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Evaluation of Drug-Induced Liver Injuries (DILI) with Human Hepatocytes: Scientific Rationale and Experimental Approaches

  • Albert P. LiEmail author
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Preclinical safety evaluation with laboratory animals may not accurately predict human drug safety due to species differences in response to toxicants. Here the Human Cell Paradigm, namely, that human-specific drug properties can be obtained with in vitro human-based experimental systems is proposed. The success of the Human Cell Paradigm depends on the physiological relevance of the in vitro system, namely, the retention of human-specific and organ-specific properties. Human hepatocytes, with complete hepatic metabolizing enzymes, transporters and cofactors, represent a practical and useful experimental system to assess human-specific hepatic drug properties. In this chapter, the scientific rationale and experimental approaches for the application of primary cultured human hepatocytes to evaluate drug-induced liver injuries (DILI) is reviewed. This review focuses on experimental approaches based on the Key Idiosyncratic Determinant (KID) hypothesis—that drugs with KID are likely to cause idiosyncratic drug toxicity. We have identified that metabolism-dependent toxicity and induction of reactive oxygen species as two important KIDs. In vitro experimental approaches with primary cultured human hepatocytes that can be applied in drug development for optimization and prioritization of chemical structures based on human hepatotoxic potential are described.

Key words

Drug-induced liver injury Human hepatocytes Preclinical safety Key idiosyncratic determinant hypothesis Metabolism-dependent toxicity Induction of reactive oxygen species 

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Copyright information

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

Authors and Affiliations

  1. 1.In Vitro ADMET Laboratories Inc.ColumbiaUSA

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