title: Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases.
abstract: Concomitant i.v. use of cocaine and heroin ("speedballing") is prevalent among drug-abusing populations. Heroin is rapidly metabolized by sequential deacetylation of two separate ester bonds to yield 6-monoacetylmorphine and morphine. Hydrolysis of heroin to 6-monoacetylmorphine is catalyzed by pseudocholinesterase. The pathway for hydrolysis of 6-monoacetylmorphine to morphine in vivo has yet to be established. Pseudocholinesterase and two human liver carboxylesterases [human liver carboxylesterase form 1 (hCE-1) and human liver carboxylesterase form 2 (hCE-2)] catalyze the rapid hydrolysis of ester linkages in cocaine. This investigation examined the relative catalytic efficiencies of hCE-1, hCE-2 and pseudocholinesterase for heroin metabolism and compared them with cocaine hydrolysis. Enzymatic formation of 6-monoacetylmorphine and morphine was determined by reverse-phase high-performance liquid chromatography. All three enzymes rapidly catalyzed hydrolysis of heroin to 6-monoacetylmorphine (hCE-1 kcat = 439 min-1, hCE-2 kcat = 2186 min-1 and pseudocholinesterase kcat = 13 min-1). The catalytic efficiency, under first-order conditions, for hCE-2-catalyzed formation of 6-monoacetylmorphine (314 min-1 mM-1) was much greater than that for either hCE-1 or pseudocholinesterase (69 and 4 min-1 mM-1, respectively). Similarly, the catalytic efficiency for hydrolysis of 6-monoacetylmorphine to morphine by hCE-2 (22 min-1 mM-1) was substantially greater than that for hCE-1 (0.024 min-1 mM-1). Cocaine competitively inhibited hCE-1-, hCE-2- and pseudocholinesterase-catalyzed hydrolysis of heroin to 6-monoacetylmorphine (Ki = 530, 460 and 130 microM, respectively) and 6-monoacetylmorphine hydrolysis to morphine (Ki = 710, 220 and 830 microM, respectively). These data demonstrate that metabolism of cocaine and heroin in humans is mediated by common metabolic pathways. The role of hepatic hCE-2 is particularly important for the hydrolysis of heroin to 6-monoacetylmorphine and of 6-monoacetylmorphine to morphine.
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Kamendulis
authors.forename: M R
authors.initials: MR
authors.lastname: Brzezinski
authors.forename: E V
authors.initials: EV
authors.lastname: Pindel
authors.forename: W F
authors.initials: WF
authors.lastname: Bosron
authors.forename: R A
authors.initials: RA
authors.lastname: Dean
mesh_terms: D002091:Butyrylcholinesterase / Q000502:physiology; D002265:Carboxylic Ester Hydrolases / Q000502:physiology*; D003042:Cocaine / Q000378:metabolism*; D003932:Heroin / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology*; D009022:Morphine Derivatives / Q000378:metabolism; D009294:Narcotics / Q000378:metabolism*
chemical_list: D009022:Morphine Derivatives; D009294:Narcotics; D003932:Heroin; D002265:Carboxylic Ester Hydrolases; D002091:Butyrylcholinesterase; D003042:Cocaine; C026979:6-O-monoacetylmorphine