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)

Phosphorothionate insecticides such as parathion (O,O-diethyl O-p-nitrophenyl phosphorothioate) and chlorpyrifos (CPS; O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothioate; Dursban) are metabolically converted by oxidative desulfuration into paraoxon and chlorpyrifos-oxon (CPO). The insecticidal action of chlorpyrifos stems from inhibition of acetylcholinesterase (AChE) by CPO, resulting in severe cholinergic toxicity. Sensory peripheral neuropathy was observed in people exposed environmentally to chlorpyrifos sprayed in confined areas. We have examined the kinetics of inhibition of AChE and butyrylcholinesterase (BChE) by paraoxon and CPO. The bimolecular rate constants (ki) for inhibition by paraoxon of recombinant human (rH) AChE, recombinant mouse (rM) AChE, and fetal bovine serum (FBS) AChE were 7.0, 4.0, and 3.2 x 10(5) M(-1) min(-1). The ki values for the inhibition by CPO of rH AChE, fetal bovine serum AChE, human RBC AChE, Torpedo AChE, and recombinant mouse (rM) AChE were 9.3, 2.2, 3.8, 8.0, and 5.1 x 10(6) M(-1) min(-1), respectively. Inhibition of human serum BChE, rH BChE, and rM BChE by CPO yielded ki values of 1.65, 1.67, and 0.78 x 10(9) M(-1) min(-1), respectively. The ki values obtained for BChE from various species were 160- to 750-fold larger than those of AChE from parallel sources. Inhibition of the single-site mutant A328Y of rH BChE by CPO displayed a 21-fold lower rate than that of wild-type rH BChE (ki, 7.9 x 10(7) vs 1.67 x 10(9) M(-1) min(-1)). The double mutant of acyl pocket residues of rH AChE, F295L/F297V, was inhibited by CPO with a 150-fold larger ki than wild type (1.5 x 10(9) vs 1.0 x 10(7) M(-1) min(-1)). The increased rate obtained with the double mutant displaying characteristics of the BChE active center provides a rationale for higher efficacy of CPO scavenging by BChE, compared with AChE.
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PMID:Inhibition of acetylcholinesterase and butyrylcholinesterase by chlorpyrifos-oxon. 974 65

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