Use of Liver-Derived Cell Lines for the Study of Drug-Induced Liver Injury

Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

In vitro liver-derived cell lines have been used extensively in toxicity testing and related studies as alternatives and complements to primary hepatocytes. Multiple hepatocyte derived cellular carcinoma cell lines, such as HepG2, Huh7, and HepaRG cells, have been established over the years, and they display distinct characteristics regarding the expression and activity levels of drug-metabolizing enzymes and other hepatocyte-specific factors. These cell lines have become useful tools and the models based on cell lines showed promising value for screening risks of drug-induced liver injury (DILI) in the early stage of drug development, although they have deficiencies in metabolism-related investigations. Engineered cell lines, expressing drug-metabolizing enzymes or other hepatic genes either stably or transiently, have partially overcome these limitations. The liver-derived cell lines have contributed significantly to mechanistic studies of DILI, and various underlying signaling pathways and signatures of DILI have been identified. In this chapter, we first introduce the major hepatic lines (e.g., HepG2, Huh7, HepaRG, Hep3B, BC2, THLE, and Fa2N-4 cells), including their origins, characteristics, advantages, and disadvantages for application in toxicity studies. We next depict the development and application of various engineered cell lines. We then discuss the current understanding of major DILI mechanisms and the endpoints for in vitro tests. The chapter is closed with a brief discussion of the challenges and opportunities in the field.

Key words

DILI In vitro cell lines HepG2 cells HepaRG cells Engineered hepatic cell lines Mechanistic studies 

Notes

Disclaimer

This chapter is not an official guidance or policy statement of the US Food and Drug Administration (FDA). No official support or endorsement by the US FDA is intended or should be inferred.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Biochemical ToxicologyNational Center for Toxicological Research, U.S. Food and Drug AdministrationJeffersonUSA
  2. 2.Division of Systems BiologyNational Center for Toxicological Research, U.S. Food and Drug AdministrationJeffersonUSA

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