In vitro competitive inhibition of plasma cholinesterase by cocaine: normal and variant genotypes.
OBJECTIVE
To determine the inhibitory constant, Ki, of cocaine for a number of the different genetic variants of human plasma cholinesterase.


METHODS
In vitro analysis of plasma cholinesterase activity in the presence of cocaine as a competitive inhibitor.


METHODS
Six normal (UU) control sera and seven sera with the following plasma cholinesterase genotypes were assayed: AA, UA, AS, UF, US, AF and SS. Plasma cholinesterase activity was determined in the samples by colorimetric measurement of propionylthiocholine metabolism over a range of concentrations. Competitive activities were then determined in the presence of varying concentrations of cocaine. Double reciprocal plots (1/v vs 1/S) were used to calculate Km and Vmax for propionylthiocholine, and Ki for cocaine for each genotype.


RESULTS
The variant forms of the plasma cholinesterase had high cocaine Ki values--all were approximately ten times greater than the Ki for normal plasma cholinesterase.


CONCLUSIONS
Since the inhibitory constant is an indirect measure of an enzyme's affinity for a competing substrate, a high Ki for cocaine at recreational or therapeutic concentrations would translate into a longer in vivo half-life. Our results support the growing evidence that low plasma cholinesterase activity predisposes to cocaine toxicity.
Schwartz
H J
HJ
Hospital for Sick Children, University of Toronto, Ontario, Canada.
Johnson
D
D
D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000097:blood / Q000187:drug effects* / Q000235:genetics; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D009294:Narcotics / Q000378:metabolism / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D009294:Narcotics; D002802:Cholinesterases; D003042:Cocaine