A comparison of hepato-cellular in vitro platforms to study CYP3A4 induction

Beyza Bulutoglu, Camilo Rey-Bedón, Safak Mert, Lipeng Tian, Yoon Young Jang, Martin L. Yarmush, O. Berk Usta

Research output: Contribution to journalArticle

Abstract

In vitro studies of drug toxicity and drug-drug interactions are crucial for drug development efforts. Currently, the utilization of primary human hepatocytes (PHHs) is the de facto standard for this purpose, due to their functional xenobiotic response and drug metabolizing CYP450 enzyme metabolism. However, PHHs are scarce, expensive, require laborious maintenance, and exhibit lot-to-lot heterogeneity. Alternative human in vitro platforms include hepatic cell lines, which are easy to access and maintain, and induced pluripotent stem cell (iPSC) derived hepatocytes. In this study, we provide a direct comparison of drug induced CYP3A4 and PXR expression levels of PHHs, hepatic cell lines Huh7 and HepG2, and iPSC derived hepatocyte like cells. Confluently cultured Huh7s exhibited an improved CYP3A4 expression and were inducible by up to 4.9-fold, and hepatocytes differentiated from human iPSCs displayed a 3.3-fold CYP3A4 induction. In addition, an increase in PXR expression levels was observed in both hepatic cell lines and iPSC derived hepatocytes upon rifampicin treatment, whereas a reproducible increase in PXR expression was not achieved in PHHs. Our results indicate that both hepatoma originated cell lines and iPSCs may provide alternative sources to primary hepatocytes, providing reliable and reproducible results for CYP3A4/PXR metabolism, upon in vitro maturation. This study may serve as a guide for the selection of suitable and feasible in vitro platforms for drug-drug interaction and toxicology studies.

Original languageEnglish (US)
Article numbere0229106
JournalPloS one
Volume15
Issue number2
DOIs
StatePublished - Jan 1 2020

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Bulutoglu, B., Rey-Bedón, C., Mert, S., Tian, L., Jang, Y. Y., Yarmush, M. L., & Berk Usta, O. (2020). A comparison of hepato-cellular in vitro platforms to study CYP3A4 induction. PloS one, 15(2), [e0229106]. https://doi.org/10.1371/journal.pone.0229106