Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1

Yukio Kato, Yoshiyuki Kubo, Daisuke Iwata, Sayaka Kato, Tomohisa Sudo, Tomoko Sugiura, Takashi Kagaya, Tomohiko Wakayama, Akiyoshi Hirayama, Masahiro Sugimoto, Kazushi Sugihara, Shuichi Kaneko, Tomoyoshi Soga, Masahide Asano, Masaru Tonuta, Toshiyuki Matsui, Morimasa Wada, Akira Tsuji

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Purpose. Solute carrier OCTN1 (SLC22A4) is an orphan transporter, the physiologically important substrate of which is still unidentified. The aim of the present study was to examine physiological roles of OCTN1. Methods. We first constructed octn1 gene knockout (octn1-/-) mice. Metabolome analysis was then performed to identify substrates in vivo. The possible association of the substrate identified with diseased conditions was further examined. Results. The metabolome analysis of blood and several organs indicated complete deficiency of a naturally occurring potent antioxidant ergothioneine in octn1-/- mice among 112 metabolites examined. Pharmacokinetic analyses after oral administration revealed, the highest distribution to small intestines and extensive renal reabsorption of [3H]ergothioneine, both of which were much reduced in octn1-/- mice. The octn1 -/- mice exhibited greater susceptibility to intestinal inflammation under the ischemia and reperfusion model. The blood ergothioneine concentration was also much reduced in Japanese patients with Crohn's disease, compared with healthy volunteers and patients with another inflammatory bowel disease, ulcerative colitis. Conclusions. These results indicate that OCTN1 plays a pivotal role for maintenance of systemic and intestinal exposure of ergothioneine, which could be important for protective effects against intestinal tissue injuries, providing a possible diagnostic tool to distinguish the inflammatory bowel diseases.

Original languageEnglish
Pages (from-to)832-840
Number of pages9
JournalPharmaceutical research
Volume27
Issue number5
DOIs
Publication statusPublished - 2010 May

Keywords

  • Crohn's disease
  • Gene knockout
  • Metabolome analysis
  • OCTN1
  • Transporter

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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  • Cite this

    Kato, Y., Kubo, Y., Iwata, D., Kato, S., Sudo, T., Sugiura, T., Kagaya, T., Wakayama, T., Hirayama, A., Sugimoto, M., Sugihara, K., Kaneko, S., Soga, T., Asano, M., Tonuta, M., Matsui, T., Wada, M., & Tsuji, A. (2010). Gene knockout and metabolome analysis of carnitine/organic cation transporter OCTN1. Pharmaceutical research, 27(5), 832-840. https://doi.org/10.1007/s11095-010-0076-z