The toxicity of troglitazone was detected in human 3D liver cells, but not

to similar extent in human 2D hepatocyte monolayers ( Fig. 4B). We found that rat 2D hepatocytes showed increased toxicity to troglitazone as compared to human 2D hepatocytes ( Fig. 3B) which is in line with previous published data ( Shen et al., 2012 and Toyoda EGFR inhibitor et al., 2001) and in contrast with the species-specific toxicity of this drug found in vivo ( Guo et al., 2006, Li et al., 2002, Shen et al., 2012 and Yokoi, 2010). Several studies have shown that troglitazone can induce cytotoxicity in human hepatocytes ( Kostrubsky et al., 2000 and Lauer et al., 2009). Our data also demonstrated that troglitazone induced trend towards increase in cytotoxicity in human monolayer hepatocytes

( Fig. 4B). In contrast to our findings one study reported higher sensitivity of human hepatocytes to troglitazone compared to rat hepatocytes ( Lauer et al., 2009). In this study only ATP content was measured after 24 h treatment of human hepatocytes with concentration of troglitazone, which kill the cells 50%. The differential toxicity effect of troglitazone observed in human 2D hepatocytes may be due to donor Galunisertib ic50 to donor genetic variability, differences in the quality of the isolated hepatocytes, their seeding densities, etc. Importantly, a clear and significant cytotoxic effect of troglitazone was seen when using human 3D liver cultures ( Fig. 4B). The toxicity results with troglitazone observed in rat and human 3D liver cells are well in line with the toxicity found from in vivo

in rats and in the clinic ( Peters et al., 2005 and Yokoi, 2010) while 2D hepatocytes were not suited to predict these species-specific liver toxicities. Recent study also demonstrated that gel entrapped 3D hepatocytes cultures were able to detect species-specific toxicity of troglitazone in vivo, in contrast to 2D hepatocytes ( Shen et al., 2012). Our data show that the human 3D liver model can recapitulate some of the main events related to troglitazone-induced toxicity such as cell apoptosis, decrease in cell viability and cytotoxicity ( Fig. 6, ( Li et al., 2003, Toyoda et al., 2002 and Zhou et al., 2008). We also studied whether human 3D liver cells will detect toxicity of several drugs known to induce idiosyncratic toxicity in the clinic. Idiosyncratic drug toxicity occurs only in a small proportion of individuals exposed to the drug and it is the most frequent cause of post-marketing warnings and withdrawals (Kaplowitz, 2005) but most in vitro and animal toxicology studies fail to predict the clinical outcome.