AsianScientist (Nov. 12, 2014) – Using liver-like cells derived from induced pluripotent stem (iPS) cells, researchers are now able to predict an individual’s sensitivity to drugs. This research has been published in the Proceedings of the National Academy of Science.
Many promising drugs have been pulled off the market due to their adverse effects on the liver. Although liver cell lines have been used to screen new pharmacological agents, they do not fully capture the genetic diversity of human populations. In particular, differences in the cytochrome P450 family of enzymes are known to have profound effects on the efficacy and adverse reaction to drugs.
One approach to testing the effect of genetic variations on drug response would be to use iPS cells to reproduce the genetic diversity of human populations. However, it is not known whether iPS-derived cells would accurately reflect the responses of the cells they were obtained from.
To test the feasiblity of using iPS-derived cells as a drug screening tool, researchers led by Professor Hiroyuki Mizuguchia from Osaka University generated liver-like cells from iPS cells and compared their response with primary hepatocytes obtained from human donors.
They found that the iPS-derived hepatocytes retained the drug metabolism and responsiveness of the donor cells. In particular, the activity levels of the cytochrome P450 enzymes CYP1A2, CYP2C9 and CYP3A4 in iPS-derived cells were found to be approximately 60 percent that of primary hepatocytes. However, the ability to induce CYP genes was only weakly correlated, suggesting that non-genetic factors could also be at play.
Nonetheless, the authors showed that iPS-derived hepatocytes were able to reproduce small-nucleotide polymorphisms in the CYP2D6 gene known to be important in the response to drugs such as the breast cancer drug tamoxifen.
The researchers hope that iPS-derived hepatocytes will not only be useful for drug screening, but also be used to develop personalized drug treatments.
The article can be found at: Takayama et al. (2014) Prediction of Interindividual Differences in Hepatic Functions and Drug Sensitivity by Using Human iPS-derived Hepatocytes.
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