1: Eur J Pharmacol 1996 Oct 24;314(1-2):203-14
Interaction of the macrolide azithromycin with phospholipids. I. Inhibition
of lysosomal phospholipase A1 activity.
Van Bambeke F, Montenez JP, Piret J, Tulkens PM, Courtoy PJ, Mingeot-Leclercq
MP
Unite de Pharmacologie Cellulaire et Moleculaire, UCL 73.70, Bruxelles,
Belgium.
vanbambeke@facm.ucl.ac.be
Azithromycin, the first clinically developed dicationic macrolide antibiotic,
displays an exceptional accumulation in lysosomes of cultured cells. In
fibroblasts incubated with 50 mg/l (66.6 microM), it induces a distinct
phospholipidosis as evidenced by biochemical and ultrastructural criteria,
which strikingly resembles alterations described previously with gentamicin,
a pentacationic aminoglycoside antibiotic which inhibits the lysosomal
catabolism of phospholipids. We show that both drugs inhibit, in an equimolar
manner, the activity of phospholipase A1 (assayed for phosphatidylcholine,
included in negatively charged liposomes), in a way consistent with the
model of 'charge neutralization' proposed already for gentamicin (Mingeot-Leclercq
et al., 1988, Biochem. Pharmacol. 37, 591). Both drugs bind to negatively
charged liposomes. Yet, in spite of this binding, azithromycin does not
induce aggregation or fusion of negatively charged vesicles, under conditions
in which gentamicin (or spermine, a fully hydrophilic polycation) causes
a massive aggregation, and bis(beta-diethylaminoethylether)hexestrol (a
dicationic amphiphile) causes fusion. The molecular interactions of azithromycin
with acidic phospholipids are further examined in a companion paper.
PMID: 8957238, UI: 97116150