Structure-activity relationships for substrates and inhibitors of mammalian liver microsomal carboxylesterases.
OBJECTIVE
Carboxylesterases are important in the detoxification of drugs, pesticides and other xenobiotics. This study was to evaluate a series of substrates and inhibitors for characterizing these enzymes.


METHODS
A series of novel aliphatic esters and thioesters were used in spectral assays to monitor human, murine and porcine esterases. A series of transition state mimics were evaluated as selective esterase inhibitors.


RESULTS
Several alpha-alkyl thioacetothioates were found to be approximately 2 to 11-fold superior to commonly used substrates for monitoring carboxylesterase activity. Insertion of a heteroatom in the acid portion of these esters in the beta or gamma position relative to the carbonyl had a dramatic effect on enzyme activity with S or O substituents often improving the kCAT/K(M) ratio of the substrate and N decreasing it. Several alpha,alpha'-bis (2-oxo-3,3,3-trifluoropropylthio)alkanes proved to be potent selective transition state mimics of the esterase activity with IC50's from 10(-5) to 10(-9)M.


CONCLUSIONS
This library of substrates and inhibitors are useful research tools for characterizing the numerous isozymes of carboxylesterases present in mammalian tissues.
College of Pharmacy, Xavier University of Louisiana, New Orleans 70125, USA.
T L
TL
Huang
T
T
Shiotsuki
T
T
Uematsu
B
B
Borhan
Q X
QX
Li
B D
BD
Hammock
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine
D004791:Enzyme Inhibitors; D006845:Hydrocarbons, Fluorinated; D002265:Carboxylic Ester Hydrolases