, 2010 and Pradere

et al., 2010). Thus, we suggest that 3D liver cell cultures represents more closely in vivo cell responses to LPS during inflammation and would be a better in vitro model then monolayer hepatocyte cultures in inflammation studies. The 3D liver co-cultures were used to detect species differences in response to drugs with known hepatotoxic profiles in rodents and man, such as fenofibrate and troglitazone. Fenofibrate is a PPARα agonist that belongs to the fibrate class of drugs that have been widely used to treat patients with atherogenic dyslipidemia. Fenofibrate has been shown in rodents to cause liver toxicity, oxidative stress, peroxisome proliferation Y-27632 order and hepatocarcinogenesis ( Cattley et al., 1998, Ohta et al., 2009 and Peters et al., 2005). Importantly, fenofibrate-induced hepatotoxicity NU7441 in rodents could not be recapitulated in rat 2D hepatocyte cultures upon treatment for 1–2 days ( Fig. 4A, ( Guo et al., 2007)). In fact published data support the important role of NPC in facilitating a response of hepatocytes to peroxisome proliferators such as fenofibrate ( Hasmall et al., 2001). In humans, the clinical use of fenofibrate is generally regarded as safe and there are no reports of hepatotoxicity or hepatocarcinogenesis ( Hottelart et al., 2002, Ohta et al., 2009 and Peters et al., 2005).

Indeed, a number of experimental observations suggest that there are species differences between rodents and humans in the response to PPARα agonists, including differences in receptor expression and activation, peroxisome proliferation, changes in cell proliferation and/or apoptosis, and induction of target genes (

Escher and Wahli, 2000 and Peters et al., 2005). Multiple factors may be involved in fenofibrate-induced liver toxicity, including the activation of Kupffer cells which secrete Gemcitabine mitogenic cytokines ( Roberts et al., 2007) and the increase expression of acyl-CoA oxidase (ACO) associated with generation of intracellular hydrogen peroxide, leading to oxidative stress, generation of lipid peroxides or free radicals that damage DNA and proteins ( Bolton et al., 2000 and Peters et al., 2005). We found that pharmacologically relevant concentrations of fenofibrate after 15 days of chronic treatment induced cytotoxicity and a decrease in cell viability in rat 3D liver cultures, but not in similarly treated human 3D liver cultures ( Fig. 4A). These results demonstrated that the 3D liver cells could detect the species-specific differences of fenofibrate-induced toxicity at very low concentrations including human Cmax. The delayed toxicity response of the cells to fenofibrate indicates that the activation of the mechanisms mediating this drug-induced toxicity require prolonged exposure.