Organoid-derived intestinal epithelial cells are a suitable model for preclinical toxicology and pharmacokinetic studies

Yu Takahashi; Makoto Noguchi; Yu Inoue; Shintaro Sato; Makoto Shimizu; Hirotatsu Kojima; Takayoshi Okabe; Hiroshi Kiyono; Yoshio Yamauchi; Ryuichiro Sato

doi:10.1016/j.isci.2022.104542

Organoid-derived intestinal epithelial cells are a suitable model for preclinical toxicology and pharmacokinetic studies

iScience. 2022 Jun 7;25(7):104542. doi: 10.1016/j.isci.2022.104542. eCollection 2022 Jul 15.

Authors

Yu Takahashi¹, Makoto Noguchi¹, Yu Inoue¹, Shintaro Sato², Makoto Shimizu³, Hirotatsu Kojima⁴, Takayoshi Okabe⁴, Hiroshi Kiyono⁵, Yoshio Yamauchi¹, Ryuichiro Sato^{1

3

6}

Affiliations

¹ Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
² Mucosal Vaccine Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
³ Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan.
⁴ Drug Discovery Initiative, The University of Tokyo, Tokyo 113-0033, Japan.
⁵ Division of Mucosal Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁶ AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.

Abstract

Intestinal organoids are physiologically relevant tools used for cellular models. However, the suitability of organoids to examine biological functions over existing established cell lines lacks sufficient evidence. Cytochrome P450 3A4 (CYP3A4) induction by pregnane X receptor ligands, glucose uptake via sodium/glucose cotransporter 1, and microsomal triglyceride transfer protein-dependent ApoB-48 secretion, which are critical for human intestinal metabolism, were observed in organoid-derived two-dimensional cells but little in Caco-2 cells. CYP3A4 induction evaluation involved a simplified method of establishing organoids that constitutively expressed a reporter gene. Compound screening identified several anticancer drugs with selective activities toward Caco-2 cells, highlighting their characteristics as cancer cells. Another compound screening revealed a decline in N-(4-hydroxyphenyl)retinamide cytotoxicity upon rifampicin treatment in organoid-derived cells, under CYP3A4-induced conditions. This study shows that organoid-derived intestinal epithelial cells (IECs) possess similar physiological properties as intestinal epithelium and can serve as tools for enhancing the prediction of biological activity in humans.

Keywords: Cell biology; Human metabolism; Stem cells research; Tissue engineering.