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Transcriptomic changes and mitochondrial toxicity in response to acute and repeat dose treatment with brequinar in

Tamara Meijer1, Bas Ter Braak2, Liesanne Loonstra-Wolters2

  • 1Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands; Amsterdam Institute of Molecular and Life Sciences (AIMMS), Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands.

Toxicology in Vitro : an International Journal Published in Association with BIBRA
|February 3, 2025
PubMed

Insights

Brequinar, a DHODH inhibitor, shows differential toxicity in human cells. Renal cells are more sensitive than liver cells, especially with repeated exposure, impacting mitochondrial respiration.

Area of Science:

  • Pharmacology
  • Toxicology
  • Cell Biology

Background:

  • Brequinar is a potent dihydroorotate dehydrogenase (DHODH) inhibitor explored for anticancer, immunosuppressive, and antiviral applications.
  • The toxicity profile of brequinar remains incompletely understood, necessitating further investigation into cellular responses.

Purpose of the Study:

  • To investigate the differential cellular responses of primary human hepatocytes (PHH) and renal proximal tubular epithelial cells (RPTEC/TERT1) to brequinar exposure.
  • To evaluate the impact of single versus repeated brequinar exposure on cellular toxicity and stress pathways.

Main Methods:

  • Exposure of PHH and RPTEC/TERT1 cells to brequinar (single 24-h exposure up to 100 μM; repeated 5-day exposure at 0.3, 3, and 20 μM).
  • Transcriptomic analysis to assess cellular responses, including drug metabolism and stress pathways.
  • Assessment of mitochondrial respiration in RPTEC/TERT1 cells.

Main Results:

  • PHH exhibited lower sensitivity to brequinar compared to RPTEC/TERT1 cells, with evidence of induced drug-metabolizing enzymes (CYP1A, CYP3A) suggesting detoxification.
  • Both cell types showed upregulation of stress response pathways (unfolded protein response, Nrf2, p53, inflammation) upon brequinar exposure.
  • RPTEC/TERT1 cells demonstrated increased sensitivity to repeated brequinar exposure, even at low concentrations (0.3 μM), and impaired mitochondrial respiration after 24-h exposure.

Conclusions:

  • Brequinar induces differential toxicity in human liver and kidney cells, with renal cells being more susceptible.
  • Repeated exposure regimens are crucial for accurately assessing brequinar's in vitro toxicity, particularly in renal cells.
  • Brequinar's impact on mitochondrial respiration and stress pathways warrants further investigation for its pharmaceutical development.
Keywords:
BrequinarHepatocytesRenal proximal tubuleRepeated dose toxicityTranscriptomics

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