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 time course of physostigmine (Phy) and metabolites in plasma, brain, and muscle, the inhibition of butyrylcholinesterase (BuChE) in plasma, and cholinesterase (ChE) activity in brain and muscle were studied in rat after iv bolus administration of 3H-Phy (100 micrograms/kg). The semilogarithmic plot of plasma Phy concentration versus time indicates a biphasic decline. These data were analyzed by nonlinear computer fitting program (PC-NONLIN) using a two-compartment open model with bolus input and first order elimination. The pharmacokinetic constants A, B, alpha, beta, AUC, K10 half-life, alpha-half-life, beta-half-life, K10, K12, and K21 were obtained. The alpha-half-life and the beta-half-life were 1.31 and 15.01 min, respectively. The apparent volume of distribution was found to be 270 ml. The clearance was 12.43 ml min-1. The half-life of Phy in brain was 11 min. The brain to plasma ratio (1.69) peaked at 15 min. Phy is metabolized to eseroline and three other metabolites, M1, M2, and M3. The distribution studies showed that the radioactivity per g of tissue was highest in kidney and liver, whereas the percentage of the administered dose in terms of radioactivity was maximum in muscle followed by liver. The maximum inhibition of BuChE (52%) correlates with the highest Phy concentration (84.6 ng/ml) in plasma at 2 min and 70% of the enzymic activity recovered by 45 min. The maximum inhibition of ChE (63%) in the brain correlates with the highest Phy concentration (128 ng/g) at 3 min, and 85% of the enzymic activity was recovered within an hour.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacokinetics and pharmacodynamics of physostigmine in the rat after intravenous administration. 289 78

Methods to unequivocally assess and quantify exposure to organophosphate anti-cholinesterase agents are highly valuable, either from a biomonitoring or a forensic perspective. Since for both OP pesticides and various nerve agents the skin is a predominant route of entry, we hypothesized that proteins in the skin might represent an ideal source of unequivocal and persistent biomarkers for exposure to these compounds. In this exploratory study we show that keratin proteins in human skin are relevant binding sites for organophosphates. The thick cornified epithelium of human plantar skin (callus) was exposed to a selection of relevant organophosphorus compounds and keratin proteins were subsequently extracted. After carboxymethylation of cysteine residues, enzymatic digestion of the keratins with pronase and trypsin was performed and the resulting amino acid and peptides were analyzed to assess whether covalent adducts had formed. LC-tandem MS analysis of the pronase digests demonstrated that tyrosine and to a lesser extent serine residues were selectively modified by organophosphate pesticides (both phosphorothioates and the corresponding oxon forms) under physiological conditions. In addition, modification of tyrosine with the nerve agent VX was unequivocally assessed. In order to elucidate specific binding sites, LC-tandem MS analysis of trypsin digests showed two separate tryptic keratin fragments, i.e. LASY*LDK and SLY*GLGGSK, with Y* the modified tyrosine residues, originating from keratin 1/6 and keratin 10, respectively. These preliminary findings, revealing novel binding targets for anti-cholinesterase organophosphates, will form a firm basis for the development of novel (non-invasive) methods for assessment of exposure to organophosphates. Whether this binding will also have biological implications remains an issue for further investigations.
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PMID:Interactions of organophosphates with keratins in the cornified epithelium of human skin. 2252 15