Drug-induced Phospholipidosis -Pathological Aspects and Its Prediction

Abstract

Drug-induced phospholipidosis (PLDsis) is an excessive accumulation of polar phospholipids in cells or tissues/organs caused by xenobiotics. Numerous drugs and chemicals are capable of inducing the storage disorder in animals and humans; however, despite their diverse pharmacological activities, each of these drugs shares common physicochemical properties: a hydrophobic aromatic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group and therefore are in the group of cationic amphiphilic drugs. In affected cells the appearance of membrane-bound inclusions, primarily lysosomal in origin, with a lamellar structure (lamellar bodies) is a definitive morphologic hallmark. Massive accumulations can occur in animal tissues such as the lung with little effect on organ function. The inducing drug also accumulates in association with the excess phospholipid. Although these alterations are generally reversible after cessation of drug treatment, PLDsis is of regulatory concern and an issue for drug safety for pharmaceutical companies. Thus, the assessment of potential target organ dysfunction and the identification of clinical biomarkers are important objectives for new drug development. Recent advances in biotechnology such as metabonomics and toxicogenomics have been providing novel tools to elucidate the mechanisms of PLDsis and to establish biomarkers for screening tests in the preclinical stages and for monitoring in the clinical phases in addition to conventional approaches such as morphology (lamellar bodies) and biochemical methods including assays of specific metabolites and phospholipase inhibition. (J Toxicol Pathol 2008; 21: 9-24)

The role of negatively charged lipids in lysosomal phospholipase A2 function

“…Thus, the presence of the histidine tag itself did not affect the electrostatic interaction. In addition, the drug AMD, positively charged under physiological conditions, shows a high affi nity to phospholipids via hydrophobic as well as hydrophilic interactions ( 19 ). Thus, AMD could diminish the negative charge produced by anionic lipids incorporated into liposomes and, as a result, weaken the electrostatic interaction between the LPLA2 and the lipid membranes in this system.…”

Screening for the Drug–Phospholipid Interaction: Correlation to Phospholipidosis

“…Recent reviews have tentatively suggested that drug-induced PLD itself likely has no major pathological consequences. [107,[200][201][202] Nevertheless, the correlation between hepatic toxicity and PLD has renewed interest in the mechanism of PLD and in high-throughput screening methods for detecting PLD. In particular, the PLD-inducing cationic amphiphilic drugs form the only group of drugs frequently associated with classical steatohepatitis.…”

Weka Machine Learning for Predicting the Phospholipidosis Inducing Potential

“…The mechanism for PPL development is a druginduced inhibition of lysosomal phospholipase activity [49]. Due to the potential organ dysfunction as a result of PPL, in addition to the conventional identification of lamellar bodies by electron microscopy, several biomarkers were established for screening tests in the preclinical stages and clinical phases [50]. A number of 17 genes were identified in HepG2 cells as potential biomarkers of PPL [51].…”