Azithromycin, a pharmacological agent which selectively inhibits some pathways of endocytosis: characterization, interests and mechanism of action.

Ph D Thesis (Pharmaceutical Sciences) - oral presentation December 4th, 2001

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Azithromycin, a pharmacological agent which selectively inhibits some pathways of endocytosis: characterization, interests and mechanism of action.

Pathways of endocytosis studied in this thesis

Membrane lipids are implicated at various stages of the endocytic process

Molecular machineries of endocytic pathways

What is the place of pharmacological inhibitors to dissect the endocytic apparatus ?

Azithromycin (AZ), a dicationic amphiphile

Pharmacological properties of AZ

Cellular pharmacokinetic properties of AZ

Cellular toxicological properties of AZ

? Could AZ affect earlier steps of the endocytic apparatus ?

AZ slows down fluid-phase endocytosis

Inhibition of fluid-phase endocytosis correlates with AZ content but is independent of phospholipidosis

AZ causes a major reduction of the number of endosomes and lysosomes and impairs accessibility of HRP to swollen and overloaded endosomes/lysosomes

? Is AZ specific to fluid-phase endocytosis ?

AZ inhibits fluid-phase endocytosis and this inhibition is reversible

AZ slows down bulk-membrane endocytosis

AZ strongly decreases the surface-pool of transferrin receptors

AZ delays sequestration of ligand/receptor in endocytic pits and recycling vesicles

AZ marginally decreases the surface-pool of Fc? receptors and delays sequestration of ligand/receptor complexes into endocytic pits

AZ does not affect phagocytosis

AZ impairs accessibility of HRP and PAP, but not of latex beads, to swollen endosomes/lysosomes

Latex beads move within the structures vacuolated by AZ, demonstrating their presence in these structures

AZ accumulation ...

? How does AZ inhibit pinocytosis ?

AZ interacts with lipids of liposomes made of cholesterol: PC: SM: PI in a pH-independent fashion

AZ reduces incorporation in the plasma membrane of three membrane tracers

AZ decreases J774 plasma membrane fluidity

General conclusion

Short-term perspectives

Long-term perspectives

Progress in cellular toxicology of azithromycin

Author: D. Tyteca

Email: tulkens@facm.ucl.ac.be

Home Page: http://www.md.ucl.ac.be/facm/PhD_and_MSc_dissertations.htm

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