ABSTRACT
AIMS: Methylamine dichloramine (CH(3)NCl(2)) produced by neutrophils may promote colon tumors and colitis via architectural and oxidative changes in crypts, which are secretory granulae composed of goblet cells located in the colorectal mucosal layer. We investigated whether CH(3)NCl(2), in comparison with the other reactive oxygen species (ROS) such as H(2)O(2) and HOCl, derived from primed neutrophils in inflammatory sites in the large intestine, is a biogenic factor for the induction of colorectal disease in mice. MAIN METHODS: Male ICR-strain mice were administered each oxidant (0.5-0.7 micromol/mouse) by enema under anesthesia. The colorectal tissues were evaluated by histopathological and immunohistochemical analyses. Hemolysis and hemoglobin oxidation by the methylamine chloramines and HOCl were examined by adding them (50-400 microM) to a sheep erythrocyte suspension (1x10(8) cells/ml) and its lysate at pH 7 and 37 degrees C. KEY FINDINGS: CH(3)NCl(2) oxidized erythrocyte hemoglobin more effectively than HOCl, indicating it has high cell permeability and selective oxidation ability. CH(3)NCl(2) mainly induced atrophy of crypts at 6 h after administration, while the other ROS tested did not. Furthermore, 4-hydroxy-2-nonenal (4-HNE) showed positive immunostains throughout the mucosal layer, including around the basal regions of atrophied crypts, only with CH(3)NCl(2), while positive immunostains were observed for 3-nitrotyrosine (3-NT) in the atrophied crypts and their surrounding lamina propria in the mucosal layer. SIGNIFICANCE: The results suggest that CH(3)NCl(2)derived from primed neutrophils may play the most important role in promoting the development of colon tumor formation and colitis by oxidative stress through its high degree of cell permeability.
