Recent Advances in Deriving Hepatocyte Like Cells from Induced Pluripotent Stem Cells in Drug Metabolism and Toxicity Studies

Human induced pluripotent stem cell-derived hepatocytes (hiPSC-hep) hold great promise as an unlimited cell source for metabolism and toxicity testing as well as models for drug targets in drug discovery. However the results from hiPSC-Heps published so far have shown limited drug metabolism functionality thus restricting their use. We recently reported on critical differences in toxicity pathways in hiPSC-hep demonstrating low metabolic capacity as compared with primary human hepatocytes and cell lines limiting the predictive and translational potential of the cells. The metabolic capacity in cells from novel differentiation protocols showed considerably improved metabolic functions. The drug metabolizing activities for the major Cytochrome P450 isoenzymes and the clearance of probe drugs were close to the activities in primary human hepatocytes. The results indicated an intrinsic clearance capacity close to primary human hepatocytes. Induction of CYP enzymes by certain drugs is another important characteristic of the hepatocyte. However, the results indicated a limited response to model inducers of the hiPSC-heps from both sources thus limiting the usefulness of the cells in drug metabolism studies. A detailed analysis of gene expression revealed important differences of metabolic pathways and expression of individual gens in hiPSC-heps, primary human hepatocytes and hepatoma cell lines. These differences will likely have an important impact when considering the application of this technology in drug discovery research.