The Endothelin-A Receptor Antagonist Zibotentan Induces Damage to the Nasal Olfactory Epithelium Possibly Mediated in Part through Type 2 Innate Lymphoid Cells

Toxicol Pathol. 2019 Feb;47(2):150-164. doi: 10.1177/0192623318816295. Epub 2018 Dec 30.


Zibotentan, an endothelin-A receptor antagonist, has been used in the treatment of various cardiovascular disorders and neoplasia. Castrated athymic nude mice receiving zibotentan for a preclinical xenograft efficacy study experienced weight loss, gastrointestinal bloat, and the presence of an audible respiratory click. Human side effects have been reported in the nasal cavity, so we hypothesized that the nasal cavity is a target for toxicity in mice receiving zibotentan. Lesions in the nasal cavity predominantly targeted olfactory epithelium in treated mice and were more pronounced in castrated animals. Minimal lesions were present in vehicle control animals, which suggested possible gavage-related reflux injury. The incidence, distribution, and morphology of lesions suggested direct exposure to the nasal mucosa and a possible systemic effect targeting the olfactory epithelium, driven by a type 2 immune response, with group 2 innate lymphoid cell involvement. Severe nasal lesions may have resulted in recurrent upper airway obstruction, leading to aerophagia and associated clinical morbidity. These data show the nasal cavity is a target of zibotentan when given by gavage in athymic nude mice, and such unanticipated and off-target effects could impact interpretation of research results and animal health in preclinical studies.

Keywords: ILC2; TH2-mediated; endothelin-A receptor antagonist; gavage injury; nasal; olfactory epithelium; zibotentan.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / toxicity*
  • Endothelin A Receptor Antagonists / administration & dosage
  • Endothelin A Receptor Antagonists / toxicity
  • Humans
  • Lymphocytes / drug effects*
  • Male
  • Mice
  • Mice, Nude
  • Nasal Cavity / drug effects
  • Olfactory Mucosa / drug effects*
  • Olfactory Mucosa / pathology
  • Prostatic Neoplasms / drug therapy
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / toxicity*
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Endothelin A Receptor Antagonists
  • Pyrrolidines
  • ZD4054