Screening for the Drug–Phospholipid Interaction: Correlation to Phospholipidosis

Abstract

Phospholipid bilayers represent a complex, anisotropic environment fundamentally different from bulk oil or octanol, for instance. Even "simple" drug association to phospholipid bilayers can only be fully understood if the slab-of-hydrocarbon approach is abandoned and the complex, anisotropic properties of lipid bilayers reflecting the chemical structures and organization of the constituent phospholipids are considered. The interactions of drugs with phospholipids are important in various processes, such as drug absorption, tissue distribution, and subcellular distribution. In addition, drug-lipid interactions may lead to changes in lipid-dependent protein activities, and further, to functional and morphological changes in cells, a prominent example being the phospholipidosis (PLD) induced by cationic amphiphilic drugs. Herein we briefly review drug-lipid interactions in general and the significance of these interactions in PLD in particular. We also focus on a potential causal connection between drug-induced PLD and steatohepatitis, which is induced by some cationic amphiphilic drugs.

<i>In vitro</i> validation of drug-induced phospholipidosis

“…4). Although the reason for the discrepancy between the results obtained from LipidTox and NBD-PE assay is not known, the sensitivity of the fl uorescent dye, the sort of phospholipid applied and the difference in the incubation time for the fl uorescently-labeled phospholipids may be involved (Alakoskela et al, 2009). …”

“…Drug uptake into lysosomes and acidic vesicles depends on the concentration and the physiochemical properties of the drug such as pKa of the amine group and lipophilicity. Other factors determining the uptake are the type of tissue affected and the presence of competition with other weak bases (Alakoskela et al, 2009).…”

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

“…As a consequence, membrane fluidity, lipid composition, and membrane protein activity might be changed. Moreover, phospholipid particles might accumulate in lysosomal lamellar bodies (Alakoskela et al, 2009;Xia et al, 2000). In 1990, a study by Rodriguez-Lafrasse et al (1990) elucidated the morphology of imipramine-treated fibroblasts as resembling that of cells that originate from Niemann-Pick type-C (NP-C) disease (Rodriguez-Lafrasse et al, 1990).…”

Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response

“…In a kidney-derived epithelial cell line, clofazimine accumulated in druginduced, autophagosome-like drug-membrane aggregates (19). These drug-membrane aggregates resembled the multilamellar bodies that form inside cells exposed to phospholipidosis-inducing, lysosomotropic amphiphilic cations (20,21). Consistent with lysosomal accumulation, clofazimine treatment also affects the activity of lysosomal enzymes, both in vitro (22) and in vivo (23).…”