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

• Published in: Pharmaceutical research Vol. 27; no. 5; pp. 832 - 840
• Main Authors: Kato, Yukio, Kubo, Yoshiyuki, Iwata, Daisuke, Kato, Sayaka, Sudo, Tomohisa, Sugiura, Tomoko, Kagaya, Takashi, Wakayama, Tomohiko, Hirayama, Akiyoshi, Sugimoto, Masahiro, Sugihara, Kazushi, Kaneko, Shuichi, Soga, Tomoyoshi, Asano, Masahide, Tomita, Masaru, Matsui, Toshiyuki, Wada, Morimasa, Tsuji, Akira
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.05.2010; Springer US; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Animals; Antioxidants - metabolism; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blotting, Southern; Blotting, Western; Carrier Proteins - genetics; Carrier Proteins - metabolism; Chemical compounds; Chromatography, High Pressure Liquid; Crohn Disease - genetics; Crohn Disease - metabolism; Crohns disease; Ergothioneine - blood; Ergothioneine - pharmacokinetics; Female; General pharmacology; Genetic engineering; Genotype; Humans; Intestinal Absorption - genetics; Intestinal Absorption - physiology; Intestines - blood supply; Ischemia - pathology; Japan; Male; Medical Law; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolites; Metabolomics; Mice; Mice, Knockout; Microvilli - metabolism; Middle Aged; Molecular biology; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Oxidative Stress - physiology; Pharmaceutical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Reperfusion Injury - pathology; Research Paper; Spectrophotometry, Ultraviolet; Young Adult; Japan; gene knockout; metabolome analysis; OCTN1; transporter; Crohn’s disease; Organic cation transporter; Pharmaceutical technology; Crohn's disease; Inflammatory disease; Carnitine; Crohn disease; Gene; Aminoacid; Genetics; Digestive diseases; Intestinal disease; Carrier protein
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-010-0076-z

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.