title: Prolonged toxic effects after cocaine challenge in butyrylcholinesterase/plasma carboxylesterase double knockout mice: a model for butyrylcholinesterase-deficient humans.
abstract: Death and toxicity after cocaine use do not correlate with cocaine blood levels. One explanation for this observation is that cocaine abusers may posses one or more of the 58 possible known mutations in the butyrylcholinesterase gene (BCHE). Butyrylcholinesterase (BChE) serves as the primary cocaine hydrolase producing a nontoxic product ecgonine methyl ester. A reduction in endogenous levels of BChE may result in increased metabolism by hepatic carboxylesterase to produce norcocaine, a toxic product. Humans have carboxylesterase in tissues but not in plasma, whereas wild-type mice have significant amounts of carboxylesterase in tissues and plasma. Knockout mice with no plasma carboxylesterase were created to eliminate the contribution of plasma carboxylesterase in cocaine hydrolysis, thereby simulating human enzyme levels. This study tested the hypothesis that reductions in BChE such as those in humans with BChE mutations contribute to increased toxicity after cocaine use. Carboxylesterase and BChE double knockout mice, models for humans with BChE deficiency, were challenged with a nonlethal dose of 100 mg/kg (-)-cocaine. Carboxylesterase/BChE double knockout mice demonstrated toxic signs significantly longer than did wild-type and carboxylesterase knockout mice. The carboxylesterase/BChE-deficient mice took approximately 2.5 times as long to recover from cocaine toxicities, including the following: hypothermia, hyperactivity, stereotypical behavior, ocular effects, and dorsiflexion of the tail. The carboxylesterase/BChE double knockout mouse model demonstrates the importance of endogenous BChE for protection against cocaine toxicity and provides an in vivo system for studying drug sensitivity of humans who carry a BChE mutation.
authors.affiliation: University of Nebraska Medical Center, Eppley Institute, 985950 Nebraska Medical Center, Omaha, NE 68198-5950, USA.
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Duysen
authors.forename: Oksana
authors.initials: O
authors.lastname: Lockridge
mesh_terms: D000818:Animals; D001049:Apnea; D001522:Behavior, Animal / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D043182:Carboxylesterase / Q000097:blood* / Q000235:genetics / Q000502:physiology; D003042:Cocaine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D013997:Time Factors
chemical_list: D043182:Carboxylesterase; D002091:Butyrylcholinesterase; D003042:Cocaine