Human liver carboxylesterase hCE-1: binding specificity for cocaine, heroin, and their metabolites and analogs.

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Brzezinski MR, Spink BJ, Dean RA, Berkman CE, Cashman JR, Bosron WF

Human liver carboxylesterase hCE-1: binding specificity for cocaine, heroin, and their metabolites and analogs.

Drug Metab Dispos. 1997 Sep;25(9):1089-96.

PubMed ID

9311626 [ View in PubMed

]

Abstract

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 K(i) values substantially. Compounds containing a variety of hydrophobic substitutions at the benzoyl group of cocaine bound to the enzyme with high affinity. The high K(i) 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cocaine	Liver carboxylesterase 1	Protein	Humans	Unknown	Binder	Details
Diamorphine	Liver carboxylesterase 1	Protein	Humans	Unknown	Not Available	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Cocaine	Liver carboxylesterase 1	Protein	Humans	Unknown	Substrate	Details