title: Hyperactivity of cathepsin B and other lysosomal enzymes in fibroblasts exposed to azithromycin, a dicationic macrolide antibiotic with exceptional tissue accumulation.
abstract: Azithromycin accumulates in lysosomes where it causes phospholipidosis. In homogenates prepared by sonication of fibroblasts incubated for 3 days with azithromycin (66 microM), the activities of sulfatase A, phospholipase A1, N-acetyl-beta-hexosaminidase and cathepsin B increased from 180 to 330%, but not those of 3 non-lysosomal enzymes. The level of cathepsin B mRNA was unaffected. The hyperactivity induced by azithromycin is non-reversible upon drug withdrawal, prevented by coincubation with cycloheximide, affects the Vmax but not the Km, and is not reproduced with gentamicin, another drug also causing lysosomal phospholipidosis. The data therefore suggest that azithromycin increases the level of lysosomal enzymes by a mechanism distinct from the stimulation of gene expression but requiring protein synthesis, and is not in direct relation to the lysosomal phospholipidosis.
authors.affiliation: Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, Bruxelles, Belgium. gerbaux@facm.ucl.ac.be
authors.forename: C
authors.initials: C
authors.lastname: Gerbaux
authors.forename: F
authors.initials: F
authors.lastname: Van Bambeke
authors.forename: J P
authors.initials: JP
authors.lastname: Montenez
authors.forename: J
authors.initials: J
authors.lastname: Piret
authors.forename: G
authors.initials: G
authors.lastname: Morlighem
authors.forename: P M
authors.initials: PM
authors.lastname: Tulkens
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D002401:Cathepsin B / Q000187:drug effects; D002412:Cations / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005839:Gentamicins / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology*; D010741:Phospholipases A / Q000187:drug effects; D054466:Phospholipases A1; D051381:Rats; D017208:Rats, Wistar; D013429:Sulfatases / Q000187:drug effects; D001619:beta-N-Acetylhexosaminidases / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D002412:Cations; D005839:Gentamicins; D017963:Azithromycin; D010741:Phospholipases A; D054466:Phospholipases A1; D013429:Sulfatases; D001619:beta-N-Acetylhexosaminidases; D002401:Cathepsin B