Drug-induced phospholipidosis – causes, effects, identification

Abstract

Adverse reactions of drugs are a significant problem in pharmacotherapy. The observed side effects may have multiple causes. They may depend on the dose and type of medicine used. They can occur during therapy or appear with a delay, after its completion. They may disappear after discontinuation of treatment or persist. In this review, we summarize the vast literature in the area of phospholipidosis, which is a major consequence of the use of cationic amphiphilic drugs (CAD). Their specific chemical structure causes the accumulation of phospholipids inside the lysosomes, which affects their proper function, however, the mechanism of phospholipidosis at the molecular level is not fully understood. Several hypotheses on the mechanism of phospholipidosis formation have been put forward - they mainly concern: the formation of complexes between phospholipids and CAD drugs, competitive inhibition of lysosomal phospholipases by CAD and increased biosynthesis of phospholipids and cholesterol under the influence of the drug. As a result of the accumulation of phospholipids in lysosomes, the so-called lamellar bodies may appear in tissues days or weeks after in vivo CAD administration, and this process is dose-dependent. Phospholipidosis is believed to be a reversible process and is assumed to be an adaptive - but not toxic - response to drugs. If the concentration of CAD or a toxic substance accumulated in lysosomes exceeds a critical value, apoptosis and autophagy may be activated. Phospholipidosis can also be caused by drugs other than CAD, oxysterols and some nanoparticles. Phospholipidosis is one of the least known complications of pharmacotherapy - methods of its detection at the initial stage as well as the full spectrum of functional disorders of the body are still being sought. Identification of phospholipidosis in cells is possible by means of electron microscopy studies confirming the presence of lamellar bodies in tissues from biopsies or by means of real-time PCR techniques examining the expression of genes correlated with the occurrence of phospholipidosis. A potential biomarker detecting this process in the blood and urine of patients is bis(monoacylglycero)phosphate (BMP). Drug-induced phospholipidosis can be detected at the preclinical stage. However, the accumulation of phospholipids and the formation of lamellar bodies found in in vitro or in animal studies does not necessarily mean organ damage in the human body. In recent years, there has been an increase in interest in the mechanism of the phospholipidosis and in the study of new drugs in terms of causing this undesirable effect. This review presents an overview of the most important studies to date related to the mechanism of phospholipidosis formation, methods of its identification and effects at the cellular level as well as on the whole organism.

Keywords

• phospholipidosis
• cationic amphiphilic drugs
• lamellar bodies