Dermal Lipofuscinosis Associated With Amiodarone Therapy

Miller, Robert A.; McDonald, Alan T. J.

doi:10.1001/archderm.1984.01650410088022

Cited by 30 publications

(13 citation statements)

References 5 publications

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“…The cells that were positive for either LC3 or CD68 were also positive for a brownish deposit already described in the skin of this and other amiodarone‐treated patients (Figure 9, bottom; Delage et al. , 1975; Miller and McDonald, 1984; Ammoury et al. , 2008; Radman et al.…”

Section: Resultssupporting

confidence: 68%

“…, 2008). This lipofuscin‐like deposit has a yellowish fluorescence of its own (Miller and McDonald, 1984; Dowson et al. , 1986), possibly explaining why the control tissue sections without the first antibodies exhibited a low level of fluorescence in the group of cells positive for LC3 and CD68 (Figure 9, top).…”

Section: Resultsmentioning

confidence: 99%

“…It is desirable to extend this preliminary investigation to additional patients with amiodarone‐induced skin discoloration. In histiocytes of such patients, the vacuoles are electron dense probably owing to the iodinated structure of the drug (Figure 1; Miller and McDonald, 1984; Ammoury et al. , 2008).…”

Section: Discussionmentioning

confidence: 99%

“…, 1987; Pintavorn and Cook, 2008), and abundant in the pigmented skin of the affected patients (paraffin sections; Ammoury et al. , 2008; electron microscopy, Miller and McDonald, 1984). Macrophages are rich in acidic vacuoles and concentrate comparatively large amounts of amiodarone (Figures 2 and 3).…”

Section: Discussionmentioning

confidence: 99%

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Intracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology

Morissette

Ammoury

Rusu

et al. 2009

British J Pharmacology

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Background and purpose:Tissue deposits of the anti-arrhythmic drug amiodarone are a major source of side effects (skin discoloration, etc.). We addressed the mechanism of the concentration of amiodarone in cells, and characterized the resulting vacuolar cytopathology and its evolution towards macroautophagy. Experimental approach: Sequestration of amiodarone in human cells (macrophages, smooth muscle cells, HEK 293a cells) was evaluated using its violet fluorescence and cytopathology using GFP-conjugated subcellular markers. Autophagic signalling was probed by immunoblotting for the effector protein LC3. A patient biopsy of amiodarone-induced blue-gray skin discoloration was investigated for the presence of macroautophagy (immunofluorescence for LC3). Key results: Most of the amiodarone (1-20 mM, 4-24 h) captured by cultured cells (macrophages were most avid) was present in enlarged vacuoles. The specific vacuolar ATPase (V-ATPase) inhibitors, bafilomycin A1 or FR167356, prevented vacuolization and drug uptake. Vacuoles in HEK 293a cells were positive for markers of late endosomes and lysosomes (GFP-Rab7, -CD63) and for an effector of macroautophagy, GFP-LC3. The vacuoles accumulated endogenous LC3 and filled with lipids (Nile red staining) following longer amiodarone treatments (Ն24 h). The electrophoretic mobility of both GFP-LC3 and endogenous LC3 changed, showing activation in response to amiodarone. Paraffin tissue sections of the pigmented skin exhibited granular LC3 accumulation in superficial dermis macrophages. Conclusion and implications: Vacuolar sequestration of amiodarone occurs at concentrations close to therapeutic levels, is mediated by V-ATPase and evolves towards persistent macroautophagy and phospholipidosis. This cytopathology is not cell type specific, but tissue macrophages appear to be particularly susceptible.

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Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Intracellular sequestration of amiodarone: role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology

Morissette

Ammoury

Rusu

et al. 2009

British J Pharmacology

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show abstract

“…Die mittels Scanning-Elektronenmikroskop durchführten Diffraktionsuntersuchungen konnten in den Lysosomen der Endothelzellen und der Makrophagen Jod nachweisen [22]. UV-Strahlung führt zu einer lysosomalen Funktionsstörung in den Amiodaron-haltigen Phagozyten mit konsekutiver Anhäufung von Lipofuszingranula im Zytoplasma [3,45].…”

Section: > Meist Besteht Von Der Initialen Einnahme Des Amiodarons Biunclassified