title: The niacin required for optimum growth can be synthesized from L-tryptophan in growing mice lacking tryptophan-2,3-dioxygenase.
abstract: In mammals, nicotinamide (Nam) is biosynthesized from l-tryptophan (l-Trp). The enzymes involved in the initial step of the l-Trp→Nam pathway are l-Trp-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO). We aimed to determine whether tdo-knockout (tdo(-/-)) mice fed a diet without preformed niacin can synthesize enough Nam to sustain optimum growth. Wild-type (WT) and tdo(-/-) mice were fed a chemically defined 20% casein diet with or without preformed niacin (30 mg nicotinic acid/kg) for 28 d. Body weight, food intake, and liver NAD concentrations did not differ among the groups. In the groups of mice fed the niacin-free diet, urinary concentrations of the upstream metabolites kynurenine (320% increase, P < 0.0001), kynurenic acid (270% increase, P < 0.0001), xanthurenic acid (770% increase, P < 0.0001), and 3-hydroxyanthranilic acid (3-HA; 450% increase, P < 0.0001) were higher in the tdo(-/-) mice than in the WT mice, while urinary concentrations of the downstream metabolite quinolinic acid (QA; 50% less, P = 0.0010) and the sum of Nam and its catabolites (10% less, P < 0.0001) were lower in the tdo(-/-) mice than in the WT mice. These findings show that the kynurenine formed in extrahepatic tissues by IDO and subsequent enzymes can be metabolized up to 3-HA, but not into QA. However, the tdo(-/-) mice sustained optimum growth even when fed the niacin-free diet for 1 mo, suggesting they can synthesize the minimum necessary amount of Nam from l-Trp, because the liver can import blood kynurenine formed in extrahepatic tissues and metabolize it into Nam via NAD and the resulting Nam is then distributed back into extrahepatic tissues.
authors.affiliation: Department of Food Science and Nutrition, School of Human Cultures, The University of Shiga Prefecture, Hassaka-cho, Hikone, Shiga, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Terakata
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fukuwatari
authors.forename: Eri
authors.initials: E
authors.lastname: Kadota
authors.forename: Mitsue
authors.initials: M
authors.lastname: Sano
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kanai
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Funakoshi
authors.forename: Katsumi
authors.initials: K
authors.lastname: Shibata
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000032:analysis; D000818:Animals; D001835:Body Weight; D004032:Diet; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007736:Kynurenic Acid / Q000652:urine; D007737:Kynurenine / Q000652:urine; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009525:Niacin / Q000008:administration & dosage*; D009536:Niacinamide / Q000096:biosynthesis*; D017378:Quinolinic Acid / Q000652:urine; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014977:Xanthurenates / Q000652:urine
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014977:Xanthurenates; D015095:3-Hydroxyanthranilic Acid; D009536:Niacinamide; D009525:Niacin; D007737:Kynurenine; C028330:xanthurenic acid; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D017378:Quinolinic Acid; D007736:Kynurenic Acid