TY - JOUR T1 - Modeling of hepatic drug metabolism and responses in CYP2C19 poor metabolizer using genetically manipulated human iPS cells JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.119.086322 SP - dmd.119.086322 AU - Sayaka Deguchi AU - Tomoki Yamashita AU - Keisuke Igai AU - Kazuo Harada AU - Yukiko Toba AU - Kazumasa Hirata AU - Kazuo Takayama AU - Hiroyuki Mizuguchi Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/04/08/dmd.119.086322.abstract N2 - Cytochrome P450 family 2 subfamily C member 19 (CYP2C19), in liver, plays important roles in terms of drug metabolism. It is known that CYP2C19 poor metabolizers (PMs) lack CYP2C19 metabolic capacity. Thus, unexpected drug-induced liver injury or decrease of drug efficacy would be caused in CYP2C19 substrate-treated CYP2C19 PMs. However, it is difficult to evaluate the safety and effectiveness of drugs and candidate compounds for CYP2C19 PMs because there is currently no model for this phenotype. Here, using human iPS cells and our highly efficient genome editing and hepatocyte differentiation technologies, we generated CYP2C19-knockout human iPS cell-derived hepatocyte-like cells (CYP2C19-KO HLCs) as a novel CYP2C19 PM model for drug development and research. The gene expression levels of hepatocyte markers were similar between WT HLCs and CYP2C19-KO HLCs, suggesting that CYP2C19 deficiency did not affect the hepatic differentiation potency. We also examined CYP2C19 metabolic activity by measuring S-mephenytoin metabolites using LC-MS. The CYP2C19 metabolic activity was almost eliminated by CYP2C19 knockout. Additionally, we evaluated whether clopidogrel (CYP2C19 substrate)-induced liver toxicity could be predicted using our model. Unexpectedly, there was no significant difference in cell viability between clopidogrel-treated WT HLCs and CYP2C19-KO HLCs. However, the cell viability in clopidogrel- and ketoconazole (CYP3A4 inhibitor)-treated CYP2C19-KO HLCs was significantly enhanced as compared with that in clopidogrel- and DMSO-treated CYP2C19-KO HLCs. This result suggests that CYP2C19-KO HLCs can predict the clopidogrel-induced liver toxicity. We succeeded in generating CYP2C19 PM model cells using human iPS cells and genome editing technologies for pharmaceutical research. ER -