Drug‐induced phospholipidosis

Abstract

Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies, most likely from an impaired phospholipid metabolism of the lysosome. Organs affected by phospholipidosis exhibit inflammatory reactions and histopathological changes. Despite significant advances in the understanding of drug-altered lipid metabolism, the relationship between impaired phospholipid metabolism and drug-induced toxicity remains enigmatic. Here we review molecular features of inheritable lysosomal storage disorders as a molecular mimicry of drug-induced phospholipidosis for an improved understanding of adverse drug reaction.

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis

“…The amount of LC3-II is correlated with the extent of autophagosome formation (23). Whereas the involvement of an autophagic process is supported by the identification of LC3-II in 7-ketocholesterol-treated human aortic smooth muscle cells, the presence of cytoplasmic structures stained by the lysosome cationic lipophilic dye, monodansylcadaverine, which is detected before the loss of mitochondrial potential in 7-ketocholesterol-treated U937 cells, suggests instead that 7-ketocholesterol is a potent inducer of phospholipidosis (29). Indeed, under treatment with cytotoxic oxysterols, these structures, which are identified both in cells with condensed and/or fragmented nuclei characteristic of apoptotic cells and in cells with swollen nuclei considered as oncotic cells, can also be stained with Nile Red, which colors neutral and polar lipids yellow and orange/red, respectively (30).…”

“…Taken together, these different observations lead us to conclude that 7-ketocholesterol is a potent inducer of phospholipidosis characterized by the following criteria: excessive accumulation of phospholipids in cells; ultrastructural appearance of multilamellar cytoplasmic inclusions, predominantly lysosomal in origin; accumulation of the inducing drug in association with phospholipids in Oxysterols, cell death, and associated events www.bjournal.com.br multilamellar structures; reversibility of alterations after interruption of drug treatment (29).…”

“…Currently, the relationship between phospholipidosis and toxicity remains unclear. It has been suggested that phospholipidosis might be a part of a defense system when the cell is confronted with a substantial accumulation of xenobiotics and their metabolites because the imprisonment of these compounds in the lamellar structures can inactivate their actions (29). Thus, phospholipidosis has been primarily considered as an adaptive response to the exposure of cationic amphiphilic drugs rather than as a toxic response.…”

The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing

“…[69,70] They are also relatively potent inhibitors of ATP synthase, which is a membrane-bound protein. [71] While reactive metabolites are produced by chlorpromazine, amiodarone is not an obvious source of chemical reactivity.…”

Weka Machine Learning for Predicting the Phospholipidosis Inducing Potential

“…An adverse effect of some cationic amphiphilic drugs is phospholipidosis (PPL) that manifests as an intracellular accumulation of phospholipids that is accompanied by the development of concentric lamellar bodies (also called lysosomal inclusion bodies or myeloid bodies) [47]. PPL may occur in multiple tissue types, mainly in lungs, liver, eyes, kidneys, cornea, nervous system, and lymphatic system, and it usually manifests only at high drug concentrations [48]. In Fig.…”