Mass spectrometric based metabolomic study of phospholipidosis associated markers of in vitro drug toxicity

Drug induced toxicity can be a barrier to clinical success of a novel pharmaceutical compound. Earlier evaluation of toxicity in the drug development pipeline can aid in reducing compound attrition in later stages of development. Excessive production of cellular phospholipids and vacuole formation in macrophages, the predominant resident immune cells in the lung, have been identified as toxicological endpoints of concern during development of inhaled therapies. Research at the University of Hertfordshire (UH) Centre for Topical Drug Delivery and Toxicology has developed an in vitro cell culture screen for the early identification of this drug-induced toxicological endpoint (Hoffman et al., 2017, Pharm. Res. 34 (12): 2466-2476). However, full de-lineation of the biochemical pathways and alteration to cell metabolism associated with the pathological changes has yet to be characterized.

Metabolomics is the analysis of metabolites in a system and can be used to identify pertinent molecules within a biological system. This can be performed by liquid chromatography mass spectrometry (LC-MS) based approaches, making use of high-resolution MS data to assist in identification of relevant metabolites. Reactive oxygen species (ROS) are naturally occurring species within biological systems that are involved in regular homeostatic processes. Additionally, they are known to have a role in drug induced toxicity.

This project aims to take a metabolomics approach to identification of molecules associated with phospholipidosis, with a focus on ROS associated biochemical pathways. Identification of molecules that are associated with ROS responses during cell toxicity testing can be of benefit for two primary reasons. Firstly, this will allow for greater mechanistic understanding of the metabolic processes involved in toxicity, which can aid in future drug development and avoidance of drug toxicity. Secondly, any identified biomarkers of toxicity can potentially be used to monitor the evolution or resolution of cell toxicity over time.