title: Component of Caramel Food Coloring, THI, Causes Lymphopenia Indirectly via a Key Metabolic Intermediate.
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.
authors.affiliation: 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.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ohtoyo
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Machinaga
authors.affiliation: Psychiatric & Neurological Disease Field, Asubio Pharma Co., Ltd., Kobe 650-0047, Japan.
authors.forename: Ryotaku
authors.initials: R
authors.lastname: Inoue
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Katsunobu
authors.initials: K
authors.lastname: Hagihara
authors.affiliation: Oncology Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yuita
authors.affiliation: New Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Tamura
authors.affiliation: New Modality Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Chiba
authors.affiliation: Project Management Department, Kitasato Daiichi Sankyo Vaccine Co., Ltd., Kitamoto 364-0026, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Muro
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
authors.affiliation: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 134-8630, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.affiliation: Biological Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo 134-8630, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kita
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nagasaki
authors.affiliation: Frontier Research Laboratories, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Takaichi
authors.initials: T
authors.lastname: Shimozato
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005505:Food Coloring Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008231:Lymphopenia / Q000139:chemically induced* / Q000378:metabolism*; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000624391:1-(4(5)-(hydroxymethyl)-1H-imidazole-2-yl)ethanone; D005505:Food Coloring Agents; D007093:Imidazoles; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; C049929:2-acetyl-4(5)-tetrahydroxybutylimidazole; D013110:Sphingosine