Pharmacogenomics of carboxylesterases: Molecular mechanism and clinical implication
Abstract
Carboxylesterases catalyze the hydrolysis of foreign compounds containing such functional groups as carboxylic acid ester, amide and thioester. These enzymes play important roles in drug metabolism, lipid mobilization, and insecticides hydrolysis. The expression of carboxylesterases is developmentally regulated in rodents and humans. The regulation of these enzymes may alter the hydrolysis based drug-drug interactions. This dissertation demonstrates pharmacogenomics of carboxylesterases in three aspects, induction inhibition and mutation of carboxylesterases, and how these changes cause the different pharmacological and toxicological significance. ^ This project of regulation of carboxylesterases is three-fold. First, the inducibility of carboxylesterases by phenobarbital is inversely related with age and so are the pharmacological and toxicological significance. Second, Orlistat is a potent inhibitor of carboxylesterases 2 and co-presence of this anti-obesity agent significantly alters pharmacological and toxicological potentials of the anticancer agent irinotecan and pentyl PABC doxazolidine (PPD), two prodrugs activated by carboxylesterases 2. Third, 5-fluorouracil, one of the most used anticancer drugs, activates the p53 and induces CES2 by transactivation and increased mRNA stability. And the cell killing activity of irinotecan and PPD is increased by 5-fluorouracil in p53 positive cells. ^
Subject Area
Health Sciences, Pharmacology|Chemistry, Pharmaceutical|Health Sciences, Pharmacy
Recommended Citation
Da Xiao,
"Pharmacogenomics of carboxylesterases: Molecular mechanism and clinical implication"
(2012).
Dissertations and Master's Theses (Campus Access).
Paper AAI3503200.
http://digitalcommons.uri.edu/dissertations/AAI3503200