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Proc Natl Acad Sci U S A. 2014 Nov 25;111(47):16772-7. doi: 10.1073/pnas.1413481111. Epub 2014 Nov 10.

Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes.

Author information

1
Laboratory of Biochemistry and Molecular Biology; iPS Cell-based Research Project on Hepatic Toxicity and Metabolism, Laboratory of Hepatocyte Regulation, and.
2
Laboratory of Biochemistry and Molecular Biology;
3
Laboratory of Biochemistry and Molecular Biology; Laboratory of Hepatocyte Regulation, and.
4
Laboratory of Applied Environmental Biology.
5
Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Ibaraki 305-8562, Japan;
6
Laboratory of Gene Regulation.
7
Laboratory of Biochemistry and Molecular Biology; Laboratory of Hepatocyte Regulation, and Department of Child Health, and.
8
Laboratory of Biochemistry and Molecular Biology; Laboratory of Regulatory Sciences for Oligonucleotide Therapeutics, Clinical Drug Development Project, and.
9
Department of Child Health, and.
10
Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan; and.
11
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;
12
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.

Abstract

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.

KEYWORDS:

CYP2D6; SNP; hepatocyte; human iPS cells; personalized drug therapy

PMID:
25385620
PMCID:
PMC4250156
DOI:
10.1073/pnas.1413481111
[Indexed for MEDLINE]
Free PMC Article

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