Modeling of drug-mediated CYP3A4 induction by using human iPS cell-derived enterocyte-like cells

Biochem Biophys Res Commun. 2016 Apr 15;472(4):631-6. doi: 10.1016/j.bbrc.2016.03.012. Epub 2016 Mar 8.

Abstract

Many drugs have potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4), in small intestinal enterocytes. Therefore, a model that can accurately evaluate drug-mediated CYP3A4 induction is urgently needed. In this study, we overlaid Matrigel on the human induced pluripotent stem cells-derived enterocyte-like cells (hiPS-ELCs) to generate the mature hiPS-ELCs that could be applied to drug-mediated CYP3A4 induction test. By overlaying Matrigel in the maturation process of enterocyte-like cells, the gene expression levels of intestinal markers (VILLIN, sucrase-isomaltase, intestine-specific homeobox, caudal type homeobox 2, and intestinal fatty acid-binding protein) were enhanced suggesting that the enterocyte-like cells were maturated by Matrigel overlay. The percentage of VILLIN-positive cells in the hiPS-ELCs found to be approximately 55.6%. To examine the CYP3A4 induction potential, the hiPS-ELCs were treated with various drugs. Treatment with dexamethasone, phenobarbital, rifampicin, or 1α,25-dihydroxyvitamin D3 resulted in 5.8-fold, 13.4-fold, 9.8-fold, or 95.0-fold induction of CYP3A4 expression relative to that in the untreated controls, respectively. These results suggest that our hiPS-ELCs would be a useful model for CYP3A4 induction test.

Keywords: CYP3A4 induction; Enterocyte-like cells; Human iPS cells; Nuclear receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Cell Culture Techniques* / methods
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • Cytochrome P-450 CYP3A / metabolism*
  • Drug Evaluation, Preclinical* / methods
  • Enterocytes / drug effects*
  • Enterocytes / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Induced Pluripotent Stem Cells / metabolism
  • Transcriptome

Substances

  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human