The mechanism for the inhibition of acetylcholinesterases by irinotecan (CPT-11)

Irinotecan (CPT-11) is an anticancer drug that occasionally produces acute cholinergic side effects. Preliminary findings suggest that these are media ted through the inhibition of acetylcholinesterase (AChE). In this study, t he inhibition of various AChEs by CPT-11 was studied. The lactone form of C PT-11 resulted in apparent noncompetitive inhibition of electric eel and bo th human recombinant and erythrocyte AChE with K-i values of 0.065, 0.19, a nd 0.29 mu M, respectively. The carboxylate form of CPT-11 was approximatel y 10 times less potent. Apparent noncompetitive inhibition of AChE may aris e through several mechanisms, and those relevant to CPT-11 were identified from key experimental findings. First, the inhibition by CPT-11 was found t o be instantly reversible in dilution studies. Second, incubation of the en zyme with CPT-11 before the introduction of neostigmine protected the enzym e from inactivation. Third, regeneration of the active enzyme after preincu bation with neostigmine was totally suppressed by the addition of 2 mu M CP T-11, indicating that CPT-11 is a potent inhibitor of decarbamoylation and, by inference, deacylation. Additional experiments with tacrine revealed fu nctional differences between these two inhibitors. Also, preliminary molecu lar modeling of the interaction between AChE and CPT-11 indicated that the latter does not bind at the same site as tacrine. Displacement studies with the peripheral site-specific ligand, propidium, confirmed that CPT-11 bind s at this site. The rapid reversibility of the inhibition of AChE by CPT-11 and the lower activity of the carboxylate form are likely reasons for the transient nature of the cholinergic toxicity observed clinically.