Review Article

Archives of Toxicology

, Volume 87, Issue 4, pp 577-610

Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies

  • J. FraczekAffiliated withDepartment of Toxicology, Faculty of Medicine and Pharmacy, Centre for Pharmaceutical Research, Vrije Universiteit Brussel Email author 
  • , J. BolleynAffiliated withDepartment of Toxicology, Faculty of Medicine and Pharmacy, Centre for Pharmaceutical Research, Vrije Universiteit Brussel
  • , T. VanhaeckeAffiliated withDepartment of Toxicology, Faculty of Medicine and Pharmacy, Centre for Pharmaceutical Research, Vrije Universiteit Brussel
  • , V. RogiersAffiliated withDepartment of Toxicology, Faculty of Medicine and Pharmacy, Centre for Pharmaceutical Research, Vrije Universiteit Brussel
  • , M. VinkenAffiliated withDepartment of Toxicology, Faculty of Medicine and Pharmacy, Centre for Pharmaceutical Research, Vrije Universiteit Brussel

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Abstract

Continuously increasing understanding of the molecular triggers responsible for the onset of diseases, paralleled by an equally dynamic evolution of chemical synthesis and screening methods, offers an abundance of pharmacological agents with a potential to become new successful drugs. However, before patients can benefit of newly developed pharmaceuticals, stringent safety filters need to be applied to weed out unfavourable drug candidates. Cost effectiveness and the need to identify compound liabilities, without exposing humans to unnecessary risks, has stimulated the shift of the safety studies to the earliest stages of drug discovery and development. In this regard, in vivo relevant organotypic in vitro models have high potential to revolutionize the preclinical safety testing. They can enable automation of the process, to match the requirements of high-throughput screening approaches, while satisfying ethical considerations. Cultures of primary hepatocytes became already an inherent part of the preclinical pharmaco-toxicological testing battery, yet their routine use, particularly for long-term assays, is limited by the progressive deterioration of liver-specific features. The availability of suitable hepatic and other organ-specific in vitro models is, however, of paramount importance in the light of changing European legal regulations in the field of chemical compounds of different origin, which gradually restrict the use of animal studies for safety assessment, as currently witnessed in cosmetic industry. Fortunately, research groups worldwide spare no effort to establish hepatic in vitro systems. In the present review, both classical and innovative methodologies to stabilize the in vivo-like hepatocyte phenotype in culture of primary hepatocytes are presented and discussed.

Keywords

Drug safety testing In vitro models Primary hepatocyte cultures Dedifferentiation Epigenetics Histone deacetylases DNA methyltransferases Liver-enriched transcription factors MicroRNA