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Oxygen-Independent Assays to Measure Mitochondrial Function in Mammals
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Direct mitochondrial dysfunction precedes reactive oxygen species production in amiodarone-induced toxicity in human

Adrian C Nicolescu1, Yanbin Ji, Jeannette L Comeau

  • 1Department of Pharmacology and Toxicology, Queen's University, Kingston, ON, Canada K7L 3N6. adrian.nicolescu@ualberta.ca

Toxicology and Applied Pharmacology
|January 15, 2008
PubMed

Insights

Amiodarone-induced pulmonary toxicity may stem from early mitochondrial dysfunction, not just reactive oxygen species. Targeting mitochondria with antioxidants could offer a therapeutic approach for this drug side effect.

Area of Science:

  • Pharmacology
  • Toxicology
  • Cell Biology

Background:

  • Amiodarone (AM) is a critical antiarrhythmic drug with known severe pulmonary toxicity, including fibrosis.
  • The exact mechanisms of amiodarone-induced pulmonary toxicity (AIPT) remain unclear, with hypotheses including inflammation, mitochondrial issues, and free radicals.
  • Reactive oxygen species (ROS) formation is a proposed contributor to AIPT.

Purpose of the Study:

  • To investigate the role of ROS and mitochondrial dysfunction in amiodarone toxicity using an in vitro model.
  • To identify early cellular events in amiodarone-induced pulmonary toxicity (AIPT).

Main Methods:

  • Utilized human peripheral lung epithelial HPL1A cells as an in vitro model for AIPT.
  • Exposed HPL1A cells to amiodarone (AM) and its metabolite N-desethylamiodarone (DEA) for varying incubation times.
  • Measured reactive oxygen species (ROS) formation, mitochondrial dysfunction, and cytochrome c translocation.
  • Assessed the protective effects of antioxidants like ubiquinone, alpha-tocopherol, Trolox C, and DMPO.

Main Results:

  • Amiodarone (AM) and its metabolite N-desethylamiodarone (DEA) exhibited toxicity to HPL1A lung epithelial cells.
  • Longer AM incubations (>6h) significantly increased ROS production.
  • Shorter AM incubations (2h) led to mitochondrial dysfunction and cytochrome c release.
  • Mitochondrial-targeting antioxidants (ubiquinone, alpha-tocopherol) were more effective in preventing AM cytotoxicity than others.

Conclusions:

  • Mitochondrial dysfunction appears to be an early event in amiodarone-induced pulmonary toxicity (AIPT), preceding significant ROS overproduction.
  • These findings suggest that targeting mitochondria with specific antioxidants may be a promising therapeutic strategy for AIPT.

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