RT Journal Article
SR Electronic
T1 Characterization of the Expression and Activity of Carboxylesterases 1 and 2 from the Beagle Dog, Cynomolgus Monkey, and Human
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2305
OP 2313
DO 10.1124/dmd.111.041335
VO 39
IS 12
A1 Eric T. Williams
A1 James A. Bacon
A1 David M. Bender
A1 Jennifer J. Lowinger
A1 Wen-Kai Guo
A1 Mariam E. Ehsani
A1 Xiliang Wang
A1 He Wang
A1 Yue-Wei Qian
A1 Kenneth J. Ruterbories
A1 Steven A. Wrighton
A1 Everett J. Perkins
YR 2011
UL http://dmd.aspetjournals.org/content/39/12/2305.abstract
AB The carboxylesterases (CESs) are a family of serine hydrolases that hydrolyze compounds containing an ester, amide, or thioester. In humans, two dominant forms, CES1 and CES2, are highly expressed in organs of first-pass metabolism and play an important role in xenobiotic metabolism. The current study was conducted to better understand species-related differences in substrate selectivity and tissue expression of these enzymes. To elucidate potential similarities and differences among these enzymes, a series of 4-nitrophenyl esters and a series of gemcitabine prodrugs were evaluated using enzyme kinetics as substrates of expressed and purified CESs from beagle dog, cynomolgus monkey, and human genes. For the substrates examined, human and monkey CES2 more efficiently catalyzed hydrolysis compared with CES1, whereas CES1 was the more efficient enzyme in dog. Quantitative real-time polymerase chain reaction and Western blot analyses indicate that the pattern of CES tissue expression in monkey is similar to that of human, but the CES expression in dog is unique, with no detectable expression of CES in the intestine. Loperamide, a selective human CES2 inhibitor, was also found to be a CES2-selective inhibitor in both dog and monkey. This is the first study to examine substrate specificity among dog, human, and monkey CESs.