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 examined neurochemically the effects of bifemelane (BF) on muscarinic ACh (mACh-R) and beta-adrenergic receptors (beta-AdR) and imipramine binding sites and the activities of acetylcholinesterase (AChE), choline acetyltransferase (CAT) and monoamine oxidase (MAO) in the P2 fractions of rat brain, ex vivo and in vitro. Male rats were given daily injections of 10, 30 mg/kg BF, p.o., for a period of 4 weeks. The Kd and Bmax values for mACh-R in the rat forebrain by administration of 10, 30 mg/kg BF decreased significantly compared with that of the control, although the Kd and Bmax values for beta-AdR and imipramine binding sites were almost identical. The Km and Vmax values of A- and B-form MAO decreased in rats that had been administered 30 mg/kg BF for 4 weeks. The binding of 3H-QNB (quinuclidinyl benzilate) on mACh-R, 125I-CYP (iodocyanopindolol) on beta-AdR and 3H-imipramine on imipramine binding sites decreased by 60, 20 and 70% in the presence of 1 microM BF, respectively, while the addition of 1 microM BF inhibited MAO activity by about 50%. However, CAT and AChE activities were not inhibited by BF.
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PMID:[Neurochemical studies on bifemelane, a new cerebral function improver. I. Effects of bifemelane on the function of neurotransmission-related enzymes and receptors in rat brain]. 254 82

Biotransformation of rifabutin, an antibiotic used for treatment of tuberculosis in patients infected with the human immunodeficiency virus (HIV), and its interactions with some macrolide and antifungal agents were studied in human intestinal and liver microsomes. Both liver and enterocyte microsomes metabolized rifabutin to 25-O-deacetylrifabutin, 27-O-demethylrifabutin, and 20-, 31-, and 32-hydroxyrifabutin. The same products (except 25-O-deacetylrifabutin) were formed by microsomes from lymphoblastoid cells that contained expressed CYP3A4. The apparent Michaelis-Menten constant (Km); approximately 10 to 12 mumol/L) and maximal velocity (Vmax; approximately 100 pmol/min/mg of protein) values for CYP-mediated metabolism were similar in liver and enterocyte microsomes. Deacetylation of rifabutin (Km approximately 16 to 20 mumol/L and Vmax approximately 50 to 100 pmol/min/mg of protein) was catalyzed by microsomal cholinesterase. Clarithromycin, ketoconazole, and fluconazole inhibited CYP-mediated metabolism of rifabutin in enterocyte microsomes equally or more potently than in liver microsomes but had no effect on cholinesterase activity. Azithromycin did not inhibit in vitro metabolism of rifabutin. This study provides evidence that CYP3A4 and cholinesterase are major enzymes that biotransform rifabutin in humans and that intestinal CYP3A4 contributes significantly to rifabutin presystemic first-pass metabolism and drug interactions with macrolide and antifungal agents.
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PMID:Metabolism of rifabutin in human enterocyte and liver microsomes: kinetic parameters, identification of enzyme systems, and drug interactions with macrolides and antifungal agents. 916 17

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

Galantamine is a reversible, competitive inhibitor of acetylcholinesterase and an allosteric modulator of nicotinic acetylcholine receptors. It is cleared by renal and hepatic mechanisms, including metabolism by the CYP 450 2D6 and 3A4 isoenzymes. The authors estimated the population pharmacokinetics of galantamine using nonlinear mixed-effects modeling as implemented in NONMEM software. Data from 15 clinical studies (1089 individuals, 7480 concentration measurements in total) were used to examine the effect of body size, demographic characteristics, and concomitant disease status on galantamine pharmacokinetic parameters. Galantamine clearance was shown to decrease with age and increase with body weight and creatinine clearance of individuals. Median clearance in male and female patients with Alzheimer's disease (AD) was 14.8 and 12.4 L/h, respectively. The dissimilarity was related to the body weight difference, not to the real gender effect. Metabolic clearance was reduced by 60% in patients with moderate or severe hepatic dysfunction (Pugh score 7 or higher). Simulations were performed to assess the impact of hepatic impairment and renal insufficiency on peak plasma concentration of galantamine. Simulations confirmed the need for slower dose titration in patients with hepatic impairment: 4 mg daily during 1 week followed by 4, 8, and 12 mg bid, with each dose level during 1 week compared to the standard titration scheme 4-8-12-16 mg bid. However, no significant differences between plasma levels in AD patients with and without severe renal insufficiency were found. CYP 450 2D6 genotype also influenced galantamine clearance but not to the extent that dose adjustment is required.
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PMID:Galantamine population pharmacokinetics in patients with Alzheimer's disease: modeling and simulations. 1275 Dec 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

Here, we describe the development of a bi-enzymatic biosensor that simplifies the sample pretreatment steps for insecticide detection, and opens the way for a highly sensitive detection of phosphorothionates in food. These compounds evolve their inhibitory activity towards acetylcholinesterases (AChEs) only after oxidation, which is performed in vivo by P450 monooxygenases. Consequently, phosphorothionates require a suitable sample pretreatment by selective oxidation to be detectable in AChE based systems. In this study, enzymatic phosphorothionate activation and AChE inhibition were integrated in a single biosensor unit. A triple mutant of cytochrome P450 BM-3 (CYP 102-A1) and Nippostrongylus brasiliensis AChE (NbAChE) was immobilized using a fluoride catalyzed sol-gel process. Different sol-gel types were fabricated and characterized regarding enzyme loading capacity and enzyme activity containment. The enzyme sol-gel itself already proved to be suitable for the highly sensitive detection of paraoxon and parathion in a spectrometric assay. A method for screen-printing of this enzyme sol-gel on thick film electrodes was developed. Finally, amperometric biosensors containing coimmobilized NbAChE and the cytochrome P450 BM-3 mutant were produced and characterized with respect to signal stability, organophosphate detection, and storage stability. The detection limits achieved were 1 microg/L for paraoxon and 10 microg/L for parathion, which is according to EC regulations the highest tolerable pesticide concentration in infant food.
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PMID:Screen-printed bienzymatic sensor based on sol-gel immobilized Nippostrongylusbrasiliensis acetylcholinesterase and a cytochrome P450 BM-3 (CYP102-A1) mutant. 1589 24

Dimethoate (DIM) is an organophosphorothionate (OPT) pesticide used worldwide as a systemic insecticide and acaricide. It is characterized by low-to-moderate acute mammalian toxicity; similarly to the other OPT pesticides, its mode of action is mediated by the inhibition of acetylcholinesterase (AChE), exerted by its toxic metabolite dimethoate-oxon or omethoate (OME), which is also used as a direct acting pesticide. Human hepatic DIM bioactivation to the toxic metabolite OME has been characterized by using c-DNA expressed human CYPs and human liver microsomes (HLM) also in the presence of CYP-specific chemical inhibitors, with a method based on AChE inhibition. The obtained kinetic parameters and AChE IC(50) have been compared with those previously obtained with other OPTs, indicating a lower efficiency in DIM desulfuration reaction and a lower potency in inhibiting AChE. Results showed that, similarly to the other OPTs tested so far, at low DIM concentration OME formation is mainly catalysed by CYP1A2, while the role of 3A4 is relevant at high DIM levels. Differently from the other OPTs, DIM desulfuration reaction showed an atypical kinetic profile, likely due to CYP3A4 autoactivation. The sigmoidicity degree of the activity curve increased with the level of CYP3A4 in HLM or disappeared in the presence of a CYP3A4 chemical inhibitor. This atypical kinetic behaviour can be considered one of the possible explanations for the recent findings that among patients hospitalized following OPT intoxication, DIM ingestion gave different symptoms and more severe poisoning (23.1% of fatal cases versus total) than chlorpyrifos (8% of deaths), which has a lower LD(50) value. Since DIM-poisoned patients poorly responded to pralidoxime, the possibility to use CYP3A4 inhibitors could be considered as a complementary treatment.
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PMID:Evidences for CYP3A4 autoactivation in the desulfuration of dimethoate by the human liver. 1789 69

Recent studies demonstrate that the therapeutic response in Alzheimer's disease (AD) is genotype-specific. More than 200 genes are potentially associated with AD pathogenesis and neurodegeneration, and approximately 1,400 genes distributed across the human genome account for 20 to 95% of variability in drug disposition and pharmacodynamics. Cytochrome P450 enzymes encoded by genes of the CYP superfamily, such as CYP1A1 (15q22-q24), CYP2A6 (19q13.2), CYP2C8 (10q24), CYP2C9 (10q24), CYP2C19 (10q24.1-q24.3), CYP2D6 (22q13.1), CYP2E1 (10q24.3-qter), and CYP3A5 (7q22.1), acting as terminal oxidases in multicomponent electron transfer chains which are called P450-containing monooxygenase systems, metabolize more than 90% of drugs. Some of the enzymatic products of the CYP gene superfamily can share substrates, inhibitors and inducers whereas others are quite specific for their substrates and interacting drugs. Some cholinesterase inhibitors (tacrine, donepezil, galantamine) are metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. The distribution of CYP2D6 genotypes in the Spanish population is the following: (a) Extensive Metabolizers (EM)(51.61%): *1/*1, 47.10%; and *1/*10, 4.52%; (b) Intermediate Metabolizers (IM)(32.26%): *1/*3, 1.95%; *1/*4, 17.42%; *1/*5, 3.87%; *1/*6, 2.58%; *1/*7, 0.75%; *10/*10, 1.30%; *4/*10, 3.23%; *6/*10, 0.65%; and *7/*10, 0.65%; (b) Poor Metabolizers (PM)(9.03%): *4/*4, 8.37%; and *5/*5, 0.65%; and (c) Ultrarapid Metabolizers (UM)(7.10%): *1xN/*1, 4.52%; *1xN/*4, 1.95%; and CYP2D6 gene duplications, 0.65%. PMs and UMs also accumulate genotypes of risk associated with APOE-, PS-, ACE-, and PRNP-related genes. Approximately, 15% of the AD population may exhibit an abnormal metabolism of cholinesterase inhibitors; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of cholinesterase inhibitors to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including cholinesterase inhibitors (e.g., donepezil), the best responders are the CYP2D6-related EMs and IMs, and the worst responders are PMs and UMs. In addition, the presence of the APOE-4 allele in genetic clusters integrating CYP2D6 and APOE genotypes contributes to deteriorate the therapeutic outcome. From these data, it can be postulated that pharmacogenetic and pharmacogenomic factors are responsible for 75-85% of the therapeutic response in AD patients treated with conventional drugs.
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PMID:Pharmacogenetic aspects of therapy with cholinesterase inhibitors: the role of CYP2D6 in Alzheimer's disease pharmacogenetics. 1790 53

Alzheimer's disease is a major health problem in developed countries. Approximately 10-15% of direct costs in dementia are attributed to pharmacological treatment, and only 10-20% of the patients are moderate responders to conventional antidementia drugs, with questionable cost effectiveness. The phenotypic expression of Alzheimer's disease is characterized by amyloid deposition in brain tissue and vessels (amyloid angiopathy), intracellular neurofibrillary tangle formation, synaptic and dendritic loss, and premature neuronal death. Primary pathogenic events underlying this neurodegenerative process include genetic factors involving more than 200 different genes distributed across the human genome, accompanied by progressive cerebrovascular dysfunction, and diverse environmental factors. Mutations in genes directly associated with the amyloid cascade (APP, PSEN1, PSEN2) are present in less than 5% of the Alzheimer's disease population; however, the presence of the epsilon4 allele of the apolipoprotein E gene (APOE) represents a major risk factor for more than 40% of patients with dementia. Genotype-phenotype correlation studies and functional genomics studies have revealed the association of specific mutations in primary loci and/or APOE-related polymorphic variants with the phenotypic expression of biological traits. It is estimated that genetics accounts for between 20% and 95% of the variability in drug disposition and pharmacodynamics. Recent studies indicate that the therapeutic response in Alzheimer's disease is genotype specific, depending on genes associated with Alzheimer's disease pathogenesis and/or genes responsible for drug metabolism (e.g. cytochrome P450 [CYP] genes). In monogenic studies, APOEepsilon4/epsilon4 genotype carriers are the worst responders to conventional treatments. Some cholinesterase inhibitors currently being use in the treatment of Alzheimer's disease are metabolized via CYP-related enzymes. These drugs can interact with many other drugs that are substrates, inhibitors or inducers of the CYP system, this interaction eliciting liver toxicity and other adverse drug reactions. CYP2D6 enzyme isoforms are involved in the metabolism of more than 20% of drugs used in CNS disorders. The distribution of the CYP2D6 genotypes in the European population of the Iberian peninsula differentiates four major categories of CYP2D6-related metabolizer types: (i) extensive metabolizers (EM) [51.61%]; (ii) intermediate metabolizers (IM) [32.26%]; (iii) poor metabolizers (PM) [9.03%]; and (iv) ultra-rapid metabolizers (UM) [7.10%]. PMs and UMs tend to show higher transaminase activity than EMs and IMs. EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacologic treatments in Alzheimer's disease. At this early stage of the development of pharmacogenomic/pharmacogenetic procedures in Alzheimer's disease therapeutics, it seems very plausible that the pharmacogenetic response in Alzheimer's disease depends on the interaction of genes involved in drug metabolism and genes associated with Alzheimer's disease pathogenesis.
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PMID:Pharmacogenetic basis for therapeutic optimization in Alzheimer's disease. 1807 56

Donepezil is the leading compound for the treatment of Alzheimer's disease (AD) in more than 50 countries. As compared with other conventional acetylcholinesterase inhibitors (AChEIs), donepezil is a highly selective and reversible piperidine derivative with AChEI activity that exhibits the best pharmacological profile in terms of cognitive improvement, responders rate (40%-58%), dropout cases (5%-13%), and side-effects (6%-13%) in AD. Although donepezil represents a non cost-effective treatment, most studies convey that this drug can provide a modest benefit on cognition, behavior, and activities of the daily living in both moderate and severe AD, contributing to slow down disease progression and, to a lesser exetnt, to delay institutionalization. Patients with vascular dementia might also benefit from donepezil in a similar fashion to AD patients. Some potential effects of donepezil on the AD brain, leading to reduced cortico-hippocampal atrophy, include the following: AChE inhibition, enhancement of cholinergic neurotransmission and putative modulation of other neurotransmitter systems, protection against glutamate-induced excitotoxicity, activation of neurotrophic mechanisms, promotion of non-amyloidodgenic pathways for APP processing, and indirect effects on cerebrovascular function improving brain perfusion. Recent studies demonstrate that the therapeutic response in AD is genotype-specific. Donepezil is metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. Approximately, 15%-20% of the AD population may exhibit an abnormal metabolism of AChEIs; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of AChEIs to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including donepezil, the best responders are the CYP2D6-related extensive (EM)(*1/*1, *1/*10) (57.47%) and intermediate metabolizers (IM)(*1/*3, *1/*5, *1/*6, *7/*10) (25.29%), and the worst responders are the poor (PM) (*4/*4)(9.20%) and ultra-rapid metabolizers (UM) (*1xN/*1) (8.04%). Pharmacogenetic and pharmacogenomic factors may account for 75%-85% of the therapeutic response in AD patients treated with donepezil and other AChEIs metabolized via enzymes of the CYP family. The implementation of pharmacogenetic protocols can optimize AD therapeutics.
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PMID:Donepezil in Alzheimer's disease: From conventional trials to pharmacogenetics. 1930 May 64


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