![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Departments of
Biochemistry and Molecular Biology (M.R.B., B.J.S.,
R.A.D., W.F.B.),
Pathology and Laboratory Medicine (R.A.D.), and
Medicine (W.F.B.),
Indiana University School of Medicine, Indianapolis,
IN and Seattle Biomedical Research Institute, Seattle, WA (C.E.B.,
J.R.C.)
Purified human liver carboxylesterase (hCE-1) catalyzes the
hydrolysis of cocaine to form benzoylecgonine, the deacetylation of
heroin to form 6-acetylmorphine, and the ethanol-dependent transesterification of cocaine to form cocaethylene. In this study, the
binding affinities of cocaine, cocaine metabolites and analogs, heroin,
morphine, and 6-acetylmorphine for hCE-1 were evaluated by measuring
their kinetic inhibition constants with 4-methylumbelliferyl acetate in
a rapid spectrophotometric assay. The naturally occurring (R)-(
)-cocaine isomer displayed the highest affinity of
all cocaine and heroin analogs or metabolites. The pseudo- or
allopseudococaine isomers of cocaine exhibited lower affinity
indicating that binding to the enzyme is stereoselective. The methyl
ester, benzoyl, and N-methyl groups of cocaine play
important roles in binding because removal of these groups increased
Ki values substantially. Compounds containing a variety of hydrophobic substitutions at the benzoyl group
of cocaine bound to the enzyme with high affinity. The high Ki value obtained for cocaethylene
relative to cocaine is consistent with weaker binding to the esterase
and a longer elimination half-life reported for the metabolite. The
spectrophotometric competitive inhibition assay used here represents an
effective method to identify drug or environmental esters metabolized
by carboxylesterases like hCE-1.
This article has been cited by other articles:
|
|
 |
|
  M. A. Schiel, S.-l. Green, W. I. Davis, P. C. Sanghani, W. F. Bosron, and S. P. Sanghani Expression and Characterization of a Human Carboxylesterase 2 Splice Variant J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 94 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Imai, M. Taketani, M. Shii, M. Hosokawa, and K. Chiba Substrate Specificity of Carboxylesterase Isozymes and Their Contribution to Hydrolase Activity in Human Liver and Small Intestine Drug Metab. Dispos., October 1, 2006; 34(10): 1734 - 1741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Tacker, N. K. Herzog, and A. O. Okorodudu Cocaethylene Affects Human Microvascular Endothelial Cell p38 Mitogen-Activated Protein Kinase Activation and Nuclear Factor-{kappa}B DNA-Binding Activity Clin. Chem., October 1, 2006; 52(10): 1926 - 1933. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Alam, D. Gilham, D. E. Vance, and R. Lehner Mutation of F417 but not of L418 or L420 in the lipid binding domain decreases the activity of triacylglycerol hydrolase J. Lipid Res., February 1, 2006; 47(2): 375 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. Quinney, S. P. Sanghani, W. I. Davis, T. D. Hurley, Z. Sun, D. J. Murry, and W. F. Bosron Hydrolysis of Capecitabine to 5'-Deoxy-5-fluorocytidine by Human Carboxylesterases and Inhibition by Loperamide J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1011 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Sanghani, S. K. Quinney, T. B. Fredenburg, W. I. Davis, D. J. Murry, and W. F. Bosron HYDROLYSIS OF IRINOTECAN AND ITS OXIDATIVE METABOLITES, 7-ETHYL-10-[4-N-(5-AMINOPENTANOIC ACID)-1-PIPERIDINO] CARBONYLOXYCAMPTOTHECIN AND 7-ETHYL-10-[4-(1-PIPERIDINO)-1-AMINO]-CARBONYLOXYCAMPTOTHECIN, BY HUMAN CARBOXYLESTERASES CES1A1, CES2, AND A NEWLY EXPRESSED CARBOXYLESTERASE ISOENZYME, CES3 Drug Metab. Dispos., May 1, 2004; 32(5): 505 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Laizure, T. Mandrell, N. M. Gades, and R. B. Parker Cocaethylene Metabolism and Interaction with Cocaine and Ethanol: Role of Carboxylesterases Drug Metab. Dispos., January 1, 2003; 31(1): 16 - 20. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Satoh, P. Taylor, W. F. Bosron, S. P. Sanghani, M. Hosokawa, and B. N. L. Du Current Progress on Esterases: From Molecular Structure to Function Drug Metab. Dispos., May 1, 2002; 30(5): 488 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kudo, K. Umehara, M. Hosokawa, G. Miyamoto, K. Chiba, and T. Satoh Phenacetin Deacetylase Activity in Human Liver Microsomes: Distribution, Kinetics, and Chemical Inhibition and Stimulation J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 80 - 88. [Abstract] [Full Text]
|
|
|
|
|
|
J. Zhang, J. C. Burnell, N. Dumaual, and W. F. Bosron Binding and Hydrolysis of Meperidine by Human Liver Carboxylesterase hCE-1 J. Pharmacol. Exp. Ther., July 1, 1999; 290(1): 314 - 318. [Abstract] [Full Text]
|
|
 |
 |
 |
|
 |
 |
 |
