Drug induced phospholipidosis: An acquired lysosomal storage disorder

Abstract

There is a strong association between lysosome enzyme deficiencies and monogenic disorders resulting in lysosomal storage disease. Of the more than 75 characterized lysosomal proteins, two thirds are directly linked to inherited diseases of metabolism. Only one lysosomal storage disease, Niemann-Pick disease, is associated with impaired phospholipid metabolism. However, other phospholipases are found in the lysosome but remain poorly characterized. A recent exception is lysosomal phospholipase A2 (group XV phospholipase A2). Although no inherited disorder of lysosomal phospholipid metabolism has yet been associated with a loss of function of this lipase, this enzyme may be a target for an acquired form of lysosomal storage, drug induced phospholipidosis.

Harmful at non-cytotoxic concentrations: SiO2-SPIONs affect surfactant metabolism and lamellar body biogenesis in A549 human alveolar epithelial cells

“…The elevated amount of intracellular phospholipids has previously been interpreted as an adaptive response to prevent the toxicity of foreign matter by sequestering them away from other cellular sites (Shayman & Abe, 2013). However, in our study, we observed ultrastructural and metabolic changes indicating significant cellular alteration that can be deleterious even at non-cytotoxic concentrations and can affect the main function of ATII cells, which is the production of lung surfactant.…”

Dysregulation of protein degradation pathways may mediate the liver injury and phospholipidosis associated with a cationic amphiphilic antibiotic drug

“…CAD drugs that cause phospholipidosis-such as amiodarone-have been associated with hepatic injury and fibrosis in animal models (Ágoston et al, 2003). Recent data provide evidence that sequestration of drugs in lysosomes can lead to significant cellular dysfunction, including impaired lysosomal protein degradation (Shayman and Abe, 2013), which is consistent with the alterations in the protein ubiquitination pathway suggested by the results in this study. Interestingly, concentrations of the parent compound in the blood at 2 and 24 h after treatment did not correlate with liver injury in PF-04287881-treated animals.…”

Lysosomal Sequestration (Trapping) of Lipophilic Amine (Cationic Amphiphilic) Drugs in Immortalized Human Hepatocytes (Fa2N-4 Cells)

“…Lysosomal trapping of drugs has also been associated with druginduced phospholipidosis, an iatrogenic lysosomal storage disorder characterized by the accumulation of phospholipids in tissues (Daniel and Wojcikowski, 1999;Anderson and Borlak, 2006;Hanumegowda et al, 2010;Shayman and Abe, 2013). At least 385 drugs that cause phospholipidosis have been identified in the Food and Drug Administration database (Advisory Committee for Pharmaceutical Science, April 2010; http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/advisorycommitteeforpharmaceuticalscienceandclinicalpharmacology/ucm210798.pdf), all of which have been identified as CADs.…”