Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes.
Interindividual differences in hepatic metabolism, which are mainly due to genetic polymorphism in its gene, have a large influence on individual drug efficacy and adverse reaction. Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells have the potential to predict interindividual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the interindividual difference in hepatic metabolism and drug response. We found that cytochrome P450 (CYP) metabolism capacity and drug responsiveness of the primary human hepatocytes (PHH)-iPS-HLCs were highly correlated with those of PHHs, suggesting that the PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness. We also demonstrated that the interindividual differences, which are due to the diversity of individual SNPs in the CYP gene, could also be reproduced in PHH-iPS-HLCs. We succeeded in establishing, to our knowledge, the first PHH-iPS-HLC panel that reflects the interindividual differences of hepatic drug-metabolizing capacity and drug responsiveness.
Laboratory of Biochemistry and Molecular Biology; iPS Cell-based Research Project on Hepatic Toxicity and Metabolism, Laboratory of Hepatocyte Regulation, and.
Kazuo
K
Takayama
Laboratory of Biochemistry and Molecular Biology;
Yuta
Y
Morisaki
Laboratory of Biochemistry and Molecular Biology;
Shuichi
S
Kuno
Laboratory of Biochemistry and Molecular Biology; Laboratory of Hepatocyte Regulation, and.
Yasuhito
Y
Nagamoto
Laboratory of Applied Environmental Biology.
Kazuo
K
Harada
Laboratory of Biochemistry and Molecular Biology;
Norihisa
N
Furukawa
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Ibaraki 305-8562, Japan;
Manami
M
Ohtaka
Laboratory of Gene Regulation.
Ken
K
Nishimura
Laboratory of Biochemistry and Molecular Biology; Laboratory of Hepatocyte Regulation, and Department of Child Health, and.
Kazuo
K
Imagawa
Laboratory of Biochemistry and Molecular Biology; Laboratory of Regulatory Sciences for Oligonucleotide Therapeutics, Clinical Drug Development Project, and.
Fuminori
F
Sakurai
Laboratory of Biochemistry and Molecular Biology;
Masashi
M
Tachibana
Department of Child Health, and.
Ryo
R
Sumazaki
Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan; and.
Emiko
E
Noguchi
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Ibaraki 305-8562, Japan;
Mahito
M
Nakanishi
Laboratory of Applied Environmental Biology.
Kazumasa
K
Hirata
Laboratory of Stem Cell Regulation, National Institute of Biomedical Innovation, Osaka 567-0085, Japan; Laboratory of Biomedical Innovation, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan;
Kenji
K
Kawabata
Laboratory of Biochemistry and Molecular Biology; iPS Cell-based Research Project on Hepatic Toxicity and Metabolism, Laboratory of Hepatocyte Regulation, and The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan mizuguch@phs.osaka-u.ac.jp.
Hiroyuki
H
Mizuguchi
D002454:Cell Differentiation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005434:Flow Cytometry; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008111:Liver Function Tests
D003577:Cytochrome P-450 Enzyme System
CYP2D6; SNP; hepatocyte; human iPS cells; personalized drug therapy