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2014-11-11

A group of researchers led by MIZUGUCHI Hiroyuki, Professor, Graduate School of Pharmaceutical Sciences, Osaka University, succeeded in making hepatocyte-like cells (HLCs), differentiated from human induced pluripotent stem (iPS) cells, that reflected interindividual differences in drug metabolism capacity and drug response and then, by making use of those cells, in developing a basic technique for predicting such differences.

There are major interindividual differences in drug metabolism capacity and degrees of hepatotoxicity. Thus, in the development of drugs, it is quite difficult to predict the risk for different individuals of hepatotoxicity caused by a particular drug. In this research, HLCs differentiated from human iPS cells were used because, it was theorized, they could be used for assisting with drug therapy based on an individual's genetic makeup and toxic assessment. This research was undertaken because it had not been clarified whether HLCs differentiated from human iPS cells reflected interindividual differences in drug metabolism capacity and drug response.

Thus, this group made primary human hepatocytes–human induced pluripotent stem cells–hepatocyte-like cells (PHH-iPS-HLCs) and studied them. Making use of such cells, interindividual differences in drug metabolism capacity and drug response in primary human hepatocytes were observed. This finding suggests that drug metabolism capacity in hepatic cells of an individual can be predicted by measuring the drug metabolism capacity in HLCs matching the individual's profile. Their findings also indicate that it is possible to predict response to drugs by one's hepatic cells by examining his or her response to drugs in HLCs differentiated from human iPS cells.

Furthermore, this group made human HLCs differentiated from human iPS cells from primary human hepatocytes (PHH-iPS-HLCs) that had Single Nucleotide Polymorphisms (SNPs) which deactivated the activity of drug-metabolizing enzyme CYP2D6. Using these human HLCs differentiated from human iPS cells, this group studied whether the deactivation of CYP2D5 could be reproduced and found that CYP2D6 was deactivated in PHH-iPS-HLCs that had SNPs.

These results suggest that HLCs differentiated from human iPS cells demonstrate drug metabolism capacity and drug response that reflect SNP information in one's drug-metabolizing enzyme. In other words, using this iPS cell technique will enable stable supply of hepatic cells possessing predictable drug-metabolizing enzyme activity, thereby leading to more precise hepatotoxicity assessment systems.

Abstract

Inter-individual 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 inter-individual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the inter-individual 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 inter-individual 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 inter-individual differences of hepatic drug-metabolizing capacity and drug responsiveness.

Significance

We found that individual cytochrome P450 (CYP) metabolism capacity and drug sensitivity could be predicted by examining them in the primary human hepatocytes–human induced pluripotent stem cells–hepatocyte-like cells (PHH-iPS-HLCs). We also confirmed that inter-individual differences of CYP metabolism capacity and drug responsiveness that are due to the diversity of individual single nucleotide polymorphisms in the CYP gene could also be reproduced in the PHH-iPS-HLCs. These findings suggest that inter-individual differences in drug metabolism capacity and drug response could be predicted by using HLCs differentiated from human iPS cells. We believe that iPS-HLCs would be a powerful technology not only for accurate and efficient drug development, but also for personalized drug therapy.

 

CYP metabolism capacity and drug responsiveness of the PHH-iPS-HLCs were highly correlated with those of genetically identical PHHs. PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness.

 

Because hepatocytes of CYP2D6 poor metabolizer are difficult to obtain, drug discovery using such hepatocytes has not been performed. In the present study, HLCs were generated from human iPSCs which had been established from donors with poor or extensive metabolizer genotype for CYP2D6.
Inter-individual differences of CYP metabolism capacity and drug responsiveness which are due to the diversity of individual SNP in CYP2D6 gene could be also reproduced in the PHH-iPS-HLCs.

 

To learn more about this research, please view the full research report entitled "Prediction of inter-individual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes" at this page of the Proceedings of the National Academy of Sciences of the United States of America website.



Related Link

Lab. of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences

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