Emerging mechanisms of drug-induced phospholipidosis.

Emerging mechanisms of drug-induced phospholipidosis. Biol Chem. 2019 Aug 01;: Authors: Breiden B, Sandhoff K Abstract Drug-induced phospholipidosis is a lysosomal storage disorder characterized by excessive accumulation of phospholipids. Its cellular mechanism is still not well understood, but it is known that cationic amphiphilic drugs can induce it. These drugs have a hydrophilic amine head group that can be protonated in the endolysosomal compartment. As cationic amphiphiles, they are trapped in lysosomes, where they interfere with negatively charged intralysosomal vesicles, the major platforms of cellular sphingolipid degradation. Metabolic principles observed in sphingolipid and phospholipid catabolism and inherited sphingolipidoses are of great importance for lysosomal function and physiological lipid turnover at large. Therefore, we propose intralysosomal vesicles also as major platforms for degradation of lipids and phospholipids reaching them by intracellular pathways like autophagy and endocytosis. Phospholipids are catabolized as components of vesicle surfaces by protonated, positively charged phospholipases, electrostatically attracted to the negatively charged vesicles. Model experiments suggest that progressively accumulating cationic amphiphilic drugs inserting into the vesicle membrane with their hydrophobic molecular moieties disturb and attenuate the main mechanism of lipid degradation as discussed here. By compens...
Source: Biological Chemistry - Category: Chemistry Tags: Biol Chem Source Type: research