Recent Progress in Prediction Systems for Drug-induced Liver Injury Using In vitro Cell Culture.

Abstract

Background: In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed.

Objective: In this study, recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as on the limitations of in vitro cell culture systems for DILI research, was carried out.

Methods: Information related to DILI was collected through a literature search of the PubMed database.

Results: The initial biological event for the onset of DILI is the formation of cellular protein adducts after drugs have been metabolically activated by drug metabolizing enzymes. The damaged peptides derived from protein adducts lead to the activation of CD4⁺ helper T lymphocytes and recognition by CD8⁺ cytotoxic T lymphocytes, which destroy hepatocytes through immunological reactions. Because DILI is a major cause of drug attrition and drug withdrawal, numerous in vitro systems consisting of hepatocytes and immune/inflammatory cells or spheroids of human primary hepatocytes containing non-parenchymal cells have been developed. These cellular-based systems have identified DILI-inducing drugs, with approximately 50% sensitivity and 90% specificity.

Conclusion: Different co-culture systems consisting of human hepatocyte-derived cells and other immune/inflammatory cells have enabled the identification of DILI-causing drugs and of the actual mechanisms of action.