TY - JOUR T1 - Human Liver Carboxylesterase hCE-1: Binding Specificity for Cocaine, Heroin, and their Metabolites and Analogs JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1089 LP - 1096 VL - 25 IS - 9 AU - Monica R. Brzezinski AU - Benjamin J. Spink AU - Robert A. Dean AU - Clifford E. Berkman AU - John R. Cashman AU - William F. Bosron Y1 - 1997/09/01 UR - http://dmd.aspetjournals.org/content/25/9/1089.abstract N2 - 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 increasedKi values substantially. Compounds containing a variety of hydrophobic substitutions at the benzoyl group of cocaine bound to the enzyme with high affinity. The highKi 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. The American Society for Pharmacology and Experimental Therapeutics ER -