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)

We measured several biochemical effects of 10 days of intragastric administration of phosphatidylcholine (10 mmoles/kg) to rats because of the expanding clinical use of chronic phosphatidylcholine treatment for disorders involving impaired cholinergic neurotransmission. The plasma and erythrocyte choline concentrations were increased 3.5-fold, which was the same percent increase as found after an acute treatment with phosphatidylcholine. The lipid and fatty acid compositions of the plasma were also altered; free and total cholesterol levels increased, triglycerides increased, the monoene fatty acids generally decreased, and the diene and tetraene fatty acids generally increased. We found no effect of this treatment on the hepatic microsomal cytochrome P-450 activity or on the N-demethylation of benzphetamine or methamphetamine. Ten days of phosphatidylcholine treatment increased the concentration of choline in the brain but had no effect on the concentration of acetylcholine, the activity of choline acetyltransferase, cholinesterase activity, the apparent KD or Bmax of muscarinic receptors, or the fatty acid composition of rat brain lipids. These findings indicate that the largest effect caused by this treatment was an increase in the choline levels. No indication of altered cholinergic metabolism was observed. Further studies of the effects of chronic phosphatidylcholine treatment are required to clarify its therapeutic mechanism of action.
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PMID:Biochemical effects of phosphatidylcholine treatment in rats. 671 9

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

Biochemical biomarkers, such as inhibition of serum butyryl cholinesterase (BuChE) and brain acetyl cholinesterase (AChE), have been useful in studies of interactive effects of pesticides in birds. Examples of interactions due to increased activation or decreased detoxication are reviewed. Studies have shown that hybrid red-legged partridges (Alectoris rufa cross) pretreated with the inducing ergosterol biosynthesis inhibiting (EBI) fungicide, prochloraz, were more sensitive to the toxic effects of the organophosphorous (OP) insecticide, malathion, than controls. A dose of 90 mg/kg prochloraz produced greater inhibition at 1, 4 and 24 h following oral administration of 50 mg/kg malathion, compared to corn oil controls. Pigeons (Columba livia) given 180 or 90 mg/kg prochloraz showed greater inhibition of BuChE activity following malathion administration than did control birds. Starlings (Stumus vulgaris), however, appeared not to be induced by 180 or 300 mg/kg prochloraz, and no difference in BuChE activity following dosing with malathion was apparent in comparison with controls. Other EBIs and OP combinations have been investigated in the partridge. Birds pretreated with prochloraz showed a trend towards greater inhibition of serum BuChE activity at most time points following dosing with the OPs dimethoate and chlorpyriphos. Birds pretreated with the EBI penconazole showed significantly greater inhibition of serum BuChE activity at 1, 4 and 24 h after malathion administration than did controls. The mechanism of increased activation of malathion due to induction of cytochrome P-450 by prochloraz is reviewed. In the case of interactions due to inhibition of detoxication, inhibition of brain AChE activity was a useful biochemical biomarker.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The study of interactive effects of pollutants: a biomarker approach. 748 47

Rats and chickens were given single oral doses of 50 mg chlorpyrifos/kg to compare toxic effects in these 2 species. Oral administration resulted in decreased cytochrome P-450 and aminopyrine N-demethylase activities and increased cytosolic glutathione S-transferase activity in rats. On the contrary, there was increased cytochrome P-450 and aminopyrine N-demethylase activities in chickens. A significantly higher inhibition of serum cholinesterase (82%) was noted in rats than in chickens (55%). Serum gamma-glutamyl transferase, a marker of hepatotoxicity, remained unchanged in both species, indicating the absence of hepatotoxicity. These studies project chlorpyrifos to be an inhibitor of hepatic microsomal drug-metabolizing enzymes in rats and an inducer in chickens, and a non-hepatotoxic organophosphate insecticide in both species when given at the dosage of 50 mg/kg.
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PMID:Comparative toxicological studies of chlorpyrifos in rats and chickens. 753 64

Many organophosphorus compounds (OPs) are potent cholinesterase inhibitors, accounting for their use as insecticides and, unfortunately, also as nerve agents. Each year there are approximately 3 million pesticide poisonings world-wide resulting in 220,00 deaths. In 1990, there were 1.36 million kg of chlorpyrifos, 4.67 million kg of diazinon and 1.23 million kg of ethyl parathion manufactured in the USA (data supplied by the USEPA). In addition to exposure risks during pesticide manufacturing, distribution and use, there are risks associated with the major international effort aimed at destroying the arsenals of nerve agents, including soman and sarin. The United States has pledged to destroy approximately 25,000 tons of chemical agents by the end of the decade. The high density lipoprotein (HDL)-associated enzyme paraoxonase (PON1) contributes significantly to the detoxication of several OPs (Fig. 1). The insecticides parathion, chlorpyrifos and diazinon are bioactivated to potent cholinesterase inhibitors by cytochrome P-450 systems. The resulting toxic oxon forms can be hydrolysed by PON1, which also hydrolyses the nerve agents soman and sarin (Fig. 1). PON1 is polymorphic in human populations and different individuals also express widely different levels of this enzyme. The Arg192 (R192) PON1 isoform hydrolyses paraoxon rapidly, while the Gln192 (Q191) isoform hydrolyses paraoxon slowly. Both isoforms hydrolyse chlorpyrifos-oxon and phenylacetate at approximately the same rate. The role of PON1 in OP detoxication is physiologically significant. Injected PON1 protects against OP poisoning in rodent model systems and interspecies differences in PON1 activity correlate well with observed median lethal dose (LD50) values. We report here a simple enzyme analysis that provides a clear resolution of PON1 genotypes and phenotypes allowing for a reasonable assessment of an individual's probable susceptibility or resistance to a given OP, extending earlier studies on this system. We also show that the effect of the PON1 polymorphism is reversed for the hydrolysis of diazoxon, soman and especially sarin, thus changing the view of which PON1 isoform is considered to be protective.
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PMID:The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. 889 66

Cholinesterase inhibitors are the first agents to be successfully developed specifically for the treatment of cognitive decline associated with Alzheimer's disease. Basic knowledge of their pharmacokinetics is important to their appropriate administration. Their pharmacokinetics help determine the magnitude and duration of their pharmacologic effects, and also the manner in which they affect the degree of cholinesterase inhibition and recovery. The clinical utility of measuring these values in daily practice awaits further research. Drug interactions with cholinesterase inhibitors may occur by pharmacokinetic or pharmacodynamic mechanisms. For the most part, interactions that are mediated by the hepatic cytochrome P-450 system have been inadequately evaluated.
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PMID:Pharmacokinetics and drug interactions of cholinesterase inhibitors administered in Alzheimer's disease. 954 65

Rivastigmine (ENA 713, or carbamoylatine) is an acetylcholinesterase (AChE) inhibitor with brain-region selectivity and a long duration of action. Both preclinical studies and studies in human volunteers have shown that rivastigmine induces substantially greater inhibition of AChE in the central nervous system (CNS) compartment than in the periphery (40% inhibition of central AChE compared with 10% inhibition of plasma butylcholinesterase in healthy volunteers). Moreover, rivastigmine preferentially inhibits the G1 enzymatic form of AChE, which predominates in the brains of patients with Alzheimer's disease (AD). Evidence from animal studies also suggests that rivastigmine is a more potent inhibitor of AChE in the cortex and hippocampus, the brain regions most affected by AD. Absorption of rivastigmine is rapid and almost complete (>96% of the administered dose). Extensive, saturable first-pass metabolism, however, leads to bioavailability of approximately 35% of the administered dose and nonlinear pharmacokinetics. The principal metabolite of rivastigmine has at least 10-fold lower activity against AChE compared with the parent drug. Rivastigmine is completely metabolized; the major route of elimination of the metabolites is renal. Although patients with AD demonstrate 30% to 50% higher plasma concentrations of rivastigmine and its principal metabolite than do healthy elderly patients, there is no evidence of drug accumulation, which is consistent with rivastigmine's short pharmacokinetic half-life. Distribution of rivastigmine into the CNS is extensive, and inhibition of AChE in the cerebrospinal fluid is detectable 1.2 hours after oral dosing in both healthy volunteers and patients with AD. Peak activity is reached somewhat more slowly in AD patients than in healthy subjects, and the inhibitory effects have a longer duration (6.0 vs 2.4 hours and 12.0 vs 8.5 hours, respectively). Rivastigmine is inactivated during the process of interacting with and inhibiting AChE, and, in contrast to other AChE inhibitors, the hepatic cytochrome P-450 (CYP-450) system is not involved in the metabolism of rivastigmine. This reduces its propensity to interact with drugs metabolized by specific CYP-450 isoenzymes. Consistent with rivastigmine's pharmacokinetic and pharmacodynamic profiles, Phase II and III trials have demonstrated that the drug is a well-tolerated and effective treatment for AD.
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PMID:Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. 973 24

The majority of insecticides currently in use throughout the world belong to the class of the organophosphorus insecticides. Many of these compounds, such as the phosphorothioate insecticides, exert their mammalian toxicity only after undergoing metabolic activation by a variety of cytochrome P450 isoforms to produce their corresponding oxygen analogs (or oxons), which are potent inhibitors of the critical enzyme acetylcholinesterase. Of the many chemicals identified that can modulate cytochrome P450-dependent activities, the flavonoids represent some of the most unusual compounds in that they have been reported to both inhibit and stimulate certain activities. The present study was undertaken to determine if representative flavonoids (at in vitro concentrations of 1-100 microM) can alter the mammalian cytochrome P450-dependent biotransformation and acute toxicity of the phosphorothioate insecticide parathion. The flavonoids 5,6-benzoflavone, flavone, and quercetin had the biphasic effect of stimulating mouse hepatic microsomal parathion oxidation at a concentration of 1 microM, and inhibiting this same activity when increased to 100 microM. In contrast, 7,8-benzoflavone was only inhibitory at all concentrations examined. All the flavonoids examined except quercetin altered the ratio of activation/detoxification of parathion by mouse hepatic microsomes, but had no effect on this same ratio with human CYP1A2. These data suggest that the changes in the activation/detoxification ratio observed with mouse hepatic microsomes resulted from selective inhibition or stimulation of various cytochrome P450 isoforms rather than a flavonoid-induced alteration in the nonenzymatic rearrangement of the putative phosphooxythirane intermediate generated by cytochromes P450 from parathion. Surprisingly, however, none of the four flavonoids in the current study affected the lethality of parathion in vivo, suggesting that the flavonoid-induced alterations in cytochrome P-450-dependent metabolism of parathion documented in vitro were simply not great enough to be of any significance in vivo.
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PMID:Flavonoid-induced alterations in cytochrome P450-dependent biotransformation of the organophosphorus insecticide parathion in the mouse. 992 30

This in vitro study was designed to identify the enzyme(s) involved in the two major metabolic pathways of rokitamycin [formations of leucomycin A7 (LMA7) from rokitamycin and of leucomycin V (LMV) from LMA7] and to assess possible drug interactions using human liver microsomes. Formation of LMA7 or LMV was NADPH-independent. Anti-rat NADPH cytochrome P-450 (CYP) reductase serum, specific inhibitors, or substrates of CYP isoforms showed no effects on the formation of LMA7 or LMV. The mean Vmax and Vmax/Km for the formation of LMA7 from rokitamycin were much greater (P <.01) than those for the formation of LMV from LMA7. Two esterase inhibitors, bis-nitro-phenylphosphate and physostigmine (100 microM), inhibited the formation of LMA7 or LMV by more than 85%, whereas no appreciable inhibition occurred by several substrates of carboxylesterase (EC 3.1.1.1). Except the moderate inhibition produced by promethazine and terfenadine, theophylline, mequitazine, chlorpheniramine, and diphenhydramine showed little or no inhibition for the formation of LMA7 or LMV. Rokitamycin, LMA7, LMV, erythromycin, and clarithromycin (up to 500 microM) had no appreciable inhibition for CYP1A2-, 2C9-, and 2D6-mediated catalytic reactions. However, rokitamycin, LMA7, erythromycin, and clarithromycin inhibited the CYP3A4-catalyzed triazolam alpha-hydroxylation with IC50 (Ki) values of 5.8 (2.0), 40, 33 (20), and 56 (43) microM, respectively. It is concluded that the formations of LMA7 from rokitamycin and of LMV from LMA7 are catalyzed mainly by human esterase enzyme [possibly cholinesterase (EC3.1.1.8)]. However, whether rokitamycin would inhibit the CYP3A-mediated drug metabolism in vivo requires further investigations in patients.
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PMID:An in vitro study on the metabolism and possible drug interactions of rokitamycin, a macrolide antibiotic, using human liver microsomes. 1038 20

This in-vitro study was designed to identify the enzyme(s) involved in the major metabolic pathway of rokitamycin, i.e. the formation of leucomycin A7, and to assess possible interactions of the drug with rat liver microsomes. Formation of leucomycin A7 was NADPH-independent and was not appreciably inhibited by anti-rat NADPH cytochrome P-450 reductase serum or cimetidine, a nonspecific inhibitor of cytochrome P-450 isoforms. Eadie-Hofstee plots for the formation of leucomycin A7 were indicative of apparently monophasic behaviour for six rat liver microsomes tested. The mean (+/- s.d.) kinetic parameters, Km, Vmax and Vmax/Km, for the formation of leucomycin A7 from rokitamycin were 47+/-13 microM, 390+/-56 nmol min(-1) (mg protein)(-1) and 8.6+/-1.6 mL min(-1) (mg protein)(-1), respectively. Three esterase inhibitors (100 microM), bis-nitrophenylphosphate, physostigmine and metrifonate inhibited the formation of leucomycin A7 by more than 60%. Metabolism of rokitamycin was inhibited by terfenadine, but not by mequitazine, whereas chlorpheniramine and theophylline activated the formation of leucomycin A7. Rokitamycin, leucomycin A7, leucomycin V, erythromycin and clarithromycin were weak inhibitors of CYP3A-catalysed 3-hydroxylation of quinine with mean IC50 values ranging from 71 to >100 microM. It is concluded that in rat liver microsomes the formation of leucomycin A7 from rokitamycin is catalysed mainly by an esterase (possibly cholinesterase, EC3.1.1.8), but not by cytochrome P-450 enzyme(s). Although in this in-vitro animal study CYP3A activity was barely inhibited by rokitamycin, the possibility cannot be totally discounted in man when rokitamycin is co-administered with drugs metabolized by CYP3A.
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PMID:An in-vitro study on the metabolism of rokitamycin and possible interactions of the drug with rat liver microsomes. 1057 88


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