2-Nitrosoamino-3-methylimidazo[4,5-f]quinoline activated by the inflammatory response forms nucleotide adducts.
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.
Lakshmi
Vijaya M
VM
VA Medical Center, and Division of Geriatric Medicine, 11G-JB, St. Louis University School of Medicine, St. Louis, MO 63125, United States.
Schut
Herman A J
HA
Zenser
Terry V
TV
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
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