Human Erythrocyte but Not Brain Acetylcholinesterase Hydrolyses Heroin to Morphine

Abstract

SUMMARY1. In human blood, heroin is rapidly hydrolysed by sequential deacylation of two ester bonds to yield first 6-monoacetylmorphine (6-MAM), then morphine.2. Serum butyrylcholinesterase (BuChE) hydrolyses heroin to 6-MAM with a catalytic efficiency of 4.5/min per mol/L, but does not proceed to produce morphine.3. In vitro, human erythrocyte acetylcholinesterase (AChE) hydrolyses heroin to 6-MAM, with a catalytic efficiency of 0.5/min per mol/L under first-order kinetics. Moreover, erythrocyte AChE, but not BuChE is capable of further hydrolysing 6-MAM to morphine, albeit at a considerably slower rate.4. Both hydrolysis steps by erythrocyte AChE were totally blocked by the selective AChE inhibitor BW284c51 but were not blocked by the BuChE-specific inhibitor, iso-OMPA (tetraisopropylpyrophosphoramide).5. The brain synaptic form of AChE, which differs from the erythrocyte enzyme in its C-terminus, was incapable of hydrolysing heroin.6. Heroin suppressed substrate hydrolysis by antibodyimmobilized erythrocyte but not by brain AChE.7. These findings reveal a new metabolic role for erythrocyte AChE, the biological function of which is as yet unexplained, and demonstrate distinct biochemical properties for the two AChE variants, which were previously considered catalytically indistinguishable.

Increased Locomotor Activity Induced by Heroin in Mice: Pharmacokinetic Demonstration of Heroin Acting as a Prodrug for the Mediator 6-Monoacetylmorphine in Vivo

“…However, the concentrations were extremely low, and the drug disappeared shortly after administration, supporting previous findings that heroin is rapidly deacetylated in the body (Inturrisi et al, 1984;Gyr et al, 2000). The biotransformation may take place by different esterases in blood, brain, and other tissues (Kamendulis et al, 1996;Salmon et al, 1999;Rook et al, 2006), but heroin may also undergo nonenzymatic degradation to 6MAM (Selley et al, 2001). Both the maximal and the total concentrations of 6MAM in brain tissue were higher after administration of heroin than after administration of 6MAM itself.…”

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

“…doses of heroin (Comer et al, 1999;Girardin et al, 2003). The metabolism of heroin to 6-MAM and morphine in plasma is attributable to esterases in blood as well as non-enzymatic degradation (Salmon et al, 1999;Selley et al, 2001;Rook et al, 2006). Rats have higher plasma esterase activity than humans (Minagawa et al, 1995;Bahar et al, 2012), which complicates extrapolation of opioid data across species but may explain why higher heroin and lower 6-MAM levels were found in humans.…”

A Monoclonal Antibody Specific for 6-Monoacetylmorphine Reduces Acute Heroin Effects in Mice

“…In rodents and humans, heroin is rapidly metabolized by sequential deacetylation to 6-monoacetylmorphine (6-MAM) and morphine (Rook et al, 2006a;Andersen et al, 2009;Gottas et al, 2013), mainly by esterase enzymes (Owen and Nakatsu, 1983;Salmon et al, 1999). In humans, morphine is further transformed by glucuronidation to pharmacologically active morphine-6-glucuronide (M6G) and inactive morphine-3-glucuronide (M3G) (Fig.…”