Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors

Carboxylesterases (CEs) are ubiquitously expressed proteins that are responsible for the detoxification of xenobiotics. They tend to be expressed in tissues likely to be exposed to such agents (e.g., lung and gut epithelia, liver) and can hydrolyze numerous agents, including many clinically used dru...

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Bibliographic Details
Published in:Chemico-biological interactions 2013-03, Vol.203 (1), p.226-230
Main Authors: Tsurkan, Lyudmila G., Hatfield, M. Jason, Edwards, Carol C., Hyatt, Janice L., Potter, Philip M.
Format: Article
Language:English
Subjects:
Alzheimer disease
Carbamate
carbamates
Carboxylesterase
Carboxylesterase - antagonists & inhibitors
Carboxylesterase - chemistry
Carboxylesterase - genetics
Carboxylic Ester Hydrolases - antagonists & inhibitors
Carboxylic Ester Hydrolases - chemistry
Carboxylic Ester Hydrolases - genetics
Cholinesterase
cholinesterase inhibitors
Cholinesterase Inhibitors - pharmacology
Drug Interactions
drugs
Humans
hydrolysis
Inhibitor
Intestines - enzymology
Kinetics
liver
Liver - enzymology
Models, Molecular
Phenylcarbamates - pharmacology
Physostigmine - analogs & derivatives
Physostigmine - pharmacology
protein synthesis
Recombinant Proteins - antagonists & inhibitors
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Rivastigmine
xenobiotics
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Summary:Carboxylesterases (CEs) are ubiquitously expressed proteins that are responsible for the detoxification of xenobiotics. They tend to be expressed in tissues likely to be exposed to such agents (e.g., lung and gut epithelia, liver) and can hydrolyze numerous agents, including many clinically used drugs. Due to the considerable structural similarity between cholinesterases (ChE) and CEs, we have assessed the ability of a series of ChE inhibitors to modulate the activity of the human liver (hCE1) and the human intestinal CE (hiCE) isoforms. We observed inhibition of hCE1 and hiCE by carbamate-containing small molecules, including those used for the treatment of Alzheimer’s disease. For example, rivastigmine resulted in greater than 95% inhibition of hiCE that was irreversible under the conditions used. Hence, the administration of esterified drugs, in combination with these carbamates, may inadvertently result in decreased hydrolysis of the former, thereby limiting their efficacy. Therefore drug:drug interactions should be carefully evaluated in individuals receiving ChE inhibitors.
ISSN:0009-2797
1872-7786
DOI:10.1016/j.cbi.2012.10.018