Quantification of three-dimensional structures in liver tissue: bile canalicular and sinusoidal networks

摘要

Unpredicted hepatotoxicity represents the most frequent reason for withdrawal of drugs from the market (Godoy et al., 2013). Therefore, large efforts are currently undertaken to establish improved techniques to predict hepatotoxicity (Shimizu et al., 2009; O’Brien et al., 2006; Okwa et al., 2013; Oloyede et al., 2013; Lu et al., 2013; Godoy et al., 2009). The perhaps most intensive activities in this field of research can be observed in establishment of hepatocyte in vitro systems (Godoy et al., 2013; Hewitt et al., 2007; Ilkavets et al., 2013; Hengstler et al., 2012, 2014; Hammad et al., 2013; Hammad, 2013). One of the concepts of this type of in vitro research is that stress responses to chemicals are similar in vitro and in vivo. Therefore, activation of stress response pathways in vitro may indicate a potential hazard (Jennings, 2013; Vinken et al., 2014). Although hepatocyte in vitro systems have promoted our understanding of mechanisms (Meyer et al., 2011; Schug et al., 2013; Godoy et al., 2010, 2012; Zellmer et al., 2010; Hengstler et al., 2014) it has also become clear that a full replacement of animal experiments for toxicity testing will not be possible within the next one or two decades (Adler et al., 2011; Hammad, 2013). Reasons are difficulties to include xenobiotic metabolism into in vitro tests, to model interactions between cell types, to extrapolate from in vivo doses to in vitro concentrations and to simulate the consequences of long term exposure in vitro (Tice et al., 2013; Ghallab, 2013). However, one additional aspect may currently be underestimated: we still know too little about mechanisms of in vivo toxicity to establish in vitro systems in a way that the most critical in vivo processes are recapitulated. Although this may seem paradoxical, progress in replacement of animal experiments currently depends on progress in understanding the mechanisms of toxicity in vivo.