Liver in the development of new drugs

The liver is considered a very important organ in the development of new drugs




The liver is considered a very important organ in the development of new drugs, since xenobiotics metabolism is one of the major functions of the liver. The hepatocyte-like cells derived from pluripotent stem cells are considered as potential models for drug screening, but they have limitations in that the drug metabolizing function is not complete as compared with the primary hepatocytes and the polarity of these cells is lost during cell culture. According to previous study, dedifferentiation of hepatocytes occurs in the culture due to the activation of signaling pathways associated with Epithelial-mesenchymal transition (EMT). Meanwhile many researches already show that Aurora-A kinase (Aur-A) is one of the important factors which can promote EMT and its inhibitors suppress EMT in many cell types. In this study, we treated several aurora kinase inhibitors to hepatoblast stage cells to induction of polarized hepatocytes.

As a result we found that phthalazinone pyrazole (PP) developed as Aur-A selective inhibitor induce differentiation into polarized hepatocytes. These cells also show higher expression of drug metabolizing enzyme genes, increased functional abilities, enhanced hepatocyte proliferation and less EMT marker expression compare with DMSO control. Our investigations further revealed that these results are mediated though not only inhibition of Aur-A but also downregulation of Snail by suppression of AKT pathway and enhanced expression of HNF4α. Over all, these findings provide insights into hepatocyte differentiation, suggesting that Aur-A and AKT inhibition in hepatoblast cells may drive differentiation into the polarized hepatocytes.