KINETICS FOR THE INHIBITION OF ACETYLCHOLINESTERASE FROM HUMAN ERYTHROCYTE BY CISPLATIN

The antitumor drug cisplatin causes neurological side-effects in patie nts treated with this drug. Since acetylcholine plays a key role in hu man neurotransmission we characterized the inhibitory effect of cispla tin on the enzyme, acetylcholinesterase. Enzyme activity was monitored spectrophotometrically using Ellman's method. The time for 50% inhibi tion (t(1/2)) was inversely proportional to the concentration of the c isplatin. The reaction was therefore assessed to have a bimolecular ra te constant of 36.5 (mM min)(-1). The K-m and V-max were both decrease d by 45 and 48%, respectively by 7.0 mM cisplatin during the reversibl e phase while the K-m was increased 138% and V-max was decreased up to 65% in the irreversible phase. The nature of the inhibition was uncom petitive and complex irreversible at the reversible and irreversible s tages respectively, The inhibition constants for reversible and irreve rsible steps were estimated as 1.12 mM and 97.70 (mM min)(-1) respecti vely, The dissociation constant for the irreversible complex was 2.62 mM. These studies show that cisplatin is an uncompetitive inhibitor of acetylcholinesterase. Such effects may contribute, at least in part, to the neurotoxic effects associated with the use of cisplatin.