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)

Chlorpyrifos, an organophosphorus insecticide, has been used to control termites since regulatory measures against the use of chlordanes were taken in September, 1986. We developed an improved gas chromatographic (GC) method for the assay of 3,5,6-trichloro-2-pyridinol (TCP) in the urine to use in the biological monitoring of exposure to chlorpyrifos. Urinary TCP was separated and determined accurately (C.V., 4%) with high sensitivity (detection limit, 10 ng/ml) and recovery (recovery greater than 90%) using a wide bore capillary column (WBC column). The accuracy and precision of the present GC method are satisfactory. The time course of urinary excretion of TCP was followed in workers. The urinary TCP level was low in the off-season and high in the busy season. Variation in the urinary TCP level corresponded to the termite control season and the length of the working period. The urinary TCP level showed a change reciprocal to the variations in the plasma cholinesterase activity. From these results, it is surmised that the urinary TCP level represents the extent of exposure to chlorpyrifos. The decrease in the level of cholinesterase activity is suggested to be due to exposure to chlorpyrifos. Determination of the urinary TCP level by GC using a WBC column is useful in the biological monitoring of chlorpyrifos in termite control workers and potentially has practical application to health care.
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PMID:Determination of 3,5,6-trichloro-2-pyridinol levels in the urine of termite control workers using chlorpyrifos. 248 40

The apparent (app) Km and app Vmax for mouse hepatic microsomal oxidative detoxification of chlorpyrifos to 3,5,6-tricholoro-2-pyridinol were 16.10 +/- 6.8 microM and 263.2 +/- 22.5 nmol/liver/min, respectively. The app Km and app Vmax for the oxidative activation of chlorpyrifos to chlorpyrifos oxon were 20.0 +/- 6.5 microM and 126.1 +/- 14.6 nmol/liver/min, respectively, whereas the app Km and app Vmax for hepatic microsomal hydrolysis of chlorpyrifos oxon to 3,5,6-trichloro-2-pyridinol were 1.87 +/- 0.36 mM and 89,450.7 +/- 12,087.3 nmol/liver/min, respectively. Under first-order conditions the capacity of mouse hepatic microsomes to detoxify chlorpyrifos oxon exceeded their capacity to generate this potent cholinesterase inhibitor from chlorpyrifos by a factor of 7.6. Pretreatment of mice with phenobarbital (70 mg/kg daily for 4 days) resulted in a 2.5-fold increase in the app Vmax's for oxidative activation and detoxification of chlorpyrifos, and a 1.6-fold increase in the app Vmax for hydrolysis of chlorpyrifos oxon. The app Km's were not altered by phenobarbital pretreatment. Administration of beta-naphthoflavone (80 mg/kg/daily for 2 days) to mice resulted in a slight decrease in the app Vmax's for oxidative activation and detoxification of chlorpyrifos, without altering the app Km's of the same reactions, or the hydrolysis of chlorpyrifos oxon. Phenobarbital and beta-naphthoflavone increased and decreased, respectively, the predicted hepatic clearance of chlorpyrifos. The acute toxicity of chlorpyrifos was slightly antagonized by phenobarbital pretreatment, but was potentiated by beta-naphthoflavone administration. These pretreatments did not affect cholinesterase, nonspecific esterase, or plasma A-esterase activities. Collectively, these results suggest that chlorpyrifos oxon formed within the liver does not escape hydrolysis by the liver, and that extrahepatic sites of activation are important in directly mediating the acute toxicity of chlorpyrifos.
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PMID:The role of hepatic biotransformation in mediating the acute toxicity of the phosphorothionate insecticide chlorpyrifos. 620 Sep 55

The kinetics of chlorpyrifos, an organophosphorothioate insecticide, and its principal metabolite, 3,5,6-trichloro-2-pyridinol (3,5,6-TCP), were investigated in six healthy male volunteers given a single 0.5 mg/kg po and, 2 or more weeks later, a 0.5 or 5.0 mg/kg dermal dose of chlorpyrifos. No signs or symptoms of toxicity or changes in erythrocyte cholinesterase were observed. Plasma cholinesterase was depressed to 15% of predose levels by the 0.5 mg/kg po dose but was essentially unchanged following the 5.0 mg/kg dermal dose. Blood chlorpyrifos concentrations were extremely low (less than 30 ng/ml), and no unchanged chlorpyrifos was found in the urine following either route of administration. Mean blood 3,5,6-TCP concentrations peaked at 0.93 micrograms/ml 6 hr after ingestion of the oral dose and at 0.063 micrograms/ml 24 hr after the 5.0 mg/kg dermal dose. 3,5,6-TCP was cleared from the blood and eliminated in the urine with a half-life of 27 hr following both the po and dermal doses. An average of 70% of the po dose but less than 3% of the dermal dose was excreted in the urine as 3,5,6-TCP; thus only a small fraction of the dermally applied chlorpyrifos was absorbed. Chlorpyrifos and its principal metabolite were rapidly eliminated and therefore have a low potential to accumulate in man on repeated exposures. Based on these data, blood and/or urinary 3,5,6-TCP concentrations could be used to quantify the amount of chlorpyrifos absorbed under actual use conditions.
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PMID:Chlorpyrifos: pharmacokinetics in human volunteers. 620 Sep 56

Chlorpyrifos (O,O'-diethyl O-[3,5,6-trichloro-2-pyridyl] phosphorothionate) is a commonly used anticholinesterase insecticide, and therefore the potential for human exposure is high. The present time course and dose response studies were conducted to delineate the toxicokinetics of chlorpyrifos and its metabolites in the pregnant rat and fetus. Time-pregnant, Long-Evans rats were treated orally with chlorpyrifos during late gestation (Gestational Days 14-18). Following euthanasia the level of chlorpyrifos and its metabolites, chlorpyrifos-oxon and 3,5,6-trichloro-2-pyridinol (TCP), were measured in both fetal and maternal brain and liver (limits of quantitation: 59.2, 28.8, and 14.0 ng/g tissue, respectively). In addition, cholinesterase inhibition was also measured in the same tissues for comparison. TCP was the only component detected. The highest level of TCP and the lowest level of cholinesterase activity showed the same time of peak effect: 5 h after the last dose. The concentration of TCP in the maternal liver was approximately fivefold higher than the TCP concentration in fetal liver, but, paradoxically, the concentration of TCP in the fetal brain was two- to fourfold higher than the TCP concentration in the maternal brain. The half-life of the TCP was identical in all tissues examined (12-15 h). These toxicokinetic results suggest that the fetal nervous system may be exposed to a higher concentration of chlorpyrifos than the maternal nervous system when the dam is orally exposed to chlorpyrifos during late gestation.
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PMID:Gestational exposure to chlorpyrifos: comparative distribution of trichloropyridinol in the fetus and dam. 1038 28

A rapid and sensitive automated coupled-column liquid chromatography/electrospray tandem mass spectrometry (LC/LC/ES-MS/MS) method has been developed for the quantitation of chlorpyrifos and 3,5,6-trichloro-2-pyridinol (TCP) in both human serum and urine. Human serum was first protein precipitated with acetonitrile, while urine was directly injected into the coupled-column system. A 10 microL aliquot was then analyzed using as first separation column a Discovery C18 5 microm 50 x 2.1 mm; the fraction containing the analyte was transferred on-line to the second column consisting of a ABZ+ 5 microm 100 x 2.1 mm, which was connected to the electrospray source (Z-spray) of a Quattro LC triple-quadrupole instrument. Chlorpyrifos was detected in positive ion mode using four multi reaction monitoring (MRM) transitions while TCP was measured in negative ion mode using three pseudo-MRM transitions. The clean-up performed by the coupled-column approach avoids the use of an internal standard for the correct quantitation of both analytes, and the highly automated procedure renders a sample throughput of more than 100 samples per day. Both compounds can be determined using the same set-up, the only difference in the procedure being the composition of the first mobile phase. The method has proved to be fast, reliable and sensitive, yielding calibration curves for both analytes with correlation coefficients greater than 0.9995. The repeatability and reproducibility at 5 and 50 ng/mL was lower than 8%. The accuracy and precision were evaluated by means of recovery experiments from fortified serum (5-50 ng/mL) and urine (1-10 ng/mL) samples, obtaining satisfactory recoveries for both compounds (87-113% in serum, and 98-109% in urine), with coefficients of variation (CVs) less than 10%. The detection limits were similar for chlorpyrifos and metabolite: 1.5 ng/mL in serum, and 0.5 ng/mL in urine, where no sample handling took place. The validated procedures provide excellent tools for the specific assessment of occupational exposure to the organophosphorus pesticide chlorpyrifos, throughout the analysis of both human serum and urine, and it is more selective and sensitive than the current assay based on the measurement of the decrease in the cholinesterase activity.
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PMID:Direct determination of chlorpyrifos and its main metabolite 3,5, 6-trichloro-2-pyridinol in human serum and urine by coupled-column liquid chromatography/electrospray-tandem mass spectrometry. 1093 42

A PBPK/PD model was developed for the organophosphate insecticide chlorpyrifos (CPF) (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), and the major metabolites CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP) in rats and humans. This model integrates target tissue dosimetry and dynamic response (i.e., esterase inhibition) describing uptake, metabolism, and disposition of CPF, CPF-oxon, and TCP and the associated cholinesterase (ChE) inhibition kinetics in blood and tissues following acute and chronic oral and dermal exposure. To facilitate model development, single oral-dose pharmacokinetic studies were conducted in rats (0.5-100 mg/kg) and humans (0.5-2 mg/kg), and the kinetics of CPF, CPF-oxon, and TCP were determined, as well as the extent of blood (plasma/RBC) and brain (rats only) ChE inhibition. In blood, the concentration of analytes followed the order TCP >> CPF >> CPF-oxon; in humans CPF-oxon was not quantifiable. Simulations were compared against experimental data and previously published studies in rats and humans. The model was utilized to quantitatively compare dosimetry and dynamic response between rats and humans over a range of CPF doses. The time course of CPF and TCP in both species was linear over the dose range evaluated, and the model reasonably simulated the dose-dependent inhibition of plasma ChE, RBC acetylcholinesterase (AChE), and brain (rat only) AChE. Model simulations suggest that rats exhibit greater metabolism of CPF to CPF-oxon than humans do, and that the depletion of nontarget B-esterase is associated with a nonlinear, dose-dependent increase in CPF-oxon blood and brain concentration. This CPF PBPK/PD model quantitatively estimates target tissue dosimetry and AChE inhibition and is a strong framework for further organophosphate (OP) model development and for refining a biologically based risk assessment for exposure to CPF under a variety of scenarios.
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PMID:A Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans. 1186 71

Several studies have reported the occurrence of sensory neuropathy with exposure to chlorpyrifos and other organophosphorus insecticides, at levels not associated with overt toxicity. We evaluated 113 chemical workers, including 53 of 66 (80%) eligible chlorpyrifos workers and 60 of 74 (81%) randomly selected referent workers, to identify evidence of sensory neuropathy or subclinical neuropathy. Compared to referents, chlorpyrifos subjects had significantly longer duration of work in chlorpyrifos-exposed areas (9.72 vs. 0.01 years; P < 0.0001), greater cumulative chlorpyrifos exposure (64.16 vs. 0.69 mg/m(3). day; P < 0.0001), higher urine 3,5,6-trichloro-2-pyridinol (TCP) excretion (108.6 vs. 4.3 microg/g creatinine; P < 0.0001), and lower plasma butyrylcholinesterase (BuChE) activity (7281 vs. 8176 mU/ml; P = 0.003). Despite exposures among chlorpyrifos subjects to levels at which well-described physiological effects on B-esterases exist, the frequency of symptoms or signs of neuropathy did not differ significantly between groups, and the only 2 subjects fulfilling criteria for confirmed neuropathy were both in the referent group. Mean nerve conduction study results were comparable to established control values and did not differ significantly between groups. We found no evidence of sensory neuropathy or isolated peripheral abnormalities among subjects with long-term chlorpyrifos exposure at levels known to be associated with the manufacturing process.
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PMID:Absence of sensory neuropathy among workers with occupational exposure to chlorpyrifos. 1511 71

The blood-brain barrier (BBB) is a structural and functional interface between the circulatory system and the brain. Organophosphorous compounds such as chlorpyrifos (CPF) may cross the BBB and disrupt BBB integrity and function. To determine events that may contribute to CPF toxicity, we used an in vitro BBB model in which bovine microvascular endothelial cells (BMEC) and neonatal rat astrocytes were co-cultured. We hypothesized that CPF is metabolized by the BBB leading to an inhibition of esterase activity and a disruption of the BBB. The co-culturing of BMECs and astrocytes resulted in tight junction formation as determined by electron microscopy, electrical resistance and western blot analysis of two tight junction-associated proteins (ZO-1 and e-cadherin). We observed time dependent increases in ZO-1 and e-cadherin expression and electrical resistance during BBB formation, which were maximal after 9-13 days of co-culturing. The CPF concentration and production of its metabolites were monitored by HPLC following 24 h exposure to CPF on the luminal side of the BBB. We found that the BBB metabolized CPF, with the metabolite 2,3,6-trichloro-2-pyridinol being the major product. CPF and its metabolites were detected on the abluminal side of the BBB suggesting that CPF crossed this barrier. CPF was also detected intracellularly and on the membrane inserts. At tested concentrations (0.1-10 microM), CPF inhibited both carboxylesterase (CaE) and cholinesterase (ChE) activities in BMECs by 43-100%, while CPF-oxon totally inhibited CaE and ChE activity in concentrations as low as 0.1 microM. CPF also caused a concentration-dependent decrease in electrical resistance, with significant inhibition observed at 1 nM and complete loss at 1 microM. These data show that low concentrations of CPF and its metabolites are present within the BBB. CPF and its metabolites, especially CPF-oxon, contribute to the inhibition of CaE and ChE activity, as well as the alteration of BBB integrity and structure.
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PMID:Chlorpyrifos alters functional integrity and structure of an in vitro BBB model: co-cultures of bovine endothelial cells and neonatal rat astrocytes. 1552 75

Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and a potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE). The pharmacokinetic and pharmacodynamic impact of acute binary exposures of rats to CPF and DZN was evaluated in this study. Rats were orally administered CPF, DZN, or a CPF/DZN mixture (0, 15, 30, or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12, and 24 h postdosing, urine was also collected at 24 h. Chlorpyrifos, DZN, and their respective metabolites, 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBC, and plasma. Coexposure to CPF/DZN at the low dose of 15/15 mg/kg did not alter the pharmacokinetics of CPF, DZN, or their metabolites in blood. A high binary dose of 60/60 mg/kg increased the C(max) and AUC and decreased the clearance for both parent compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and coexposures, and the extent of inhibition was plasma > RBC > or = brain. The overall relative potency for ChE inhibition was CPF/DZN > CPF > DZN. A comparison of the ChE response at the low binary dose (15/15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These experiments represent important data concerning the potential pharmacokinetic and pharmacodynamic interactions for pesticide mixtures and will provide needed insight for assessing the potential cumulative risk associated with occupational or environmental exposures to these insecticides.
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PMID:Pharmacokinetic and pharmacodynamic interaction for a binary mixture of chlorpyrifos and diazinon in the rat. 1588 62

Previous studies have indicated that juvenile rats are more susceptible than adults to the acute toxicity from exposure to the organophosphorus insecticide chlorpyrifos (CPF) and age-dependent differences in metabolism and sensitivity to cholinesterase (ChE) inhibition may be responsible. Metabolism involves CYP450 activation and detoxification of CPF to CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP), as well as cholinesterase (acetyl- and butyrylcholinesterase), carboxylesterase (CaE), and A-esterase (PON-1) detoxification of CPF-oxon to TCP. The pharmacokinetics of CPF, TCP, and the extent of blood (plasma/RBC), and brain ChE inhibition in rats were determined on postnatal days (PND)-5, -12, and -17 following oral gavage administration of 1 and 10mg CPF/kg of body weight. As has been seen in adult animals, for all preweanling ages the blood TCP exceeded the CPF concentration, and within each age group there was no evidence of non-linear kinetics over the dose range evaluated. Consistent with previous results, younger animals demonstrated a greater sensitivity to ChE inhibition as evident by the age-dependent inhibition of plasma, RBC, and brain ChE. The brain may be particularly sensitive in younger animals (i.e. PND-5) due to substantially lower levels of ChE activity relative to later preweanling stages and adults. Of particular importance was the observation that even in rats as young as PND-5, the CYP450 metabolic capacity was adequate to metabolize CPF to both TCP and CPF-oxon based on the detection of TCP in blood and extensive ChE inhibition (biomarker of CPF-oxon) at all ages. In addition, the increase in the blood TCP concentration ( approximately 3-fold) in PND-17 rats relative to the response in the younger rats, are consistent with an increase in CYP450 metabolic capacity with age. This is the first reported study that evaluated both the pharmacokinetics of the parent pesticide, the major metabolite, and the extent of ChE inhibition as a function of preweanling age. The results suggest that in the preweanling rat, CPF was rapidly absorbed and metabolized, and the extent of metabolism and ChE inhibition was age-dependent.
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PMID:Age-dependent pharmacokinetic and pharmacodynamic response in preweanling rats following oral exposure to the organophosphorus insecticide chlorpyrifos. 1634 27


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