Suppression of oxidant-induced glutathione synthesis by erythromycin in human bronchial epithelial cells

Respiration. 2008;75(2):202-9. doi: 10.1159/000111569. Epub 2007 Nov 21.


Background: Macrolide antibiotics have anti-inflammatory effects which are utilized for the treatment of chronic inflammatory airway diseases. Recently, their anti-inflammatory effects have been proposed to be beneficial in patients with chronic obstructive pulmonary disease (COPD).

Objectives: Since the molecular mechanisms of anti-inflammatory effects are associated with inhibition of activator protein 1 (AP-1) and nuclear factor (NF)-kappaB, and both are reported to be involved in the expression of gamma-glutamylcysteine synthetase (gamma-GCS), we set out to determine if these drugs influence the oxidant-antioxidant balance in human bronchial epithelial (HBE) cells.

Methods: 16HBE cells were preincubated with erythromycin (EM) at different concentrations and times and then exposed to hydrogen peroxide (0.01 mM). Levels of interleukin (IL)-8 and glutathione (GSH), and activity of gamma-GCS and gamma-GCS heavy subunit (gamma-GCS-HS) protein production were assayed. AP-1 and NF-kappaB binding to the 5'-flanking region of IL-8 and gamma-GCS-HS genes was assessed by electrophoretic mobility-shift assay.

Results: The increase in IL-8 levels and activity of AP-1 induced by H(2)O(2) were abrogated by preincubation of the cells with EM (5 mug/ml) for 36 h. We also showed that preincubation with EM for 48 h inhibited H(2)O(2)-induced GSH levels, gamma-GCS activity and expression of gamma-GCS-HS, and decreased AP-1 binding to the gamma-GCS-HS 5'-flanking region.

Conclusions: The confirmation of antioxidants maintaining enzyme suppression by EM raised concerns on whether this drug could disrupt the oxidant/ antioxidant balance during long-term use. These data provide important insights into the treatment of inflammatory lung diseases with macrolide antibiotics.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bronchi / cytology
  • Cell Line
  • Cell Proliferation / drug effects
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Erythromycin / pharmacology*
  • Glutamate-Cysteine Ligase / genetics
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / biosynthesis*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Interleukin-8 / biosynthesis
  • NF-kappa B / metabolism
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / metabolism
  • Transcription Factor AP-1 / metabolism


  • Anti-Bacterial Agents
  • Interleukin-8
  • NF-kappa B
  • Transcription Factor AP-1
  • Erythromycin
  • Hydrogen Peroxide
  • Glutamate-Cysteine Ligase
  • Glutathione