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Research ArticleArticle

In Vivo Gene Expression Profile of Human Intestinal Epithelial Cells: From the Viewpoint of Drug Metabolism and Pharmacokinetics

Kazuo Takayama, Kohei Ito, Akiko Matsui, Tomoki Yamashita, Kentaro Kawakami, Daisuke Hirayama, Wataru Kishimoto, Hiroshi Nakase and Hiroyuki Mizuguchi
Drug Metabolism and Disposition March 2021, 49 (3) 221-232; DOI: https://doi.org/10.1124/dmd.120.000283
Kazuo Takayama
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Kohei Ito
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Akiko Matsui
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Tomoki Yamashita
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Kentaro Kawakami
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Daisuke Hirayama
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Wataru Kishimoto
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Hiroshi Nakase
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Hiroyuki Mizuguchi
Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan (K.T., T.Y., H.M.); Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan (K.T., H.M.); Department of Pharmacokinetics and Nonclinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (K.I., A.M., W.K.); Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan (K.K., D.H., H.N.); and Global Center for Medical Engineering and Informatics (H.M.) and Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) (H.M.), Osaka University, Osaka, Japan
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Abstract

Orally administered drugs are absorbed and metabolized in the intestine. To accurately predict pharmacokinetics in the intestine, it is essential to understand the intestinal expression profiles of the genes related to drug absorption, distribution, metabolism, and excretion (ADME). However, in many previous studies, gene expression analysis in the intestine has been carried out using specimens from patients with cancer. In this study, to obtain more accurate gene expression profiles, biopsy samples were collected under endoscopic observation from the noninflammatory regions of 14 patients with inflammatory bowel disease, and RNA-seq analysis was performed. Gene expression analysis of drug-metabolizing enzymes (cytochromes P450), non–cytochrome P450 enzymes, nuclear receptors, drug-conjugating enzymes (UDP-glucuronosyltransferases and sulfotransferases), and apical and basolateral drug transporters was performed in biopsy samples from the duodenum, ileum, colon, and rectum. The proportions of the cytochromes P450 expressed in the ileum were 25% (CYP3A4), 19% (CYP2C18), and 14% (CYP3A5). CYP3A4 and CYP2C19 were highly expressed in the duodenum and ileum, but not in the colon and rectum. In the ileum, apical transporters such as P-gp, peptide transporter 1, breast cancer resistance protein, MRP2, and ASBT were strongly expressed, and the expression levels of P-gp and ASBT in the ileum were higher than those in other regions. In the ileum, basolateral transporters such as OSTα, OSTβ, and MRP3 were strongly expressed. We succeeded in obtaining gene expression profiles of ADME-related genes in human intestinal epithelial cells in vivo. We expect that this information would be useful for accurate prediction of the pharmacokinetics of oral drugs.

SIGNIFICANCE STATEMENT To obtain gene expression profiles of ADME-related genes in human intestinal epithelial cells in vivo, biopsy samples were collected under endoscopic observation from the noninflammatory regions of 14 patients with inflammatory bowel disease, and RNA-seq analysis was performed. Gene expression profiles of drug-metabolizing enzymes (cytochromes P450), non–cytochrome P450 enzymes, nuclear receptors, drug-conjugating enzymes (UDP-glucuronosyltransferases and sulfotransferases), and apical and basolateral drug transporters in biopsy samples from the duodenum, ileum, colon, and rectum were obtained in this study.

Footnotes

    • Received October 13, 2020.
    • Accepted December 12, 2020.
  • This research is supported by the grants from JSPS KAKENHI [Grants 18H05033, 18H05373].

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/dmd.120.000283.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 49 (3)
Drug Metabolism and Disposition
Vol. 49, Issue 3
1 Mar 2021
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Research ArticleArticle

Gene Expression Profile of Human Intestinal Epithelial Cells

Kazuo Takayama, Kohei Ito, Akiko Matsui, Tomoki Yamashita, Kentaro Kawakami, Daisuke Hirayama, Wataru Kishimoto, Hiroshi Nakase and Hiroyuki Mizuguchi
Drug Metabolism and Disposition March 1, 2021, 49 (3) 221-232; DOI: https://doi.org/10.1124/dmd.120.000283

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Research ArticleArticle

Gene Expression Profile of Human Intestinal Epithelial Cells

Kazuo Takayama, Kohei Ito, Akiko Matsui, Tomoki Yamashita, Kentaro Kawakami, Daisuke Hirayama, Wataru Kishimoto, Hiroshi Nakase and Hiroyuki Mizuguchi
Drug Metabolism and Disposition March 1, 2021, 49 (3) 221-232; DOI: https://doi.org/10.1124/dmd.120.000283
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