Differences in the Epigenetic Regulation of Cytochrome P450 Genes between Human Embryonic Stem Cell-Derived Hepatocytes and Primary Hepatocytes

摘要: Human pluripotent stem cell-derived hepatocytes have the potential to provide in vitro model systems for drug discovery and hepatotoxicity testing. However, these cells are currently unsuitable toxicity efficacy testing because of their limited expression genes encoding drug-metabolizing enzymes, especially cytochrome P450 (CYP) enzymes. Transcript levels major CYP were much lower human embryonic (hESC-Hep) than primary (hPH). To verify mechanism underlying this reduced genes, including CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP2E1, we investigated epigenetic regulation terms DNA methylation histone modifications hESC-Hep hPH. CpG islands hypermethylated hESC-Hep, whereas they had an open chromatin structure, as represented by hypomethylation sites permissive modifications, Inhibition methyltransferases (DNMTs) during hepatic maturation induced demethylation CYP1A1 leading up-regulation transcription. Combinatorial inhibition DNMTs deacetylases (HDACs) increased transcript CYP2D6. Our findings suggest that is modulated regulatory factors such HDACs.