2. Academic Validation
  3. Component of Caramel Food Coloring, THI, Causes Lymphopenia Indirectly via a Key Metabolic Intermediate

Component of Caramel Food Coloring, THI, Causes Lymphopenia Indirectly via a Key Metabolic Intermediate

  • Cell Chem Biol. 2016 May 19;23(5):555-560. doi: 10.1016/j.chembiol.2016.04.007.
Mamoru Ohtoyo 1,  Nobuo Machinaga 2,  Ryotaku Inoue 3,  Katsunobu Hagihara 4,  Hiroshi Yuita 5,  Masakazu Tamura 6,  Ryuji Hashimoto 6,  Jun Chiba 2,  Fumihito Muro 7,  Jun Watanabe 2,  Yoshimasa Kobayashi 8,  Koji Abe 4,  Yasuo Kita 9,  Miyuki Nagasaki 10,  Takaichi Shimozato 10
Affiliations

Affiliations

  • 1 New Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: otoyo.mamoru.v7@daiichisankyo.co.jp.
  • 2 Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
  • 3 Psychiatric & Neurological Disease Field, Asubio Pharma Co., Ltd., Kobe 650-0047, Japan.
  • 4 Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
  • 5 Oncology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
  • 6 New Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 7 Project Management Department, Kitasato Daiichi Sankyo Vaccine Co., Ltd., Kitamoto 364-0026, Japan.
  • 8 Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan.
  • 9 Biological Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo 134-8630, Japan.
  • 10 Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
PMID: 27185637 DOI: 10.1016/j.chembiol.2016.04.007
Abstract

Caramel color is widely used in the food industry, and its many variations are generally considered to be safe. It has been known for a long time that THI (2-acetyl-4-(tetrahydroxybutyl)imidazole), a component of caramel color III, causes lymphopenia in Animals through sphingosine 1-phosphate (S1P) lyase (S1PL) inhibition. However, this mechanism of action has not been fully validated because THI does not inhibit S1PL in vitro. To reconcile this situation, we examined molecular details of THI mechanism of action using "smaller" THI derivatives. We identified a bioactive derivative, A6770, which has the same lymphopenic effect as THI via S1PL inhibition. In the case of A6770 we observe this effect both in vitro and in vivo, and demonstrate that A6770 is phosphorylated and inhibits S1PL in the same way as 4-deoxypyridoxine. In addition, A6770 was detected in rat plasma following oral administration of THI, suggesting that A6770 is a key metabolic intermediate of THI.

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