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 chlorofluorocarbon substitute 1,2-dichloro-1,1-difluoroethane (HCFC-132b) undergoes oxidative metabolism in rats to give a range of metabolites, including chlorodifluoroacetaldehyde [Harris and Anders (1991) Chem. Res. Toxicol. 4, 180]. The present experiments were undertaken after studies to characterize an unidentified metabolite of HCFC-132b revealed that chlorodifluoroacetaldehyde was toxic in vivo: rats given chlorodifluoroacetaldehyde died showing signs of cholinergic stimulation. Because some fluoroketones are known inhibitors of hydrolases, including acetylcholinesterase, the inhibitory effects of chlorodifluoroacetaldehyde on acetylcholinesterase (electric eel and human erythrocyte), on pseudocholinesterase (horse serum), on carboxylesterase (pig liver), and on alpha-chymotrypsin (bovine pancreas) were studied. In aqueous solution, the ratio chlorodifluoroacetaldehyde:chlorodifluroacetaldehyde hydrate, as determined by 1H nuclear magnetic resonance spectroscopy, was 1:157. Chlorodifluoroacetaldehyde was a slow-binding inhibitor of both acetylcholinesterases, of pseudocholinesterase, and of carboxylesterase; the Ki values, corrected for the aldehyde:hydrate ratio, were 150 nM, 1.7 nM, 3.7 nM, and 23 pM, respectively, as determined by final velocity of the progress curves; the kon values were 9.1 x 10(4), 1.1 x 10(5), 3.2 x 10(4), and 9.2 x 10(5) M-1 min-1, respectively. Chlorodifluoroacetaldehyde did not inhibit alpha-chymotrypsin. Acetaldehyde and trichloroacetaldehyde were classical competitive inhibitors of acetylcholinesterase. These results show that hydrochlorofluorocarbon metabolites may exert significant biological effects.
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PMID:Slow-binding inhibition of carboxylesterase and other serine hydrolases by chlorodifluoroacetaldehyde. 829 40

The kinetics of time- and concentration-dependent covalent organophosphorus inhibition of carboxylesterase isoenzymes (EC 3.1.1.1) and cholinesterase isoenzymes (EC 3.1.1.7 and EC 3.1.1.8) were investigated using a wide range of organophosphate inhibitor concentrations (10(-10)-10(-3) mol/l) and different inhibition times. Computerized analysis of inhibition curves by weighted non-linear least-squares curve fitting was compared to graphic analysis by iterative elimination of exponential functions. Possible experimental errors due to inhibitor saturation kinetics and enzymatic organophosphate hydrolysis were thoroughly investigated. In mammalian heart muscle, three different cholinesterase isoenzymes were identified. High sensitivity and specificity of the classic differential inhibition test for carboxylesterase activity of hen brain neuropathy target esterase (NTE) could be confirmed independently with both methods of inhibition curve analysis.
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PMID:Computerized analysis of covalent inhibition kinetics for identification of heart muscle cholinesterase and brain carboxylesterase isoenzymes. Design of differential inhibition assays. 834 80

The influence of genotypes of the major histocompatibility complex (MHC) on susceptibility to acute and delayed effects of an organophosphorus ester was measured in adult White Leghorn chickens from lines differing in response to sheep red blood cell (SRBC) antigen. Chickens from lines selected for high (HA) or low (LA) antibody response to SRBC and homozygous for B13B13 or B21B21 genotypes at the MHC were administered a single subcutaneous injection of diisopropyl phosphorofluoridate (DFP) at dosages of 0, 0.25, 0.50, or 1.0 mg/kg body weight using corn oil as the carrier. Criteria for toxicological responses included clinical, biochemical, and pathological measures. Clinical signs of acute cholinergic poisoning and delayed neuropathy were dose related. Brain and blood cholinesterase and carboxylesterase activities were more sensitive to inhibition by DFP than were liver cholinesterase and carboxylesterase activities. Cholinergic signs 3 h after administration of DFP were more pronounced in line HA than in line LA chickens. Pathological evidence of delayed neuropathy 2 wk after DFP administration was also more evident in HA than LA chickens. Although less pronounced than that for lines, differences in neurotoxic manifestations following DFP administration were greater for chickens of B21B21 than B13B13 genotypes. Activity of A-esterases, which hydrolyze organophosphorus esters without being inhibited by them, was lower in plasma of line HA than line LA chickens. Differences among the genotypes in activity of other esterases were not found in chickens not receiving DFP. These results indicated that responses of chickens to the neurotoxicant DFP were influenced by the background genome of the chickens.
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PMID:Differences between genetic stocks of chickens in response to acute and delayed effects of an organophosphorus compound. 834 37

The ability of a selected strain of the malaria vector Anopheles gambiae to encapsulate the early oocysts of the malaria parasite Plasmodium cynomolgi B has previously been shown to be genetically linked to specific esterase phenotypes. This association between Plasmodium susceptibility and esterase phenotype is found in the An. gambiae G3 strain from which the Plasmodium-refractory and -susceptible mosquito strains were derived. Genetic crosses had suggested that the esterase phenotypes reflect the assortment of two alleles at one esterase genetic locus, with the two esterase homozygotes showing Plasmodium-susceptible and -refractory phenotypes and the esterase heterozygote being intermediate in susceptibility. By using a variety of specific esterase inhibitors in conjunction with esterase staining of gel-electrophoresed mosquito homogenates, we found that the bands previously thought to reflect one genetic locus are actually the product of two different esterase loci, Est1, a cholinesterase, and Est2, a carboxylesterase. In addition, examination of chromosomal inversions and the esterase phenotype in the An. gambiae G3 strain revealed that different forms of a polymorphic inversion on the left arm of chromosome two (the 2La inversion) are inseparably associated with different alleles at these two esterase loci. We conclude that the genetic association among the esterase-linked Plasmodium-susceptibility locus and the two esterase loci is maintained by the suppression of recombination in 2La inversion heterozygotes in the An. gambiae G3 strain and its selected derivatives.
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PMID:Association of two esterase genes, a chromosomal inversion, and susceptibility to Plasmodium cynomolgi in the African malaria vector Anopheles gambiae. 837 56

A cDNA encoding human liver carboxylesterase and its gene were isolated. Nucleotide sequence analyses of the cDNA revealed that the predicted enzyme protein consists of 567 amino acids, including 18 amino acids of a putative signal peptide. Comparison of the deduced amino acid sequences of this enzyme with those of seven other carboxylesterases in various mammalian species, together with experimental data from several other laboratories, showed that these enzymes can be classified into three groups depending on the sequences at their carboxyl terminals and the presence or absence of one exon. A human carboxylesterase gene was found to span approximately 30 kb and to have 14 small exons. Alignments of this gene with those of human cholinesterase and rat cholesterol esterase indicated insertional sites at some introns and homologous amino acid sequences around them, although these genes have different numbers of exons. Thus the results supported the conclusion that these esterases evolved from a common ancestral gene.
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PMID:Molecular cloning and characterization of a human carboxylesterase gene. 840 73

We characterized the interaction of the prodrug dipivefrin hydrochloride (DPE) with esterase activity in the rabbit cornea. The esterases which were identified included: (1) cholinesterase, (2) acetylcholinesterase, (3) a mixture containing carboxylesterase, acetylesterase and arylesterase, and (4) a non-specific esterase. DPE suppressed all of their activities as well as that of the mixture containing carboxylesterase, acetylesterase and arylesterase, and a nonspecific esterase. However, its effect on cholinesterase was larger than on any of the other activities, suggesting that DPE is a better substrate for cholinesterase than for any of the other esterases. These measurements along with those of substrate-dependent inhibition of 14C-DPE hydrolysis indicated that the DPE-esterase interaction was competitive based on changes in the apparent Km values which were extracted from Lineweaver-Burk plots of esterase activity. The substrate for cholinesterase competed with DPE most strongly among substrates. These results seem to suggest that DPE is hydrolyzed by various corneal esterases, mainly cholinesterase.
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PMID:Characterization of esterases involved in the hydrolysis of dipivefrin hydrochloride. 844 67

Neuroblastoma cell lines were used to examine the differential interspecies response (i.e., species selectivity) to organophosphates (OPs). Baseline activities of the major target esterases, i.e., cholinesterase, carboxylesterase, and neurotoxic esterase, were assayed in mouse and several human neural candidate cell lines. These activities were found to be variable within individual cell lines and among the various tested cell lines. Cytotoxicity data using the neutral red fluorometric assay were collected on both human (SH-SY5Y) and mouse (NB41A3) neuroblastoma clones exposed to a variety of OP insecticides. IC50 data indicated that the tested mouse cell line was consistently more sensitive than the human cell line to equimolar doses of various OP compounds (e.g., mipafox, parathion, paraoxon, DFP, leptophos oxon, fenthion, and fenitrothion). This difference in cytotoxic sensitivity was most pronounced in response to compounds requiring metabolic bioactivation (i.e., protoxicants). Cytotoxicity data also demonstrated that the NB41A3 mouse neuroblastoma cell line was more metabolically competent than the SH-SY5Y human cell line in converting the protoxicant parathion to its neurotoxic metabolite, paraoxon. B-lymphoblastoids, genetically engineered with human P450 cDNAs, demonstrated higher cytotoxic sensitivity to parathion than unengineered cells, indicating that cytochrome P450-associated monooxidase activity could also influence cytotoxic sensitivity to parathion in culture. These data suggest that interspecies-selectivity in response to OP-related cytotoxicity is influenced by intercellular differences in metabolism and baseline esterase activities.
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PMID:Differential cytotoxic sensitivity in mouse and human cell lines exposed to organophosphate insecticides. 851 93

The involvement of carboxylesterase, acetylcholinesterase, butyrylcholinesterase and cholesterol esterase in pharmacology and toxicology are well recognized. However, there are few papers concerning the comparative studies of these serine hydrolases in terms of molecular level. Recently, we have studied various aspects of carboxylesterases using cDNAs of carboxylesterase isozymes purified from 9 animal species and human liver microsomes, and found that there is high homology of the N-terminal amino acid sequences of the isozymes tested. On the other hand, we compared the amino acid sequences at the active site of the individual esterases and found that the sequences of all esterases tested are strictly conserved. These results strongly suggest that the esterases involved are classified into the serine hydrolase super family.
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PMID:Molecular aspects of carboxylesterase isoforms in comparison with other esterases. 859 91

A new type of organophosphorus compounds-beta, beta-diphenylethylphosphonic acid fluoroanhydride esters-with various alkyl radicals (CH3, C2H5, C3H7, i-C3H7, C4H9, i-C4H9, C5H11, C6H13) and a phenyl radical (C6H5) have been tested as inhibitors of horse serum butyryl cholinesterase (EC 3.1.1.8) and two forms of reindeer liver carboxyl esterase (EC 3.1.1.1). All the tested compounds are strong irreversible inhibitors of butyryl cholinesterase and strong combined type inhibitors of carboxylesterase. The values of inhibitory constants have been found to depend on the structure of the alkyl radical in the inhibitor molecule.
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PMID:[Features of inhibiting butyrylcholinesterase and carboxylesterase hydrolysis with fluoranhydride esters of beta,beta-diphenylethylphosphonic acid]. 872 6

The protective effect of phosphotriesterase (PTE) on cholinesterase (ChE) and carboxylesterase (CaE) activities was studied in mice. The PTE pretreatment (120 U/g body wt, 9.6 micrograms/g body wt) given i.v. 10 min before diisopropyl fluorophosphate, sarin, or soman variably prevented ChE inhibition in erythrocytes and plasma and CaE in plasma. PTE also protected the brain and lung ChEs against inactivation by organophosphates (OPs). The recovery of the enzymes was dependent on the OP used. Postexposure therapy with PTE, given 1.5 hr after paraoxon, also prevented ChE inhibition in erythrocytes, brain, and lung 24 hr after exposure. The distribution studies with [125I]PTE showed that PTE does not markedly gain access into the central nervous system.
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PMID:Protection of organophosphate-inactivated esterases with phosphotriesterase. 878 87


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