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.
Huang
T L
TL
College of Pharmacy, Xavier University of Louisiana, New Orleans 70125, USA.
Shiotsuki
T
T
Uematsu
T
T
Borhan
B
B
Li
Q X
QX
Hammock
B D
BD
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