title: Inhibition of human carboxylesterases hCE1 and hiCE by cholinesterase inhibitors.
abstract: 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.
authors.affiliation: Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Tsurkan
authors.forename: M Jason
authors.initials: MJ
authors.lastname: Hatfield
authors.forename: Carol C
authors.initials: CC
authors.lastname: Edwards
authors.forename: Janice L
authors.initials: JL
authors.lastname: Hyatt
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
mesh_terms: D043182:Carboxylesterase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D007422:Intestines / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D048448:Phenylcarbamates / Q000494:pharmacology; D010830:Physostigmine / Q000031:analogs & derivatives / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000068836:Rivastigmine
chemical_list: D002800:Cholinesterase Inhibitors; D048448:Phenylcarbamates; D011994:Recombinant Proteins; C576198:phenethylcymserine; C412047:tolserine; D010830:Physostigmine; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase; D000068836:Rivastigmine