High-Content Screening: Understanding and Managing Mechanistic Data to Better Predict Toxicity

Abstract

An increased understanding of the cellular pathways involved in toxicity responses, coupled with a simultaneous advance in technology, has allowed for a shift in the way that the safety assessment of novel chemicals is performed. The development of assays that offer a high-throughput and low-cost option in comparison to more traditional approaches has been a focus of recent years.Early identifi cation of compounds which have the potential to cause Drug Induced Liver Injury (DILI) remains a major challenge for the pharmaceutical industry. Improvements in the mechanistic understanding of the cellular processes involved in this complex response have allowed for models to be generated and more reliable predictions to be made.High-Content Screening (HCS) describes an approach whereby multiple end points can be monitored in a single assay. The focus of this chapter is to introduce HCS with relation to using automated fl uorescence microscopy in order to assess phenotypic changes within cells and, more specifi cally, how this can be incorporated into the drug discovery process.We discuss the advantages that HCS can offer, whilst highlighting important factors to take into account when considering establishing the approach within a laboratory. Four papers whereby HCS has been used to highlight the potential of compounds to cause DILI are reviewed and compared. In addition, an option for including HCS as part of a wider workfl ow to identify environmental toxicants is introduced.