COCAINE DETOXIFICATION BY BUTYRYLCHOLINESTERASE

HUMAN PLASMA BUTYRYLCHOLINESTERASE (EC 3.1.1.8), ALSO REFERRED TO AS PSEUDOCHOLINESTERASE, IS AN ENZYME WITH NO KNOWN BIOLOGICAL FUNCTION. HOWEVER, IT IS CLINICALLY SIGNIFICANT IN THAT IT IS INHIBITED BY A NUMBER OF ANTI-ACETYLCHOLINESTERASE TOXINS AND DRUGS AND IS RESPONSIBLE FOR HYDROLYZING AND INACTIVATING OTHERS. BUTYRYLCHOLINESTERASE IS ALSO THE ONLY ENZYME YET IDENTIFIEDTHAT IS CAPABLE OF HYDROLYZING COCAINE TO BIOLOGICALLY INACTIVE METABOLITES. APPROXIMATELY 5% OF THE POPULATION CARRIES ANY OF SEVERAL GENETIC DEFECTS THAT AFFECT BUTYRYLCHOLINESTERASE ACTIVITY. THIS POPULATION IS SENSITIVE TO SUCCINYLCHOLINE, A MUSCLE RELAXANT COMMONLY USED IN SURGICAL ANAESTHESIA. RECENTLY, IT HAS BEEN PROPOSED THAT INDIVIDUALS DEFICIENT IN BUTYRYLCHOLINESTERASESHOULD ALSO BE HYPERSENSITIVE TO COCAINE, A POSSIBILITY THATCOULD EXPLAIN SOME OF THE SMALL FRACTION OF THE COCAINE-ABUSING POPULATION WHO EXPERIENCE ACUTE, LIFE-THREATENING REACTIONS TO COCAINE. WE PROPOSE THAT IN THESE CASES, AND IN OTHERS INVOLVING LARGE OVERDOSES, TREATMENT WITH BUTYRYLCHOLINESTERASE WOULD ACCELERATE THE INACTIVATION OF COCAINE THEREBY PROVIDING A USEFUL ADJUVANT THERAPY. WE INTEND TO DEVELOP A METHOD FOR PURIFYING LARGE QUANTITIES OF HUMAN PLASMA BUTYRYLCHOLINESTERASE SUITABLE FOR THE PRODUCTION OF PHARMACEUTICAL QUALITY MATERIAL. WE WILL TEST ITS ABILITY TO DETOXIFY COCAINE IN MICE. HUMAN PLASMA BUTYRYLCHOLINESTERASE (EC 3.1.1.8), ALSO REFERRED TO AS PSEUDOCHOLINESTERASE, IS AN ENZYME WITH NO KNOWN BIOLOGICAL FUNCTION. HOWEVER, IT IS CLINICALLY SIGNIFICANT IN THAT IT IS INHIBITED BY A NUMBER OF ANTI-ACETYLCHOLINESTERASE TOXINS AND DRUGS AND IS RESPONSIBLE FOR HYDROLYZING AND INACTIVATING OTHERS. BUTYRYLCHOLINESTERASE IS ALSO THE ONLY ENZYME YET IDENTIFIEDTHAT IS CAPABLE OF HYDROLYZING COCAINE TO BIOLOGICALLY INACTIVE METABOLITES. APPROXIMATELY 5% OF THE POPULATION CARRIES ANY OF SEVERAL GENETIC DEFECTS THAT AFFECT BUTYRYLCHOLINESTERASE ACTIVITY. THIS POPULATION IS SENSITIVE TO SUCCINYLCHOLINE, A MUSCLE RELAXANT COMMONLY USED IN SURGICAL ANAESTHESIA. RECENTLY, IT HAS BEEN PROPOSED THAT INDIVIDUALS DEFICIENT IN BUTYRYLCHOLINESTERASESHOULD ALSO BE HYPERSENSITIVE TO COCAINE, A POSSIBILITY THATCOULD EXPLAIN SOME OF THE SMALL FRACTION OF THE COCAINE-ABUSING POPULATION WHO EXPERIENCE ACUTE, LIFE-THREATENING REACTIONS TO COCAINE. WE PROPOSE THAT IN THESE CASES, AND IN OTHERS INVOLVING LARGE OVERDOSES, TREATMENT WITH BUTYRYLCHOLINESTERASE WOULD ACCELERATE THE INACTIVATION OF COCAINE THEREBY PROVIDING A USEFUL ADJUVANT THERAPY. WE INTEND TO DEVELOP A METHOD FOR PURIFYING LARGE QUANTITIES OF HUMAN PLASMA BUTYRYLCHOLINESTERASE SUITABLE FOR THE PRODUCTION OF PHARMACEUTICAL QUALITY MATERIAL. WE WILL TEST ITS ABILITY TO DETOXIFY COCAINE IN MICE.