A novel aromatic mutagen, 5-amino-6-hydroxy-8 H-benzo[6,7]azepino[5,4,3- de]quinolin-7-one (ABAQ), induces colonic preneoplastic lesions in mice

Abstract

The benzoazepinoqunolinone derivative, 5-amino-6-hydroxy-8H-benzo[6,7]azepino[5,4,3-de]quinolin-7-one (ABAQ), which is produced in a mixture of glucose and tryptophan incubated at 37 °C under physiological conditions in the presence or absence of hydroxyl radicals caused by the Fenton reaction, is a novel aromatic mutagen. In the current study, we determined the tumor-initiating potency of ABAQ using an inflammation-relate, two-stage mouse colon carcinogenesis model. Male Crj: CD-1 (ICR) mice were treated with the single intragastric administration (100 or 200 mg/kg body weight) of ABAQ followed by subsequent 1-week oral exposure to 2% dextran sodium sulfate (DSS) in drinking water. The ABAQ treatment alone resulted in high-grade dysplasia, which is a precursor to colorectal cancer, in the colon. Following the administration of DSS after ABAQ treatment, the incidence and frequency of high-grade dysplastic lesions increased; the values were highest in the mice treated with 200 mg/kg body weight of ABAQ followed by DSS. The lesions expressing β-catenin in their nuclei and cytoplasm exhibited high proliferation activity without the expression of programmed cell death 4. These findings indicate that ABAQ has a tumor-initiating activity in the mouse colon, with or without inflammation, although the potential pro-inflammatory effect of high doses of ABAC should be investigated.

Keywords: ABAQ, 5-amino-6-hydroxy-8H-benzo[6,7]azepino[5,4,3-de]quinolin-7-one; AOM, azoxymethane; Benzoazepinoqunolinone; Colon; DSS, dextran sodium sulfate; Dextran sodium sulfate; Fenton reaction; H&E, hematoxylin and eosin; HCA, heterocyclic amine; Heterocyclic amines; High-grade dysplasia; Initiation; Maillard reaction; MeIQx, 2-amino-3,8-dimethylimidazo[4,5-flquinoxaline; Mice; PAH, polycyclic aromatic hydrocarbons; PDCD4; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; i.g, intragastric.

Fig. 1

(a) Chemical structure of ABAQ (ABAQ, C₁₆H₁₁N₃O₂, MW = 277.28). (b) A high-grade colonic dysplasia on H&E-stained section from a mouse in group 2 (200 ppm ABAQ + DSS). Note: Nuclear atypia in the crypts and Paneth's granules (red in color) in the cytoplasm of some dysplastic crypt cells. H&E stain; bar, 50 μm. (c) Many nuclei in the high-grade dysplasia in a serial section from (b) are positive for MCM2. MCM2 immunohistochemistry; bar, 50 μm. (d) Most nuclei in the high-grade dysplasia in a serial section from (b) are negative for PDCD4, whereas the nuclei in the surrounding normal crypts are positive for PDCD4. PDCD4 immunohistochemistry; bar, 50 μm. (e) The cytoplasmic expression of β-catenin is present in the high-grade dysplasia lesion developed in the colon of a mouse from group 2 (200 ppm ABAQ + DSS). Some nuclei are weakly positive for β-catenin. β-Catenin immunohistochemistry; bar, 50 μm. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)