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Research ArticleArticle

The Mechanism for the Inhibition of Acetylcholinesterases by Irinotecan (CPT-11)

Helen M. Dodds and Laurent P. Rivory
Molecular Pharmacology December 1999, 56 (6) 1346-1353; DOI: https://doi.org/10.1124/mol.56.6.1346
Helen M. Dodds
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Laurent P. Rivory
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Abstract

Irinotecan (CPT-11) is an anticancer drug that occasionally produces acute cholinergic side effects. Preliminary findings suggest that these are mediated through the inhibition of acetylcholinesterase (AChE). In this study, the inhibition of various AChEs by CPT-11 was studied. The lactone form of CPT-11 resulted in apparent noncompetitive inhibition of electric eel and both human recombinant and erythrocyte AChE withK i values of 0.065, 0.19, and 0.29 μM, respectively. The carboxylate form of CPT-11 was approximately 10 times less potent. Apparent noncompetitive inhibition of AChE may arise through several mechanisms, and those relevant to CPT-11 were identified from key experimental findings. First, the inhibition by CPT-11 was found to be instantly reversible in dilution studies. Second, incubation of the enzyme with CPT-11 before the introduction of neostigmine protected the enzyme from inactivation. Third, regeneration of the active enzyme after preincubation with neostigmine was totally suppressed by the addition of 2 μM CPT-11, indicating that CPT-11 is a potent inhibitor of decarbamoylation and, by inference, deacylation. Additional experiments with tacrine revealed functional differences between these two inhibitors. Also, preliminary molecular 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 binds 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.

Footnotes

    • Received February 1, 1999.
    • Accepted September 20, 1999.
  • Send reprint requests to: Dr. Laurent Rivory, Medical Oncology, Sydney Cancer Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia 2050. E-mail:lrivory{at}canc.rpa.cs.nsw.gov.au

  • ↵1 This project was supported in part by a generous donation from Pharmacia and Upjohn, Australia. H.M.D. is the grateful recipient of a National Health and Medical Research Council Dora Lush Scholarship.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (6)
Molecular Pharmacology
Vol. 56, Issue 6
1 Dec 1999
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Research ArticleArticle

The Mechanism for the Inhibition of Acetylcholinesterases by Irinotecan (CPT-11)

Helen M. Dodds and Laurent P. Rivory
Molecular Pharmacology December 1, 1999, 56 (6) 1346-1353; DOI: https://doi.org/10.1124/mol.56.6.1346

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Research ArticleArticle

The Mechanism for the Inhibition of Acetylcholinesterases by Irinotecan (CPT-11)

Helen M. Dodds and Laurent P. Rivory
Molecular Pharmacology December 1, 1999, 56 (6) 1346-1353; DOI: https://doi.org/10.1124/mol.56.6.1346
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