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Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

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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.

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Abbreviations

CD:

Crohn’s disease

CE-TOFMS:

capillary electrophoresis time-of-flight mass spectrometry

OCTN:

Organic carnitine/organic cation transporter

UC:

ulcerative colitis

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ACKNOWLEDGEMENTS

We thank Lica Ishida, Kazuhiro Suzuki and Ryutaro Matsuhashi for technical assistance in Kanazawa University. We also thank Maki Sugawara and Naoko Toki for technical assistance in Keio University. We thank Prof. Shoichi Iseki in Kanazawa University for fruitful discussion. This study was supported in part by a Grant-in-Aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan, and a grant from the Mochida Memorial Foundation (Tokyo, Japan) for Medical and Pharmaceutical Research.

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, 920-1192, Japan

    Yukio Kato, Yoshiyuki Kubo, Daisuke Iwata, Sayaka Kato, Tomohisa Sudo, Tomoko Sugiura & Akira Tsuji

  2. Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, 920-0934, Japan

    Takashi Kagaya & Shuichi Kaneko

  3. Department of Histology and Embryology, Graduate School of Medical Science, Kanazawa University, Kanazawa, 920-0934, Japan

    Tomohiko Wakayama

  4. Institute for Advanced Biosciences, Keio University, Yamagata, 997-0035, Japan

    Akiyoshi Hirayama, Masahiro Sugimoto, Tomoyoshi Soga & Masaru Tomita

  5. Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, 920-0934, Japan

    Kazushi Sugihara & Masahide Asano

  6. Department of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, 818-8502, Japan

    Toshiyuki Matsui

  7. Division of Molecular Biology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Nagasaki, 859-3298, Japan

    Morimasa Wada

Authors
  1. Yukio Kato
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  2. Yoshiyuki Kubo
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  3. Daisuke Iwata
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  4. Sayaka Kato
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  6. Tomoko Sugiura
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  7. Takashi Kagaya
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  8. Tomohiko Wakayama
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  11. Kazushi Sugihara
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  13. Tomoyoshi Soga
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  14. Masahide Asano
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  15. Masaru Tomita
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  16. Toshiyuki Matsui
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  17. Morimasa Wada
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  18. Akira Tsuji
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Corresponding author

Correspondence to Akira Tsuji.

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Supplementary Table II

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Kato, Y., Kubo, Y., Iwata, D. et al. Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1. Pharm Res 27, 832–840 (2010). https://doi.org/10.1007/s11095-010-0076-z

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  • DOI: https://doi.org/10.1007/s11095-010-0076-z

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