Primary Hepatocytes: Current Understanding of the Regulation of Metabolic Enzymes and Transporter Proteins, and Pharmaceutical Practice for the Use of Hepatocytes in Metabolism, Enzyme Induction, Transporter, Clearance, and Hepatotoxicity Studies

Abstract

This review brings you up-to-date with the hepatocyte research on: 1) in vitro-in vivo correlations of metabolism and clearance; 2) CYP enzyme induction, regulation, and cross-talk using human hepatocytes and hepatocyte-like cell lines; 3) the function and regulation of hepatic transporters and models used to elucidate their role in drug clearance; 4) mechanisms and examples of idiosyncratic and intrinsic hepatotoxicity; and 5) alternative cell systems to primary human hepatocytes. We also report pharmaceutical perspectives of these topics and compare methods and interpretations for the drug development process.

Highlight report: perspectives in stem cell research—unbiased quantification of the similarity between in vitro generated and primary hepatocytes

“…Primary human cells still represent a gold standard in toxicological research (Heise et al 2012;Ghallab 2013Ghallab , 2014a. However, their use is hampered by difficult availability (Hewitt et al 2007;Hengstler et al 2000). Theoretically, stem cells offer a possibility to overcome this limitation.…”

Highlight report: towards the replacement of in vivo repeated dose systemic toxicity testing

“…It is also well established that induction or inhibition of detoxifying enzymes (Gebhardt et al 2003;Hengstler et al 2000;Hewitt et al 2007) or protective factors (Ilowski et al 2010(Ilowski et al , 2011 plays an important role in repeated dose toxicity. Moreover, much progress has been achieved in physiologically based toxicokinetic modelling to predict relevant concentrations for in vitro testing (Mielke et al 2011).…”

Selenium: an element with two faces

“…The reason was consumption of plants containing high levels of selenium. Symptoms of selenosis in humans are similar to those observed in the horses of Fort Randall: fatigue, hair loss, gastrointestinal symptoms, liver damage, and neurological and CNS symptoms, including aggressiveness.Selenium (Brozmanová et al 2010;Valdiglesias et al 2010; Grotto et al 2009a, b) and oxidative as well as antioxidative mechanisms in general (Bolt and Hengstler 2010;Nishimura et al 2010;Cederbaum et al 2009; Grotto et al 2009a, b;Hewitt et al 2007;Wang et al 2009;Glahn et al 2008) represent cutting-edge topics in toxicology. Therefore, the editors are pleased that Cristina W Nogueira and Joao BT Rocha from Santa Maria University in Brazil have accepted our invitation to contribute a comprehensive review on the pharmacology and toxicology of selenium and organoselenium compounds (Nogueira and Rocha 2011).…”