Heterocyclic
amines and
inflammation have been implicated in the etiology of
colon cancer. We have recently demonstrated that during autoxidation of the inflammatory mediator
nitric oxide 2-amino-3-methylimidazo[4,5-f]
quinoline (IQ) undergoes nitrosation to form 2-nitrosoamino-3-methylimidazo[4,5-f]
quinoline (N-NO-IQ). This study evaluates the genotoxicity of N-NO-IQ and compares the adducts it forms to those of 2-hydroxyamino-3-methylimidazo[4,5-f]
quinoline (N-
OH-IQ). N-NO-IQ was incubated with
2'-deoxyguanosine 3'-monophosphate (dGp) under a variety of inflammatory conditions. 32P-Postlabeling demonstrated the presence of multiple adducts. Incubation of N-
OH-IQ with dGp at pH 7.4, 5.5, or 2.0 resulted in the formation of a single major adduct,
N-(deoxyguanosin-8-yl)-IQ (dG-C8-IQ). Using a combination of 32P-postlabeling, HPLC, and nuclease P1 treatment, N-NO-IQ was shown to produce dG-C8-IQ under several different conditions. HOCl oxidation of N-NO-IQ increased dG-C8-IQ formation, and this was further increased as pH decreased from 7.4 to 5.5. Oxidation of N-NO-IQ formed a new adduct, adduct 2, while in the absence of
oxidants adduct m was the major adduct. Adducts 2 and m were not formed by N-
OH-IQ and not further identified. The results demonstrate that N-NO-IQ forms
N-(deoxyguanosin-8-yl)-IQ, is genotoxic, is activated by conditions that mediate inflammatory responses, and is a possible
cancer risk factor for individuals with
colitis,
inflammation of the colon.