Human hepatocyte systems for in vitro toxicology analysis

Abstract

Drug induced liver injury (DILI) is still the leading single cause of drug failure during clinical phases and after market approval. Currently, many laboratories aim to develop appropriate in vitro systems to predict drug hepatotoxicity. Primary human hepatocytes are still the gold standard, but they have substantial disadvantages such as rapid dedifferentiation in vitro and lack of cell proliferation. In addition to primary human hepatocytes, liver cancer-derived cell lines such as HepG2, cytochrome P450 (CYP450) overexpressing HepG2 cell clones and HepaRG were studied intensively. In contrast to HepG2, HepaRG show promising characteristics of differentiated primary human hepatocytes, but they represent only one donor. There is some hope that this lack of donor variability can be solved by the use of iPS-derived hepatocytes. However, iPS technology still seems to need some improvement to produce physiologically relevant hepatocytes. Upcyte hepatocytes represent the most recent technical advancement combining some features of primary human hepatocytes such as physiological activity and donor variability with the ability of cell lines for extended proliferation. Altogether, more work is needed to develop and validate appropriate in vitro systems for precise prediction of DILI risk.