title: In vivo genotoxicity of a novel heterocyclic amine, aminobenzoazepinoquinolinone-derivative (ABAQ), produced by the Maillard reaction between glucose and l-tryptophan.
abstract: We recently demonstrated that a novel heterocyclic amine, 5-amino-6-hydroxy-8H-benzo[6,7]azepino[5,4,3-de]quinolin-7-one (ABAQ), is produced from glucose and l-tryptophan by the Maillard reaction at physiological temperature and pH, and that ABAQ was strongly mutagenic for Salmonella strains in the presence of S9 mix. Here, we present the results of three in vivo genotoxicity assays of ABAQ. The comet assay revealed that DNA damage was significantly increased in the livers, kidneys, lungs, and bone marrows of ICR mice, 3h after i.p. injection of ABAQ (50mg/kg body weight (bw)). To evaluate clastogenicity, the peripheral blood micronucleus test was performed, also in ICR mice. ABAQ induced micronucleated reticulocytes (MNRETs) in a dose-dependent manner; the frequency of MNRETs was significantly elevated at all i.p. doses (12.5, 25, and 50mg/kg bw) after 48h. To investigate the mutagenicity of ABAQ in vivo, gpt delta transgenic mice were treated with five consecutive administrations of ABAQ by gavage at doses of 25 or 50mg/kg per week for 3 weeks. The frequencies of gpt mutations (MF) in the liver of mice increased significantly compared with controls, in a dose-dependent manner. No significant increase of gpt MF was detected in the kidneys. Base substitutions predominated; both G:C→A:T and A:T→C:G mutations were significantly increased by ABAQ. The Spi(-) MF was also significantly increased in the liver after ABAQ treatment. If formed in vivo, ABAQ may give rise to adverse genotoxic effects.
authors: Division of Cancer Development System, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. Electronic address: ytotsuka@ncc.go.jp.
authors: Yukari
authors: Y
authors: Totsuka
authors: Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan.
authors: Tetsushi
authors: T
authors: Watanabe
authors: Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan.
authors: Souleymane
authors: S
authors: Coulibaly
authors: Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan.
authors: Sae
authors: S
authors: Kobayashi
authors: Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan.
authors: Marina
authors: M
authors: Nishizaki
authors: Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan.
authors: Miho
authors: M
authors: Okazaki
authors: Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan.
authors: Tomohiro
authors: T
authors: Hasei
authors: Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, Yada, Shizuoka, Japan.
authors: Keiji
authors: K
authors: Wakabayashi
authors: Division of Cancer Development System, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors: Hitoshi
authors: H
authors: Nakagama
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000737:chemistry / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D020552:Comet Assay; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics; D005947:Glucose / Q000737:chemistry; D006912:Hydroxyquinolines / Q000737:chemistry / Q000633:toxicity*; D007093:Imidazoles / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D015416:Maillard Reaction; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D015162:Micronucleus Tests; D015394:Molecular Structure; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D009154:Mutation / Q000187:drug effects; D010430:Pentosyltransferases / Q000235:genetics; D014364:Tryptophan / Q000737:chemistry; D014764:Viral Proteins / Q000235:genetics
chemical_list: C545879:5-amino-6-hydroxy-8H-benzo(6,7)azepino(5,4,3-de)quinolin-7-one; D001552:Benzazepines; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D006912:Hydroxyquinolines; D007093:Imidazoles; D009153:Mutagens; D014764:Viral Proteins; C065410:gam protein, Coliphage; D014364:Tryptophan; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D010430:Pentosyltransferases; C071962:Gpt protein, E coli; D005947:Glucose
keywords: Comet assay; Diabetes mellitus (DM); Maillard reaction product; Micronucleated erythrocytes; gpt delta transgenic mice