Pharmaceutical Research

, Volume 27, Issue 5, pp 832–840 | Cite as

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 Tomita
  • Toshiyuki Matsui
  • Morimasa Wada
  • Akira Tsuji
Research Paper

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.

KEY WORDS

Crohn’s disease gene knockout metabolome analysis OCTN1 transporter 

ABBREVIATIONS

CD

Crohn’s disease

CE-TOFMS

capillary electrophoresis time-of-flight mass spectrometry

OCTN

Organic carnitine/organic cation transporter

UC

ulcerative colitis

Supplementary material

11095_2010_76_MOESM1_ESM.doc (308 kb)
Supplementary Table I(DOC 99 kb)
11095_2010_76_MOESM2_ESM.doc (298 kb)
Supplementary Table II(DOC 129 kb)
11095_2010_76_MOESM3_ESM.doc (240 kb)
Supplementary Table III(DOC 210 kb)
11095_2010_76_MOESM4_ESM.pdf (447 kb)
Supplementary Figure 1(PDF 446 kb)
11095_2010_76_MOESM5_ESM.pdf (2 mb)
Supplementary Figure 2(PDF 2058 kb)
11095_2010_76_MOESM6_ESM.pdf (285 kb)
Supplementary Figure 3(PDF 284 kb)

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Yukio Kato
    • 1
  • Yoshiyuki Kubo
    • 1
  • Daisuke Iwata
    • 1
  • Sayaka Kato
    • 1
  • Tomohisa Sudo
    • 1
  • Tomoko Sugiura
    • 1
  • Takashi Kagaya
    • 2
  • Tomohiko Wakayama
    • 3
  • Akiyoshi Hirayama
    • 4
  • Masahiro Sugimoto
    • 4
  • Kazushi Sugihara
    • 5
  • Shuichi Kaneko
    • 2
  • Tomoyoshi Soga
    • 4
  • Masahide Asano
    • 5
  • Masaru Tomita
    • 4
  • Toshiyuki Matsui
    • 6
  • Morimasa Wada
    • 7
  • Akira Tsuji
    • 1
  1. 1.Division of Pharmaceutical Sciences, Graduate School of Natural Science and TechnologyKanazawa UniversityKanazawaJapan
  2. 2.Department of GastroenterologyKanazawa University HospitalKanazawaJapan
  3. 3.Department of Histology and Embryology, Graduate School of Medical ScienceKanazawa UniversityKanazawaJapan
  4. 4.Institute for Advanced BiosciencesKeio UniversityYamagataJapan
  5. 5.Division of Transgenic Animal Science, Advanced Science Research CenterKanazawa UniversityKanazawaJapan
  6. 6.Department of GastroenterologyFukuoka University Chikushi HospitalFukuokaJapan
  7. 7.Division of Molecular Biology, Faculty of Pharmaceutical SciencesNagasaki International UniversityNagasakiJapan

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