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Massive cell vacuolization induced by organic amines such as procainamide
Guillaume Morissette1, Emmanuel Moreau, René C-Gaudreault
1Centre de recherche de L'Hôtel-Dieu, Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada.
The Journal of Pharmacology and Experimental Therapeutics
|March 10, 2004
Summary
Basic drugs like procaine cause cell vacuolization. This study explores drug structure, concentration, and mechanisms, revealing acidic organelle swelling as a key factor in vacuole formation.
Area of Science:
- Cell Biology
- Pharmacology
- Toxicology
Background:
- Basic drugs, including procaine, are known to induce vacuolization in various cell types.
- Understanding the concentration-effect and structure-activity relationships of this phenomenon is crucial for drug safety and cellular mechanism elucidation.
Purpose of the Study:
- To investigate the concentration-dependent effects and structure-activity relationships of basic drugs inducing cell vacuolization.
- To elucidate the underlying mechanism of drug-induced vacuolization using multiple cell lines.
- To identify the cellular origin and key factors involved in the vacuolization process.
Main Methods:
- Utilized three distinct cell lines: rabbit pulmonary artery smooth muscle cells (SMCs), COS-1 cells, and human embryonic kidney 293 cells.
- Administered a range of basic amine compounds and other drugs at varying concentrations (100 microM to 2.5 mM).
- Employed techniques including drug washing, bafilomycin A1 cotreatment, and ceramide uptake analysis to study vacuole formation and drug localization.
Main Results:
- Massive vacuolization was observed in SMCs and COS-1 cells with compounds like procaine and procainamide at 2.5 mM, and chloroquine, propranolol, diphenhydramine, and neutral red at 100-250 microM.
- Human embryonic kidney 293 cells showed milder responses, indicating cell-type selectivity.
- Procainamide-induced vacuolization was reversible, largely prevented by bafilomycin A1, suggested a Golgi origin, and involved drug accumulation in acidic organelles.
Conclusions:
- Drug-induced vacuolization is mediated by the osmotic swelling of acidic organelles, driven by the trapping of charged basic drugs at low pH.
- The process is influenced by drug structure, concentration, and cell type, with drug transport potentially being a limiting factor.
- Vacuolization does not necessarily induce apoptosis but can reduce cell proliferation and migration, highlighting potential cytotoxic effects.