well tolerated and patient compliance and patient and caregiver acceptability are good. The favourable tolerability and safety profiles of these agents make them suitable first-line therapy for dementia. In addition, patients who have tolerability and/or safety problems in maintenance treatment that limit the use of donepezil or galantamine may benefit from switching to rivastigmine.
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PMID:The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. 1213 67

Pesticides, such as parathion, are metabolized by cytochrome p-450 system to paraoxon, which is a potent cholinesterase inhibitor. Paraoxonase (PON) catalyzes the hydrolysis of these toxic metabolites and protects against pesticide toxicity. A glutamine/arginine (Gln/Arg) polymorphism at amino acid position 192 of PON has been described. The Arg/Arg genotype is associated with higher serum paraoxonase activity compared to Gln/Gln. The Arg/Gln genotype is associated with intermediate serum PON activity. The potential association between PON genotype and symptoms of chronic pesticide toxicity was examined among 100 farm workers. As part of a cross-sectional study of pesticide toxicity among mixed-race farm workers in the Western Cape. South Africa, 100 farm workers were genotyped for polymorphism of the paraoxonase gene at amino acid position 192. Subjects with two or more of the following symptoms were considered to have evidence of chronic toxicity: abdominal pain, nausea, rhinorrhea, dizziness, headache, somnolence, fatigue, gait disturbance, limb numbness, paresthesias, limb pain, or limb weakness. In multivariable logistic regression analysis, the independent predictors of chronic toxicity were previous history of head trauma resulting in loss of consciousness (OR 2.8, 95% CI = 1.7-6.7), having worked as a pesticide applicator (OR 5.4, 95% CI = 3.2-8.9), and having one of the two "slow metabolism" (Gln/Gln or Gln/Arg) genotypes (OR 2.9, 95% CI = 1.7-6.9). Furthermore, the prevalence of chronic toxicity increased in a stepwise fashion from 15% among pesticide nonapplicators with a "fast metabolism" (Arg/Arg) genotype, to 42.9% among pesticide nonapplicators with "slow metabolism" (Gln/Gln or Gln/Arg) genotypes, to 58.8% among pesticide applicators with "fast metabolism" genotype, and 75.0% among pesticide applicators with "slow metabolism" genotypes (P = 0.001). Age, number of years on the job, smoking history, alcohol history, education level, plasma or red blood cell cholinesterase level, or previous history of acute organophosphate poisoning were not statistically significant predictors of chronic toxicity. The PON genotype is an important determinant of a farmworker's susceptibility to chronic pesticide poisoning.
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PMID:Association between human paraoxonase gene polymorphism and chronic symptoms in pesticide-exposed workers. 1262 27

The neurotoxic poison from the roe of Fugu, a globe fish living in the waters of Japan, was investigated with reference to its effect on the main oxidation-reduction systems, acetyl-cholinesterase and choline-acetylase in the brain of the guinea-pig.It was found that the poison inhibited the choline-acetylase activity, even in a concentration of 4.4x10(-7). Acetyl-cholinesterase and cytochrome-c-oxidase activities were also inhibited in concentration of 1.3x10(-5) and 0.8x10(-5) respectively.
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PMID:Susceptibility of certain enzymes of the central nervous system to tetrodotoxin. 1348 63

A search of the scientific literature was carried out for physiochemical and biological data [i.e., IC50, LD50, Kp (cm/h) for percutaneous absorption, skin/water and tissue/blood partition coefficients, inhibition ki values, and metabolic parameters such as Vmax and Km] on 31 organophosphorus pesticides (OPs) to support the development of predictive quantitative structure-activity relationship (QSAR) and physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models for human risk assessment. Except for work on parathion, chlorpyrifos, and isofenphos, very few modeling data were found on the 31 OPs of interest. The available percutaneous absorption, partition coefficients and metabolic parameters were insufficient in number to develop predictive QSAR models. Metabolic kinetic parameters (Vmax, Km) varied according to enzyme source and the manner in which the enzymes were characterized. The metabolic activity of microsomes should be based on the kinetic activity of purified or cDNA-expressed cytochrome P450s (CYPs) and the specific content of each active CYP in tissue microsomes. Similar requirements are needed to assess the activity of tissue A- and B-esterases metabolizing OPs. A limited amount of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CaE) inhibition and recovery data were found in the literature on the 31 OPs. A program is needed to require the development of physicochemical and biological data to support risk assessment methodologies involving QSAR and PBPK/PD models.
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PMID:Physicochemical and biological data for the development of predictive organophosphorus pesticide QSARs and PBPK/PD models for human risk assessment. 1511 52

Deltamethrin and other pyrethroids have been extensively used in Argentina since 1980, for the chemical control of Triatoma infestans Klug (Hemiptera: Reduviidae). Recently, resistance to deltamethrin was detected in field populations by the survival of bugs exposed by topical application to the diagnostic dose estimated on the CIPEIN susceptible strain. Results of the current study showed low resistant ratios (RRs) to deltamethrin for the resistant populations (RR ranged from 2.0 for San Luis colony to 7.9 for Salta colony). Biochemical studies were made on the most resistant colony (Salta) and the susceptible strain (CIPEIN), in order to establish the importance of degradative mechanisms as a cause of the detected resistance. Esterase activity was measured on 3 days old first instars through phenylthioacetate and a-naphtyl acetate activities. The results showed a significant difference in no cholinesterase esterase activity from susceptible (7.6 +/- 0,7 micro M S./i.min.) and Salta resistant colony (9.5 +/- 0.8 microM S./i.min.). Cytochrome p450 mono-oxygenase (p450) activity was measured on individual insects through ethoxycoumarine deethylase (ECOD) activity using a fluorescence microplate reader. The dependence of ECOD activity on age and body region of the nymphs, and pH and time of incubation were studied in order to optimize the measurement. As a result, comparative studies were performed on abdomens of 2 days old first instars at pH 7.2 and 4 h incubation time. ECOD activity of first nymphs was significantly lower in the susceptible colony (61.3 +/- 9.08 pg ECOD/ insect) than in the resistant one (108.1+/- 5.7 pg ECOD/ insect). These results suggest that degradative esterases (no-cholinesterase) and mono-oxygenases cytochrome p450, play an important role in the resistance to deltamethrin in Salta colony from Argentina.
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PMID:Role of enhanced detoxication in a deltamethrin-resistant population of Triatoma infestans (Hemiptera, Reduviidae) from Argentina. 1527 11


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