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)

Kinetic parameters of parathion and paraoxon uptake were determined in isolated and perfused rabbit and guinea pig lungs. They were related to organophosphate-induced lung cholinesterase inhibition. A single pass procedure was used to perfuse the lungs with an artificial medium perfusate containing paraoxon or parathion. The paraoxon and parathion concentrations were determined in the effluents collected at chosen intervals over an 18-min period beginning at the start of perfusion. Three inflowing concentrations (1 nmol/ml, 10 nmol/ml, and 20 nmol/ml) were tested in guinea pig lungs and one (10 nmol/ml) in rabbit lungs. Cholinesterase activity was determined at time 0 and at the end of the experiment. The lungs abundantly extracted paraoxon and parathion over the perfusion period. The extraction ratio was consistently greater in guinea pig than in rabbit lungs. The uptake velocity varied biexponentially in time, suggesting the existence of two compartments. Initial uptake velocities (A, B) and slopes (alpha and beta) were calculated for both compartments. In guinea pigs, A, B and A + B increased proportionally to the supply rate of paraoxon and parathion while a and b remained constant. No significant difference was observed between parathion and paraoxon uptake kinetics. Parameter B was the only one to differ significantly between the two species (rabbits: 8.19 +/- 1.53 for parathion and 6.85 +/- 1.26 for paraoxon; guinea pigs: 12.75 +/- 0.88 for parathion and 15.02 +/- 3.84 for paraoxon). In the lungs of both species, there was a linear relation between y, the percentage of cholinesterase inhibition induced by either organophosphate, and X, the total amount of drug taken up by the lung tissue (in nmol/g/18 min). The following equations were obtained: y = 0.128 x + 0.979 (R2 = 0.89, p < 0.001 for paraoxon); y = 0.120 x - 6.57 (R2 = 0.82, p < 0.005 for parathion). No difference was observed between the two organophosphates. After treatment with the cytochrome P450 inhibitor piperonyl butoxide, the above relations ceased to apply, but this treatment did not influence the kinetics of paraoxon and parathion uptake. The IC50 value calculated for paraoxon, i.e., the paraoxon concentration required to produce 50% inhibition of lung cholinesterase activity, was similar for guinea pigs (2.22 10(-7) +/- 0.22 M) and rabbits (2.36 10(-7) +/- 0.24 M). In conclusion, the biexponential evolution of the velocity of paraoxon and parathion uptake by the lungs thus demonstrates the presence of two pools. The lower extraction ratios calculated for rabbit lungs reflect the lower initial uptake velocity of the second compartment. In the range of concentrations investigated in guinea pigs, no saturable mechanism could be demonstrated for paraoxon and parathion. Cytochrome P450-related lung metabolic activity, through which parathion is converted to paraoxon, appears as a major step in parathion-induced lung cholinesterase inhibition, although it does not appear to affect parathion toxicokinetics.
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PMID:Relationship between parathion and paraoxon toxicokinetics, lung metabolic activity, and cholinesterase inhibition in guinea pig and rabbit lungs. 865 21

Biochemical indices were investigated for their potential use as variables of sublethal toxicity in Daphnia (cholinesterase) and Chironomus (cholinesterase and biotransformation enzymes). Parathion, dichlorvos, and aldicarb caused dose-related inhibition of cholinesterase (ChE) in 24-h bioassays with both species. Ratios of Daphnia and Chironomus ChE IC50 values to corresponding immotility EC50 values derived from the same experiment covered the range 0.26 to 1.2. Estimates of the ChE inhibition caused by the immotility EC50 were in the range 53-99% below control activity. ChE IC50 values of dichlorvos, parathion, and aldicarb were 0.17, 0.61, and 95 microg/liter in Daphnia and 6.2, 2.9, and 27 microg/liter in Chironomus, respectively. Cytochrome P450-dependent monooxygenase activities (ethoxyresorufin-O-deethylase, methoxyresorufin-O-deethylase, and ethoxycoumarin-O-deethylase) were detectable in Chironomus but not in Daphnia. Chironomus monooxygenase activities were significantly inhibited to about 30% of control values after 4 days of exposure to 50 microg/liter 3, 4-dichloroaniline but remained unchanged by 0.5 microg/liter parathion. An approximately 1.3-fold induction of monooxygenase activities was caused by the model inducer naphthalene (0.1mg/liter). These results suggest that cytochrome P450-dependent monooxygenase activities may be useful variables in toxicity tests with aquatic insects.
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PMID:Altered cholinesterase and monooxygenase levels in Daphnia magna and Chironomus riparius exposed to environmental pollutants. 993 Dec 32

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