Research Spotlight: Drug-Induced Phospholipidosis: Mechanistic Insights

Posted on July 28, 2021

Drug Induced Phospholipidosis

Drug-induced phospholipidosis (DIPL) is known to be commonly caused by the intake of a special class of drugs called cationic amphiphilic drugs (CAD). The mechanism by which phospholipidosis occurs is still largely unknown. DIPL is a reversible process but if not caught in time it can be deadly. DIPL is an acquired lysosomal storage disorder that results in excess storage of phospholipids in lysosomes. The most commonly affected organs include the lungs, liver or kidney and is associated with pulmonary fibrosis, hepatic steatosis, and kidney injury, respectively. Several questions surround the use of CADs and research on DIPL. The primary question investigated by research out of the University of Michigan and Purdue University concerns the pathological significance of phospholipidosis.

Previously, this group of researchers identified an enzyme called lysosomal phospholipase A2 (LPLA2). In this study, the inhibition of LPLA2 by CADs is being investigated. They assayed a library of 163 compounds for inhibition of LPLA2. Most of these compounds were used as a result of literature reviews identifying them as causes of phospholipidosis. Most of these compounds are cationic amphiphiles and several are central nervous system penetrants. The rest of the assayed compounds had not previously been reported to cause DIPL but had similar chemical properties to the ones reported as causing DIPL.

The study yielded three important findings. First, almost all of the drugs that were previously reported to cause phospholipidosis were also observed to inhibit LPLA2 (measured by a decrease in 1-O-acylceramide formation). A second important finding was that the LPLA2 inhibition assay identified several CADs that are known to cause phospholipidosis but would not be predicted to do so based on in silico models that use pKa and ClogP of CADs. This shows that the inhibition of LPLA2 serves as a more sensitive and accurate method for prediction of DIPL than methods based on pKa and ClogP alone. The third and final important takeaway from this sudy is that LPLA2 inhibition could identify drugs or other chemical entities that are approved by regulatory agencies that cause DIPL but have not been previously identified as doing so.

This research utilized Avanti’s DOPC and DODPC products to prepare liposomes used in LPLA2 binding assays. To read the full article click the link below!

Inhibition of Lysosomal Phospholipase A2 Predicts Drug-Induced Phospholipidosis