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)

Bambuterol, a dimethylcarbamate, carbamoylates butyrylcholinesterase (BChE; EC 3.1.1.8). The carbamoylated enzyme is not very stable and the final product of the two-step hydrolysis is a bronchodilator drug, terbutaline (1-(3,5-dihydroxyphenyl)-2-t-butylamino-ethanol sulphate). Both bambuterol and terbutaline inhibit BChE, but their affinities differ in human serum BChE variants (U, A, F, K and S) due to their positive charge. Bambuterol inhibition rate constants for the homozygous usual (UU), Kalow (KK), fluoride-resistant (FF) or atypical (AA) variant ranged from 4.4 to 0.085min (-1)microM(-1). Terbutaline showed competitive reversible inhibition for all BChE variants. The dissociation constants for UU, FF and AA homozygotes were 0.18, 0.31 and 3.3 mM, respectively. The inhibition rate or dissociation constants for heterozygotes were distributed between the respective constants for the corresponding homozygotes. A 50-fold difference in inhibition between the UU and AA enzyme might affect terbutaline release in humans. The affinity of all studied BChE variants for terbutaline was low, which suggests that terbutaline originating from bambuterol hydrolysis should not affect the hydrolysis of bambuterol by BChE.
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PMID:Interaction of human butyrylcholinesterase variants with bambuterol and terbutaline. 1544 25

The developmental neurotoxicity of chlorpyrifos (CPF) involves mechanisms other than inhibition of cholinesterase. In the current study, we examined the ability of CPF to evoke lipid peroxidation in the developing brain of fetal and neonatal rats. CPF given to pregnant rats on gestational days 17-20 or to neonatal rats on postnatal days 1-4, failed to elicit increases in thiobarbituric acid-reactive species (TBARS) in brain regions even when the dose was raised above the threshold for systemic toxicity and hepatic damage. In contrast, CPF administration during the second postnatal week, the peak period of neuronal cell differentiation and synaptogenesis, did evoke significant increases in TBARS even at a dose devoid of systemic toxicity. Terbutaline, which is chemically unrelated to CPF and which stimulates neuronal cell metabolism through direct actions on beta-adrenoceptors, also elicited oxidative damage in the developing brain with greater sensitivity in the second postnatal week. These results indicate that diverse compounds can exert convergent effects on brain development through their shared potential to elicit oxidative stress, and that the net outcome is dependent upon specific developmental stages in which metabolic demand is especially high. Furthermore, given the common use of terbutaline in the therapy of preterm labor, and the nearly ubiquitous exposure of the human population to organophosphorus pesticides, the combined oxidative burden of exposure to both agents may contribute to the worsened neurodevelopmental outcomes noted in animal models of such dual exposures.
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PMID:Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination. 1596 56

During early neonatal development, the future reactivity of the heart to cardiac autonomic stimulation is programmed by the timing and intensity of the arrival of parasympathetic and sympathetic inputs. In neonatal rats, we examined the effects of exposure to terbutaline, a beta-adrenoceptor (betaAR) agonist used to arrest preterm labor, and chlorpyrifos (CPF), a widely used organophosphate pesticide that acts in part through inhibition of cholinesterase, using scenarios mimicking the likely developmental stages corresponding to peak human exposures: postnatal days (PN) 2-5 for terbutaline and PN11-14 for CPF. Terbutaline evoked a progressive deficit in cardiac betaAR binding but did not interfere with the ability of the receptors to stimulate adenylyl cyclase (AC). Terbutaline also reduced expression of m2 muscarinic acetylcholine receptors and suppressed their ability to inhibit AC. Surprisingly, CPF produced similar actions, a decrement in betaAR and m2 muscarinic receptor binding and a loss of the cholinergic AC response, and also augmented the ability of betaARs to stimulate AC. The effects of CPF are thus unlikely to reside in cholinergic hyperstimulation resulting from cholinesterase inhibition but instead involve other actions converging on receptors and cell signaling. Exposure to both agents, terbutaline followed by CPF, produced a summation of the two individual effects. Our findings at the level of cell signaling thus indicate that neonatal exposure to terbutaline or CPF, or sequentially to both agents, results in an imbalance of cardiac autonomic inputs favoring increased excitability, an outcome that may have an impact on cardiovascular responses.
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PMID:Imbalances emerge in cardiac autonomic cell signaling after neonatal exposure to terbutaline or chlorpyrifos, alone or in combination. 1625 8