Cation trapping by cellular acidic compartments: beyond the concept of lysosomotropic drugs

Authors: Marceau, FrançoisBawolak, Marie-ThérèseLodge, RobertBouthillier, JohanneGagné-Henley, AngéliqueC. Gaudreault, RenéMorissette, Guillaume
Abstract: “Lysosomotropic” cationic drugs are known to concentrate in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping); they draw water by an osmotic mechanism, leading to a vacuolar response. Several aspects of this phenomenon were recently reexamined. (1) The proton pump vacuolar (V)-ATPase is the driving force of cationic drug uptake and ensuing vacuolization. In quantitative transport experiments, V-ATPase inhibitors, such as bafilomycin A1, greatly reduced the uptake of cationic drugs and released them in preloaded cells. (2) Pigmented or fluorescent amines are effectively present in a concentrated form in the large vacuoles. (3) Consistent with V-ATPase expression in trans-Golgi, lysosomes and endosomes, a fraction of the vacuoles is consistently labeled with trans-Golgi markers and protein secretion and endocytosis are often inhibited in vacuolar cells. (4) Macroautophagic signaling (accumulation of lipidated and membrane-bound LC3 II) and labeling of the large vacuoles by the autophagy effector LC3 were consistently observed in cells, precisely at incubation periods and amine concentrations that cause vacuolization. Vacuoles also exhibit late endosome/lysosome markers, because they may originate from such organelles or because macroautophagosomes fuse with lysosomes. Autophagosome persistence is likely due to the lack of resolution of autophagy, rather than to nutritional deprivation. (5) Increased lipophilicity decreases the threshold concentration for the vacuolar and autophagic cytopathology, because simple diffusion into cells is limiting. (6) A still unexplained mitotic arrest is consistently observed in cells loaded with amines. An extended recognition of relevant clinical situations is proposed for local or systemic drug administration.
Document Type: Article de recherche
Issue Date: 13 December 2011
Open Access Date: 21 November 2017
Document version: AM
Permalink: http://hdl.handle.net/20.500.11794/15930
This document was published in: Toxicology and Applied Pharmacology, Vol. 259 (1), 1–12 (2012)
https://doi.org/10.1016/j.taap.2011.12.004
Academic Press
Alternative version: 10.1016/j.taap.2011.12.004
22198553
Collection:Articles publiés dans des revues avec comité de lecture

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