Shimizu_2014_Drug.Metab.Dispos_42_1103

Reference

Title : Screening of specific inhibitors for human carboxylesterases or arylacetamide deacetylase - Shimizu_2014_Drug.Metab.Dispos_42_1103
Author(s) : Shimizu M , Fukami T , Nakajima M , Yokoi T
Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 42 :1103 , 2014
Abstract :

Esterases catalyze the hydrolysis of therapeutic drugs containing esters or amides in their structures. Human carboxylesterase (CES) and arylacetamide deacetylase (AADAC) are the major enzymes that catalyze the hydrolysis of drugs in the liver. Characterization of the enzyme(s) responsible for drug metabolism is required in drug development and to realize optimal drug therapy. Because multiple enzymes may show a metabolic potency for a given compound, inhibition studies using chemical inhibitors are useful tools to determine the contribution of each enzyme in human tissue preparations. The purpose of this study was to find specific inhibitors for human CES1, CES2, and AADAC. We screened 542 chemicals for the inhibition potency toward hydrolase activities of p-nitrophenyl acetate by recombinant CES1, CES2, and AADAC. We found that digitonin and telmisartan specifically inhibited CES1 and CES2 enzyme activity, respectively. Vinblastine potently inhibited both AADAC and CES2, but no specific inhibitor of AADAC was found. The inhibitory potency and specificity of these compounds were also evaluated by monitoring the effects on hydrolase activity of probe compounds of each enzyme (CES1: lidocaine, CES2: CPT-11, AADAC: phenacetin) in human liver microsomes. Telmisartan and vinblastine strongly inhibited the hydrolysis of CPT-11 and/or phenacetin, but digitonin did not strongly inhibit the hydrolysis of lidocaine, indicating that the inhibitory potency of digitonin was different between recombinant CES1 and liver microsomes. Although we could not find a specific inhibitor of AADAC, the combined use of telmisartan and vinblastine could predict the responsibility of human AADAC to drug hydrolysis.

PubMedSearch : Shimizu_2014_Drug.Metab.Dispos_42_1103
PubMedID: 24751575
Gene_locus related to this paper: human-AADAC , human-CES1 , human-CES2

Related information

Inhibitor Vinblastine
Substrate Vinblastine    Phenacetin    Vicagrel
Gene_locus Vinblastine    Phenacetin    Vicagrel    human-AADAC    human-CES1    human-CES2

Citations formats

Shimizu M, Fukami T, Nakajima M, Yokoi T (2014)
Screening of specific inhibitors for human carboxylesterases or arylacetamide deacetylase
Drug Metabolism & Disposition: The Biological Fate of Chemicals 42 :1103

Shimizu M, Fukami T, Nakajima M, Yokoi T (2014)
Drug Metabolism & Disposition: The Biological Fate of Chemicals 42 :1103