Cocaine abuse is a major medical and health concern. There is no FDA-approved medication for treating cocaine overdose/addiction. Butyrylcholinesterase (BChE) catalyzed hydrolysis is the primary pathway for (-)-cocaine detoxification mammals, but native BChE has a very low catalytic efficiency against it. Rationally designed mutations of human BChE in this laboratory have led to ~2000 fold improved catalytic efficiencies against (-)-cocaine.Clinical trials show that the high-activity mutants of human BChE, known as cocaine hydrolases (CocHs), are promising therapeutic agents for treating cocaine abuse.Hydrolysis viaBChE is not the only pathway for cocaine removal; ~5% (-)-cocaine is metabolized in the liver to produce norcocaine, which is still toxic to the body. Statistical data report that 73% of cocaine users also consume alcohol. Alcohol can react with (-)-cocaine to produce a significantly more cytotoxic compound, cocaethylene. It is unknown whether native human BChE or any of CocHs can efficiently hydrolyze norcocaine or cocaethylene.The kinetic parameters of native human BChE   and CocHs  against norcocaine and cocaethylene have been determined for the first time  in the present study. The most effective enzymes have at least a ~500-fold improved catalytic efficiency against all of the substrates (cocaine, norcocaine, and cocaethylene).Although the catalytic efficiencies at which norcocaine and cocaethylene substrates can be hydrolyzed by CocHs are relatively (3~20 times) lower than these compared to (-)-cocaine, the novel enzymes can effectively hydrolyze all three cytotoxic compounds produced from the simultaneous abuse of cocaine and alcohol in both addiction and overdose models.Supported by the NSF CHE-1111761, NIH R01DA032910, and NIH R01DA035552.

Novel mutants of human butyrylcholinesterase as therapeutic enzymes in metabolizing cocaine, norcocaine, and cocaethylene

246th National Meeting (2013)

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