title: Effects of azithromycin on glutathione S-transferases in cystic fibrosis airway cells.
abstract: Anti-inflammatory properties of azithromycin (AZM) have been proposed as possible mechanisms of clinical beneficial effects in patients with cystic fibrosis (CF). Altered glutathione (GSH) transport in cystic fibrosis transmembrane regulator protein (CFTR)-deficient cells leads to the occurrence of oxidative stress that finally induces glutathione S-transferase (GST) activity. The present investigation was aimed to verify the effects of AZM on GST activity and expression in CF airway cells in vitro and in vivo. AZM exposure significantly decreased GSTT1 and GSTM1 mRNA and protein expression in IB3-1, restoring the levels to those observed in non-CF C38 cells, which also express lower levels of gamma-glutamyltransferase (GGT) activity than IB3-1. In another CF cell line, 2CFSMEo-, AZM produced 45% reduction in GSTT1 and GSTM1 mRNA levels. AZM reduced GST activity by approximately 25% and 40% in IB3-1 and 2CFSMEo- cells, respectively. GSTP1 was similarly expressed in all CF and non-CF cells and was unaffected by AZM. The anti-inflammatory cytokine IL-10 down-modulated GST activity at similar levels, supporting a link between GST inhibition and anti-inflammatory properties of AZM. In bronchoalveolar lavage fluid of CF mice homozygous for the F508 del mutation, GSTM1 protein levels were undetectable after AZM treatment. The association between increased GST expression and activity, together with its reversal by AZM treatment in vitro and in vivo, suggest novel antioxidant properties for this drug. The issue whether decreased GST activity may directly concur to anti-inflammatory properties of AZM or is rather a marker of the oxidative status of CF cells will require additional studies.
authors.affiliation: Cystic Fibrosis Center-Azienda Ospedaliera di Verona, Piazzale Stefani 1, 37126 Verona, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bergamini
authors.forename: Cristina
authors.initials: C
authors.lastname: Cigana
authors.forename: Claudio
authors.initials: C
authors.lastname: Sorio
authors.forename: Marco
authors.initials: M
authors.lastname: Della Peruta
authors.forename: Alfonso
authors.initials: A
authors.lastname: Pompella
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corti
authors.forename: François A
authors.initials: FA
authors.lastname: Huaux
authors.forename: Teresinha
authors.initials: T
authors.lastname: Leal
authors.forename: Baroukh M
authors.initials: BM
authors.lastname: Assael
authors.forename: Paola
authors.initials: P
authors.lastname: Melotti
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005260:Female; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D007527:Isoenzymes; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017963:Azithromycin; D005982:Glutathione Transferase