title: 2-Nitrosoamino-3-methylimidazo[4,5-f]quinoline activated by the inflammatory response forms nucleotide adducts.
abstract: 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.
authors.affiliation: VA Medical Center, and Division of Geriatric Medicine, 11G-JB, St. Louis University School of Medicine, St. Louis, MO 63125, United States.
authors.forename: Vijaya M
authors.initials: VM
authors.lastname: Lakshmi
authors.forename: Herman A J
authors.initials: HA
authors.lastname: Schut
authors.forename: Terry V
authors.initials: TV
authors.lastname: Zenser
mesh_terms: D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D006868:Hydrolysis; D018836:Inflammation Mediators / Q000737:chemistry / Q000378:metabolism*; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D010472:Perchlorates / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry / Q000633:toxicity*; D015719:Single-Strand Specific DNA and RNA Endonucleases / Q000737:chemistry
chemical_list: C505049:2-nitrosoamino-3-methylimidazo(4,5-f)quinoline; D018736:DNA Adducts; D003848:Deoxyguanine Nucleotides; D018836:Inflammation Mediators; D009153:Mutagens; D009711:Nucleotides; D010472:Perchlorates; D011804:Quinolines; C034009:2'-deoxyguanosine 3'-phosphate; D015719:Single-Strand Specific DNA and RNA Endonucleases