Using high-content screening technology for studying drug-induced hepatotoxicity in preclinical studies

ABSTRACT

Introduction: The need for alternatives to animal experimentation and traditional testing methods has been widely discussed in recent years. This has led scientists and regulatory authorities to investigate alternative methods for toxicity testing. High-content screening (HCS) has emerged as a powerful tool in predictive toxicology since it permits molecular, cellular and tissue-based toxicity assessments. HCS allows automated image acquisition and analysis, and provides information on multiple properties of individual cells loaded simultaneously with fluorescent dyes, which is used for drug safety evaluations.

Areas covered: Herein, the authors review the principles of HCS technology and some of the most widely used HCS assays for studying drug-induced hepatotoxicity in preclinical studies in general and in the pharmaceutical industry in particular.

Expert opinion: The widespread acceptation of HCS by pharmaceutical companies and academic researchers highlights the potential usefulness of this technology as a prioritization tool in drug development. The improvement of different key points such as fluorescent probes or bioinformatics tools will consolidate HCS in drug discovery.

KEYWORDS:

• High-content screening
• drug-induced liver injury
• cell models

Article highlights

• HCS assays have been satisfactorily applied to detect cell changes associated with hepatotoxic insults in different cell systems such as HepG2 cells or primary human hepatocytes.

• It allows studying different cell subpopulations and performing multiple simultaneous measurements per cell by loading them with several fluorescent dyes, and the elimination of unwanted cells.

• Multiplexed measurements allow the reduction of the number of cells, reagents and tested compounds compared to conventional assays based on single endpoint determination, which permits medium to high-throughput screenings to be done in early drug development steps.

• Different pharmaceutical companies are using HCS assays which highlight the importance of this technology on drug discovery.

• Advances in HCS will increase the prediction of human DILI by consolidating its role in drug develpment.This box summarizes key points contained in the article

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors acknowledge the support from the ALIVE Foundation, the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness) and EROF (EU) funds (grant number PI13/00986). L.Tolosa was a recipient of a Miguel Servet I Contract from the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness).