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Mechanism of Off-Target Interactions and Toxicity of Tamoxifen and Its Metabolites

Maria Flynn1, Kali Amelia Heale1, Laleh Alisaraie1,2

  • 1School of Pharmacy, Memorial University of Newfoundland , A1B 3V6 St. John's, Newfoundland, Canada.

Chemical Research in Toxicology
|June 1, 2017
PubMed

Insights

Tamoxifen, used for breast cancer, causes nausea by interacting with histamine, muscarinic, and dopamine receptors. This study reveals off-target interactions, aiding in developing safer cancer treatments.

Area of Science:

  • Pharmacology
  • Computational Chemistry
  • Toxicology

Background:

  • Tamoxifen is a key breast cancer treatment.
  • Tamoxifen and its metabolites cause adverse effects, notably nausea.
  • The precise mechanisms behind tamoxifen's toxicity are not fully understood.

Purpose of the Study:

  • To identify off-target receptors of tamoxifen and its metabolites.
  • To elucidate the molecular interactions contributing to tamoxifen's toxicity.
  • To provide a basis for developing safer tamoxifen analogues.

Main Methods:

  • Computational analysis of tamoxifen and metabolite interactions with off-target receptors.
  • Comparison of these interactions with endogenous substrates.
  • Evaluation of computational findings with in vivo and in vitro data.

Main Results:

  • Identified interactions of tamoxifen and 22 metabolites with histamine H1/H3, muscarinic M1/M4/M5, and dopamine D2 receptors.
  • Computational analysis revealed specific interaction modes associated with toxicity.
  • Results were validated using existing experimental data.

Conclusions:

  • Tamoxifen and its metabolites interact with histamine, muscarinic, and dopamine receptors, explaining nausea.
  • This research provides foundational knowledge for understanding tamoxifen-induced nausea.
  • The findings support the development of improved tamoxifen analogues with reduced side effects.

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