Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The disposition of the organophosphate anticholinesterase, diisopropylfluorophosphate (DFP), was studied in guinea pigs after inhalation exposure. The tissue disposition of [3H]DFP and its metabolites was determined in the major tissues of the guinea pig from 5 min to 24 hr after treatment. [3H]DFP rapidly penetrated all tissues, where it was quickly hydrolyzed to the inactive metabolite, free [3H]diisopropylphosphoric acid ([3H]DIP), or was covalently bound to tissue in the form of bound [3H]DIP. Tissue concentrations of [3H]DFP and free [3H]DIP followed a biphasic curve, with an initial phase representing a very rapid decrease in tissue concentrations, followed by a slower phase of tissue clearance. Concentrations of free [3H]DIP generally exceeded those of [3H]DFP; however, by 4 hr the greater portion of the radioactivity in all the tissues was in the form of bound [3H]DIP. Bound [3H]DIP levels did not follow a biphasic clearance curve and declined at a slower rate than [3H]DFP and free [3H]DIP tissue levels. By 5 min the greatest accumulation of bound [3H]DIP occurred in the liver (nearly 20% of the total body burden), with a noticeably small amount in the brain (0.1%). Tissue concentrations of nonextractable radioactivity, thought to be [3H]monoisopropylphosphoric acid ([3H]MIP), were appreciable and persistent throughout the time course. Total cholinesterase activity in the brain and red blood cells was inhibited by about 90%, with plasma pseudo- and true cholinesterase activity inhibited by 99 and 97%, respectively. The time course of recovery of enzyme activity in these tissues failed to correlate with the respective tissue levels of either bound [3H]DIP or [3H]MIP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The disposition of [3H]diisopropylfluorophosphate in guinea pigs after inhalation. 290 19

The biodisposition of [3H]diisopropylfluorophosphate (DFP) and its metabolites was studied in mice after inhalation administration. In addition, the time course of DFP-induced cholinesterase inhibition in selected tissues, hypothermia, and motor coordination were studied to determine a possible correlation with [3H]DFP, or its metabolites. The time course of tissue concentrations of [3H]DFP showed that [3H]DFP rapidly penetrated all tissues and was quickly hydrolyzed to [3H]diisopropylphosphoric acid (free [3H]DIP) or was covalently bound to tissue (bound [3H]DIP). By 1 hr, the greater portion of the radioactivity was in the form of bound [3H]DIP. Cholinesterase inhibition in brain, lung, diaphragm, and plasma was temporally related to concentrations of bound [3H]DIP between 5 min and 1 day, except at early time points for the lung. Motor incoordination (rotarod test) produced by DFP exposure had a rapid onset, with complete recovery by 10 hr. DFP-induced hypothermia (rectal temperature) had a very similar time-course profile to that of motor incoordination. The time course of hypothermia and motor incoordination was correlated with neither free [3H]DFP nor bound [3H]DIP concentrations in the brain, nor with cholinesterase inhibition in brain. These findings suggest that non-cholinesterase bound [3H]DIP may contribute to the depression of these centrally mediated effects.
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PMID:Relationship between the pharmacological effects and the biodisposition of [3H]diisopropylfluorophosphate in mice after inhalation. 403 91

Wild-type (wt) butyrylcholinesterase (BuChE) and the E197D and D70G mutants were inhibited by diisopropylfluorophosphate (DFP) or soman under standard conditions of pH, temperature and pressure. The effect of hydrostatic and osmotic pressures on the aging process of DFP-phosphorylated enzymes (diisopropylphosphoryl-BuChE (DIP-BuChE)) was investigated. Hydrostatic pressure strongly increased the rate of aging of wt enzyme. The activation volumes (deltaV*) for the dealkylation reaction was -150 ml/mol for DIP-wtBuChE. On the other hand, pressure had little effect on the aging of the DIP-E197D mutant and no effect on the DIP-D70G mutant, indicating that the transition state of the aging reaction (dealkylation of an isoproxy chain) was associated with an extended conformation/hydration change in wtBuChE but not in mutants. The rate of aging decreased with osmotic pressure, supporting the idea that water is important for stabilizing the transition state. Molecular dynamics simulations were performed on the wtDIP adduct to relate the kinetic data to hydration changes in the enzyme active site gorge. The pH dependence of the melting temperature (Tm) of native and soman-wtBuChE, as determined by differential scanning calorimetry (DSC), indicated that the stabilization energy of aged BuChE is mainly due to the salt bridge between protonated H438 and PO-, with pK(H438) = 8.3. Electrophoresis under high pressure up to 2.5 kbar showed that aged wtBuChE did not undergo pressure-induced molten globule transition unlike the native enzyme. This transition was not seen for the mutant enzymes, indicating that mutants are resistant to the penetration of water into their structure. Our results support the conclusion that D70 and E197 are major residues for the water/H-bond network dynamics in the active site gorge of BuChE, both residues acting like valves. In mutant enzymes, mutated residues function like check valves: forced penetration of water in the gorge is difficult, release of water is facilitated.
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PMID:Structural and hydration changes in the active site gorge of phosporhylated butyrylcholinesterase accompanying the aging process. 1042 35